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Vitamin K₂ (menaquinone). In menaquinone the side chain is composed of a varying number of isoprenoid residues.

Vitamin K is a group of structurally similar, fat soluble vitamins that are needed for the posttranslational modification of certain proteins required for blood coagulation and in metabolic pathways in bone and other tissue. They are 2-methyl-1,4-naphthoquinone (3-)derivatives. This group of vitamins includes two natural vitamers: vitamin K₁ and vitamin K₂.

Vitamin K₁ is also known as vitamin K_j, phylloquinone or phytomenadione (also called phytonadione). Vitamin K₁ is required for blood coagulation and is synthesized by plants, is found in green leafy vegetables, and can be found in soybean oil.

Vitamin K₂ is involved in bone metabolism. Vitamin K₂ homologs (menaquinones) are characterized by the number of isoprenoid residues comprising the side chain. Menaquinones are abbreviated MK-n, where n represents the number of isoprenoid side chains. Thus, menaquinone-4 abbreviated MK-4, has 4 isoprene residues in the side chain. Bacteria can produce a range of vitamin K₂ forms, including the conversion of K₁ to K₂ (MK-7) by bacteria in the small intestines. No known toxicity exists for vitamins K₁ and K₂.

Three synthetic types of vitamin K are known: vitamins K₃, K₄, and K₅. Although the natural K₁ and K₂ forms are nontoxic, the synthetic form K₃ (menadione) has shown toxicity.^[1]

Vitamin K was identified in 1929 by Danish scientist Henrik Dam when he investigated the role of cholesterol by feeding chickens a cholesterol-depleted diet.^[2] After several weeks, the animals developed hemorrhages and started bleeding. These defects could not be restored by adding purified cholesterol to the diet. It appeared that—together with the cholesterol—a second compound had been extracted from the food, and this compound was called the coagulation vitamin. The new vitamin received the letter K because the initial discoveries were reported in a German journal, in which it was designated as Koagulationsvitamin.

Subtypes of vitamin K₂

Vitamin K₂ (menaquinone), is itself a category of vitamin K that includes many types of vitamin K₂. The two subtypes of vitamin K₂ that have been most studied are menaquinone-4 (menatetrenone, MK4) and menaquinone-7 (MK7).

MK4 is produced via conversion of vitamin K₁ in the body, in the testes, pancreas and arterial walls.^[3] While major questions still surround the biochemical pathway for the transformation of vitamin K₁ to MK4, studies demonstrate that the conversion is not dependent on gut bacteria, occurring in germ-free rats^[4]^[5] and in parenterally-administered K₁ in rats.^[6]^[7] In fact, tissues that accumulate high amounts of MK4 have a remarkable capacity to convert up to 90% of the available K₁ into MK4.^[8]^[9]

In contrast to MK4, menaquinone-7 (MK7) is not produced by humans but is converted from phylloquinone in the intestines by gut bacteria.^[10] However, bacteria-derived menaquinones (MK7) appear to contribute minimally to overall vitamin K status.^[11]^[12] MK4 and MK7 are both found in the United States in dietary supplements for bone health.

The US FDA has not approved any form of vitamin K for the prevention or treatment of osteoporosis; however, MK4 has been shown to decrease fractures up to 87%.^[13] In the amount of 45 mg daily MK4 has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of osteoporosis.^[14]

Vitamin K₂ (MK4, but not MK7 or vitamin K₁) has also been shown to prevent bone loss and/or fractures in the following circumstances:

caused by corticosteroids (e.g., prednisone, dexamethasone, prednisolone),^[15]^[16]^[17]^[18]
anorexia nervosa,^[19]
cirrhosis of the liver,^[20]
postmenopausal osteoporosis,^[21]^[22]^[23]^[24]^[25]^[26]
disuse from stroke,^[27]
Alzheimer's disease,^[28]
Parkinson disease,^[29]
primary biliary cirrhosis^[30]
and leuprolide treatment (for prostate cancer).^[31]

Vitamin K absorption and dietary need

Previous theory held that dietary deficiency is extremely rare unless the intestine (small bowel) was heavily damaged, resulting in malabsorption of the molecule. The other at-risk group for deficiency were those subject to decreased production of K₂ by normal flora, as seen in broad spectrum antibiotic use.^[32] Taking broad-spectrum antibiotics can reduce vitamin K production in the gut by nearly 74% in people compared with those not taking these antibiotics.^[33] Diets low in vitamin K also decrease the body's vitamin K concentration.^[34] Additionally, in the elderly there is a reduction in vitamin K₂ production.^[35]

Recent research results also demonstrate that the small intestine and large intestine (colon) seem to be inefficient at absorbing vitamins K.^[36]^[37] These results are reinforced by human cohort studies, where a majority of the subjects showed inadequate vitamins K amounts in the body. This was revealed by the presence of large amounts of incomplete gamma-carboxylated proteins in the blood, an indirect test for vitamins K deficiency.^[38]^[39]^[40] And in an animal model MK4 was shown to prevent arterial calcifications, pointing to its potential role in cardiovascular disease prevention.^[41] In this study vitamin K₁ was also tested and shown to not prevent arterial calcifications.

Chemical structure

All members of the vitamin K group of vitamins share a methylated naphthoquinone ring structure (menadione), and vary in the aliphatic side chain attached at the 3-position (see figure 1). Phylloquinone (also known as vitamin K₁) invariably contains in its side chain four isoprenoid residues, one of which is unsaturated.

Menaquinones have side chains composed of a variable number of unsaturated isoprenoid residues; generally they are designated as MK-n, where n specifies the number of isoprenoids.

It is generally accepted that the naphthoquinone is the functional group, so that the mechanism of action is similar for all K-vitamins. Substantial differences may be expected, however, with respect to intestinal absorption, transport, tissue distribution, and bio-availability. These differences are caused by the different lipophilicity of the various side chains, and by the different food matrices in which they occur.

There are three synthetic forms of vitamin K, vitamins K₃, K₄, and K₅, which are used in many areas including the pet food industry (vitamin K₃) and to inhibit fungal growth (vitamin K₅).^[42]

Physiology

Vitamin K is involved in the carboxylation of certain glutamate residues in proteins to form gamma-carboxyglutamate residues (abbreviated Gla residues). The modified residues are often (but not always) situated within specific protein domains called Gla domains. Gla residues are usually involved in binding calcium. The Gla residues are essential for the biological activity of all known Gla-proteins.^[43]

At this time^[update] 15 human proteins with Gla domains have been discovered, and they play key roles in the regulation of three physiological processes:

Blood coagulation: (prothrombin (factor II), factors VII, IX, X, protein C, protein S, and protein Z).^[44]
Bone metabolism: osteocalcin, also called bone Gla-protein (BGP), matrix Gla protein (MGP),^[45] and periostin.^[46]
Vascular biology: growth arrest-specific protein 6 (Gas6)^[47]
unknown function: proline-rich g-carboxy glutamyl proteins (PRGPs) 1 and 2, and transmembrane g-carboxy glutamyl proteins (TMGs) 3 and 4.^[48]

Like other liposoluble vitamins (A, D, E), vitamin K is stored in the fat tissue of the human body.

Recommended amounts

The U.S. Dietary Reference Intake (DRI) for an Adequate Intake (AI) of vitamin K for a 25-year old male is 120 micrograms/day. The Adequate Intake (AI) for adult women is 90 micrograms/day, for infants is 10–20 micrograms/day, for children and adolescents 15–100 micrograms/day. In 2002 it was found that to get maximum carboxylation of osteocalcin, one may have to take up to 1000 μg of vitamin K₁.^[49]

Toxicity

Although allergic reaction from supplementation is possible, there is no known toxicity associated with high doses of the phylloquinone (vitamin K₁) or menaquinone (vitamin K₂) forms of vitamin K and therefore no tolerable upper intake level (UL) has been set.^{[citation needed]}

Blood clotting (coagulation) studies in humans using 45 mg per day of vitamin K₂ (as MK4)^[26] and even up to 135 mg/day (45 mg three times daily) of K2 (as MK4),^[50] showed no increase in blood clot risk. Even doses in rats as high as 250 mg/kg body weight did not alter the tendency for blood-clot formation to occur.^[51]

However, a synthetic form of vitamin K, vitamin K₃ (menadione), is demonstrably toxic. In fact, the FDA has banned this synthetic form of the vitamin from over-the-counter supplements because large doses have been shown to cause allergic reactions, hemolytic anemia, and cytotoxicity in liver cells.^[1]

Drug interactions

Phylloquinone (K₁)^[52]^[53] or menaquinone (K₂) are capable of blocking the blood thinning action of anticoagulants like warfarin, which work by interfering with the action of vitamin K. They also reverse the tendency of these drugs to cause arterial calcification in the long term.

Sources

Vitamin K₁ is found chiefly in leafy green vegetables such as spinach, swiss chard, and Brassica (e.g. cabbage, kale, cauliflower, broccoli, and brussels sprouts); some fruits such as avocado, kiwifruit and grapes are also high in vitamin K. By way of reference, two tablespoons of parsley contain 153% of the recommended daily amount of vitamin K.^[54] Some vegetable oils, notably soybean, contain vitamin K, but at levels that would require relatively large calorific consumption to meet the USDA recommended levels.^[55] Colonic bacteria synthesize a significant portion of humans' vitamin K needs; this is one of the reasons why newborns often receive a vitamin K shot at birth - in order to tide them over until day 5-7 when their colon becomes colonized.

It is believed^{[by whom?]} that phylloquinone's tight binding to the thylakoid membranes in the chloroplasts is the reason behind the poor bioavailability of vitamin K in green plants. For example, cooked spinach has a 5% bioavailability of phylloquinone. However when one adds fat to the spinach, the bioavailability increases to 13% due to the increased solubility of vitamin K in fat.^[56]

Vitamin K₂ (Menaquinone-4) is synthesized by animal tissues and is found in meat, eggs, and dairy products.^[57] Menaquinone-7 is synthesized by bacteria during fermentation and is found in fermented soybeans (natto).^[58] In natto 0% of vitamin K is from MK-4 and in cheese 2–7%.^[59]

Deficiency

Average diets are usually not lacking in vitamin K and primary vitamin K deficiency is rare in healthy adults. Newborn infants are at an increased risk of deficiency. Other populations with an increased prevalence of vitamin K deficiency include individuals who suffer from liver damage or disease (e.g. alcoholics), people with cystic fibrosis, inflammatory bowel diseases or those who have recently had abdominal surgeries. Groups that may suffer from secondary vitamin K deficiency include bulimics, those on stringent diets, and those taking anticoagulants. Other drugs that have been associated with vitamin K deficiency include salicylates, barbiturates, and cefamandole, although the mechanism is still unknown. There is no difference between the sexes as both males and females are affected equally. Symptoms of deficiency include heavy menstrual bleeding in women, anemia, bruising, and bleeding of the gums or nose. They could also have disorders such as coagulopathy.^[59]

Osteoporosis^[60]^[61] and coronary heart disease^[62]^[63] are strongly associated with lower levels of K₂ (menaquinone). Menaquinone is not inhibited by salicylates as happens with K₁, so menaquinone supplementation can alleviate the chronic vitamin K deficiency caused by long term aspirin use.^{[citation needed]}

Biochemistry

Function

The function of vitamin K in the cell is to convert glutamate in proteins to gamma-carboxyglutamate (Gla).

Within the cell, vitamin K undergoes electron reduction to a reduced form of vitamin K (called vitamin K hydroquinone) by the enzyme vitamin K epoxide reductase (or VKOR).^[64] Another enzyme then oxidizes vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called the gamma-glutamyl carboxylase^[65]^[66] or the vitamin K-dependent carboxylase. The carboxylation reaction will only proceed if the carboxylase enzyme is able to oxidize vitamin K hydroquinone to vitamin K epoxide at the same time; the carboxylation and epoxidation reactions are said to be coupled reactions. Vitamin K epoxide is then re-converted to vitamin K by vitamin K epoxide reductase. The reduction and subsequent re-oxidation of vitamin K coupled with carboxylation of Glu is called the vitamin K cycle.^[67] One of the reasons humans are rarely deficient in vitamin K is that vitamin K is continually recycled in cells.

Warfarin and other coumarin drugs block the action of the vitamin K epoxide reductase.^[68] This results in decreased concentrations of vitamin K and vitamin K hydroquinone in the tissues, such that the carboxylation reaction catalyzed by the glutamyl carboxylase is inefficient. This results in the production of clotting factors with inadequate Gla. Without Gla on the amino termini of these factors, they no longer bind stably to the blood vessel endothelium and cannot activate clotting to allow formation of a clot during tissue injury. As it is impossible to predict what dose of warfarin will give the desired degree of suppression of the clotting, warfarin treatment must be carefully monitored to avoid over-dosing. (See the warfarin article.)

Gamma-carboxyglutamate proteins, or Gla-proteins

At present, the following human Gla-containing proteins have been characterized to the level of primary structure: the blood coagulation factors II (prothrombin), VII, IX, and X, the anticoagulant proteins C and S, and the Factor X-targeting protein Z. The bone Gla-protein osteocalcin, the calcification inhibiting matrix Gla protein (MGP), the cell growth regulating growth arrest specific gene 6 protein (Gas6), and the four transmembrane Gla proteins (TMGPs) the function of which is at present unknown. Gas6 can function as a growth factor that activates the Axl receptor tyrosine kinase and stimulates cell proliferation or prevents apoptosis in some cells. In all cases in which their function was known, the presence of the Gla residues in these proteins turned out to be essential for functional activity.

Gla-proteins are known to occur in a wide variety of vertebrates: mammals, birds, reptiles, and fish. The venom of a number of Australian snakes acts by activating the human blood clotting system. Remarkably, in some cases activation is accomplished by snake Gla-containing enzymes that bind to the endothelium of human blood vessels and catalyze the conversion of procoagulant clotting factors into activated ones, leading to unwanted and potentially deadly clotting.

Another interesting class of invertebrate Gla-containing proteins is synthesized by the fish-hunting snail Conus geographus.^[69] These snails produce a venom containing hundreds of neuro-active peptides, or conotoxins, which is sufficiently toxic to kill an adult human. Several of the conotoxins contain 2–5 Gla residues.^[70]

Methods of assessment

Prothrombin time test:

Measures the time required for blood to clot

Blood sample mixed with citric acid and put in a fibrometer.

Delayed clot formation indicates a deficiency.

Unfortunately insensitive to mild deficiency as the values do not change until the concentration of prothrombin in the blood has declined by at least 50% ^[71]

Plasma Phylloquinone:

Was found to be positively correlated with phylloquinone intake in elderly British women, but not men ^[72]

However an article by Schurges et al. reported no correlation between FFQ and plasma phylloquinone ^[73]

Urinary γ-carboxyglutamic acid:

Urinary Gla responds to changes in dietary vitamin K intake.

Several days are required before any change can be observed.

In a study by Booth et al. increases of phylloquinone intakes from 100 μg to between 377–417 μg for 5 days did not induce a significant change Response may be age-specific ^[74]

Function in bacteria

Many bacteria, such as Escherichia coli found in the large intestine, can synthesize vitamin K₂ (menaquinone-7),^[75] but not vitamin K₁ (phylloquinone). In these bacteria, menaquinone will transfer two electrons between two different small molecules, in a process called anaerobic respiration.^[76] For example, a small molecule with an excess of electrons (also called an electron donor) such as lactate, formate, or NADH, with the help of an enzyme, will pass two electrons to a menaquinone. The menaquinone, with the help of another enzyme, will in turn transfer these 2 electrons to a suitable oxidant, such fumarate or nitrate (also called an electron acceptor). Adding two electrons to fumarate or nitrate will convert the molecule to succinate or nitrite + water, respectively. Some of these reactions generate a cellular energy source, ATP, in a manner similar to eukaryotic cell aerobic respiration, except that the final electron acceptor is not molecular oxygen, but say fumarate or nitrate (In aerobic respiration, the final oxidant is molecular oxygen (O₂) , which accepts four electrons from an electron donor such as NADH to be converted to water.) Escherichia coli can carry out aerobic respiration and menaquinone-mediated anaerobic respiration.

Vitamin K injection in newborns

The blood clotting factors of newborn babies are roughly 30 to 60% that of adult values; this may be due to the reduced synthesis of precursor proteins and the sterility of their guts. Human milk contains between 1 and 4 micrograms/litre of vitamin K₁, while formula derived milk can contain up to 100 micrograms/litre in supplemented formulas. Vitamin K₂ concentrations in human milk appear to be much lower than those of vitamin K₁. It is estimated that there is a 0.25 to 1.7% occurrence of vitamin K deficiency bleeding in the first week of the infant's life with a prevalence of 2-10 cases per 100,000 births.^[77] Premature babies have even lower levels of the vitamin and are at a higher risk from this deficiency.

Bleeding in infants due to vitamin K deficiency can be severe, leading to hospitalizations, blood transfusions, brain damage and death. Supplementation with vitamin K can prevent most cases of vitamin K deficiency bleeding in the newborn. Intramuscular administration of vitamin K is more effective in preventing late vitamin K deficiency bleeding than oral administration.^[78]^[79]

USA

As a result of the occurrences of vitamin K deficiency bleeding, the Committee on Nutrition of the American Academy of Pediatrics has recommended that 0.5 to 1.0 mg vitamin K₁ be administered to all newborns shortly after birth.^[79]

UK

In the UK, vitamin K is administered to newborns as either a single injection at birth or three orally administered doses given at birth and then over the baby's first month.

Controversy

Controversy arose in the early 1990s regarding this practice when two studies were shown suggesting a relationship between parenteral administration of vitamin K and childhood cancer (14)^{[verification needed]}^{[citation needed]}. However, poor methods and small sample sizes led to the discrediting of these studies and a review of the evidence published in 2000 by Ross and Davies found no link between the two.^[80]^{[verification needed]}

Vitamin K and bone health

There is physiological and observational evidence that vitamin K plays a role in bone growth and the maintenance of bone density, but efforts to delay the onset of osteoporosis by vitamin K supplementation have proven ineffective.

Vitamin K takes part in the post translational modification as a cofactor in γ-carboxylation of vitamin K dependant proteins (VKDPs). VKDPs have glutamate residues (Glu). Biophysical studies have suggested that supplemental vitamin K promotes osteotrophic processes and slows osteoclastic processes via calcium bonding. Study of Atkins et al.^[81] revealed that phylloquinone, menatetrenone (MK4) and menadione promote in vitro mineralisaton by human primary osteoblasts. Other studies have shown that vitamin K antagonists (usually a class of anticoagulants) lead to early calcification of the epiphysis and epiphysial line in mice and other animals, causing seriously decreased bone growth. This is due to defects in osteocalcin and matrix Gla protein. Their primary function is to prevent overcalcification of the bone and cartilage. Vitamin K is important in the process of carboxylating glutamic acid (Glu) in these proteins to gamma-carboxyglutamic acid (Gla), which is necessary for their function.^[82]^[83] Vitamin D is reported to regulate the OC transcription by osteoblast thereby showing that vitamin K and vitamin D work in tandem for the bone metabolism and development. Lian and his group discovered two nucleotide substitution regions which they named "osteocalcin box" in the rat and human osteocalcin genes.^[84] They found a region 600 nucleotides immediately upstream from the transcription start site that support a 10-fold stimulated transcription of the gene by 1,25-dihydroxy vitamin D.

Vitamin K₁ and bone health

Data from the 1998 Nurses Health Study, an observational study, indicated an inverse relationship between dietary vitamin K₁ and the risk of hip fracture. After being given 110 micrograms/day of vitamin K, women who consumed lettuce one or more times per day had a significantly lower risk of hip fracture than women who consumed lettuce one or fewer times per week. In addition to this, high intakes of vitamin D but low intakes of vitamin K were suggested to pose an increased risk of hip fracture.^[83]^[85] The Framingham Heart Study^[86] is another study that showed the similar result. Subjects in the highest quartile of vitamin K₁ intake (median K₁ intake of 254 μg/ day) has 35% lower risk of hip fracture than those in the lowest quartile. Comparing with the daily recommended intake (DRI) of 90 and 120 μg/ day, both the above intakes are higher than existing DRI.

In the face of this evidence, a large multicentre randomized placebo-controlled trial was performed to test the supplementation of vitamin K in post-menopausal women with osteopenia. Despite heavy doses of vitamin K₁, no differences were found in bone density between the supplemented and placebo groups.^[87]

Vitamin K₂ (MK4) and bone health

In contrast, MK4 has been shown in numerous studies to reduce fracture risk, stop and reverse bone loss. In Japan, MK4 in the dose of 45 mg daily is recognized as a treatment for osteoporosis.^[85]^[88] MK4 has been shown to decrease fractures up to 87%.^[13] In the amount of 45 mg daily MK4 has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of osteoporosis.^[14]

MK4 (but not MK7 or vitamin K₁) prevented bone loss and/or fractures in the following circumstances:

caused by corticosteroids (e.g., prednisone, dexamethasone, prednisolone),^[15]^[16]^[17]^[18]
anorexia nervosa,^[19]
cirrhosis of the liver,^[20]
postmenopausal osteoporosis,^[21]^[22]^[23]^[24]^[25]^[26]
disuse from stroke,^[27]
Alzheimer's disease,^[28]
Parkinson disease,^[29]
primary biliary cirrhosis^[30] and
leuprolide treatment (for prostate cancer).^[31]

Vitamin K₂ (MK7) and bone health

Menaquinone-7 (MK7), which is abundant in fermented soybeans (natto), has been demonstrated to stimulate osteoblastic bone formation and to inhibit osteoclastic bone resorption.^[89] In another study, use of MK-7 caused significant elevations of serum Y-carboxylated osteocalcin concentration, a biomarker of bone formation. MK-7 also completely inhibited a decrease in the calcium content of bone tissue by inhibiting the bone-resorbing factors parathyroid hormone and prostaglandin E₂.^[90] On 19 February 2011, HSA (Singapore) approved a health supplement which contains vitamin K₂ (MK7) and vitamin D₃ for increasing bone mineral density.^[91]

Vitamin K and Alzheimer's disease

Research into the antioxidant properties of vitamin K indicates that the concentration of vitamin K is lower in the circulation of carriers of the APOE4 gene, and recent studies have shown its ability to inhibit nerve cell death due to oxidative stress. It has been hypothesized that vitamin K may reduce neuronal damage and that supplementation may hold benefits to treating Alzheimer's disease, although more research is necessary in this area.^[92]

Vitamin K used topically

Vitamin K may be applied topically, typically as a 5% cream, to diminish postoperative bruising from cosmetic surgery and injections, broken capillaries (spider veins), to treat rosacea and to aid in the fading of hyperpigmentation and dark under-eye circles.^{[citation needed]}

Vitamin K and cancer

While researchers in Japan were studying the role of vitamin K₂ as the menaquinone-4 (MK-4) form in the prevention of bone loss in females with liver disease, they discovered another possible effect. This two year study which involved 21 women with viral liver cirrhosis found that women in the supplement group were 90% less likely to develop liver cancer.^[93]^[94] A German study performed on men with prostate cancer found a significant inverse relationship between vitamin K₂ consumption and advanced prostate cancer.^[95]

Vitamin K as antidote for poisoning by 4-hydroxcoumarin drugs

Vitamin K is a true antidote for poisoning by 4-hydroxycoumarin anticoagulant drugs (sometimes loosely referred to as coumarins). These include the pharmaceutical warfarin, and also anticoagulant-mechanism poisons such as bromadiolone, which are commonly found in rodenticides. 4-Hydroxycoumarin drugs possess anticoagulatory and rodenticidal properties because they inhibit vitamin K-dependent synthesis of some clotting factors by the liver. Death is usually a result of internal hemorrhage. Treatment usually consists of repeated intravenous doses of vitamin K, followed by doses in pill form for a period of at least two weeks, though possibly up to 2 months, afterwards (in the case of the more potent 4-hydoxycoumarins used as rodenticides). If caught early, prognosis is good, even when great amounts of the drug or poison are ingested.

History of discovery

In 1929, Danish scientist Henrik Dam investigated the role of cholesterol by feeding chickens a cholesterol-depleted diet.^[2] After several weeks, the animals developed hemorrhages and started bleeding. These defects could not be restored by adding purified cholesterol to the diet. It appeared that—together with the cholesterol—a second compound had been extracted from the food, and this compound was called the coagulation vitamin. The new vitamin received the letter K because the initial discoveries were reported in a German journal, in which it was designated as Koagulationsvitamin. Edward Adelbert Doisy of Saint Louis University did much of the research that led to the discovery of the structure and chemical nature of vitamin K.^[96] Dam and Doisy shared the 1943 Nobel Prize for medicine for their work on vitamin K (K₁ and K₂) published in 1939. Several laboratories synthesized the compound(s) in 1939.^[97]

For several decades the vitamin K-deficient chick model was the only method of quantifying vitamin K in various foods: the chicks were made vitamin K-deficient and subsequently fed with known amounts of vitamin K-containing food. The extent to which blood coagulation was restored by the diet was taken as a measure for its vitamin K content. Three groups of physicians independently found this: Biochemical Institute, University of Copenhagen (Dam and Johannes Glavind), University of Iowa Department of Pathology (Emory Warner, Kenneth Brinkhous, and Harry Pratt Smith), and the Mayo Clinic (Hugh Butt, Albert Snell, and Arnold Osterberg).^[98]

The first published report of successful treatment with vitamin K of life-threatening hemorrhage in a jaundiced patient with prothrombin deficiency was made in 1938 by Smith, Warner, and Brinkhous.^[99]

The precise function of vitamin K was not discovered until 1974, when three laboratories (Stenflo et al.,^[100] Nelsestuen et al.,^[101] and Magnusson et al.^[102]) isolated the vitamin K-dependent coagulation factor prothrombin (Factor II) from cows that received a high dose of a vitamin K antagonist, warfarin. It was shown that while warfarin-treated cows had a form of prothrombin that contained 10 glutamate amino acid residues near the amino terminus of this protein, the normal (untreated) cows contained 10 unusual residues that were chemically identified as gamma-carboxyglutamate, or Gla. The extra carboxyl group in Gla made clear that vitamin K plays a role in a carboxylation reaction during which Glu is converted into Gla.

The biochemistry of how vitamin K is used to convert Glu to Gla has been elucidated over the past thirty years in academic laboratories throughout the world.

References

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^ Sell, DR (1990). "End-stage renal disease and diabetes catalyze the formation of a pentose-derived crosslink from aging human collagen". Journal of Clinical Investigation. 85 (2): 380–384. doi:10.1172/JCI114449. PMC 296435. PMID 2298912. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
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^ Ronden, JE (1998). "Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat". Biochimica et Biophysica Acta (BBA) - General Subjects. 1379 (1): 69–75. doi:10.1016/S0304-4165(97)00089-5. PMID 9468334. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Thijssen, HHW (1994). "Vitamin K distribution in rat tissues: dietary phylloquinone is a source of tissue menaquinone-4". British Journal of Nutrition. 72 (3): 415–425. doi:10.1079/BJN19940043. PMID 7947656. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Will, BH (1992). "Comparative Metabolism and Requirement of Vitamin K in Chicks and Rats". Journal of Nutrition. 122 (12): 2354–2360. PMID 1453219. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Davidson, RT (1998). "Conversion of Dietary Phylloquinone to Tissue Menaquinone-4 in Rats is Not Dependent on Gut Bacteria". Journal of Nutrition. 128 (2): 220–223. PMID 9446847. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Ronden, JE (1998). "Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat". Biochimica et Biophysica Acta (BBA) - General Subjects. 1379 (1): 69–75. doi:10.1016/S0304-4165(97)00089-5. PMID 9468334. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
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^ Suttie, JW (1995). "The importance of menaquinones in human nutrition". Annual Review of Nutrition. 15: 399–417. doi:10.1146/annurev.nu.15.070195.002151. PMID 8527227.
^ Weber, P (2001). "Vitamin K and bone health". Nutrition. 17 (10): 880–887. doi:10.1016/S0899-9007(01)00709-2. PMID 11684396.
^ ^a ^b Sato, Y (2005). "Menatetrenone and vitamin D2 with calcium supplements prevent nonvertebral fracture in elderly women with Alzheimer's disease". Bone. 36 (1): 61–8. doi:10.1016/j.bone.2004.09.018. PMID 15664003. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
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External links

Jane Higdon, "Vitamin K", Micronutrient Information Center, Linus Pauling Institute, Oregon State University
Vitamin K: Another Reason to Eat Your Greens
Vitamin K: Signs of Deficiency
Vitamin K: Vitamin Deficiency, Dependency, and Toxicity: Merck Manual Professional
An Alternative Perspective on Vitamin K Prophylaxis
Health Benefits of Vitamin K₂
Vitamin K content: USDA National Nutrient Database for Standard Reference, Release 19

[Higdon-1] Higdon (February 2008). "Vitamin K". Linus Pauling Institute, Oregon State University. Retrieved 2008-04-12.

[Dam-2] Dam, H. (1935). "The Antihæmorrhagic Vitamin of the Chick.: Occurrence And Chemical Nature". Nature. 135 (3417): 652–653. doi:10.1038/135652b0. {{cite journal}}: Cite has empty unknown parameter: |coauthors= (help)

[3] Sell, DR (1990). "End-stage renal disease and diabetes catalyze the formation of a pentose-derived crosslink from aging human collagen". Journal of Clinical Investigation. 85 (2): 380–384. doi:10.1172/JCI114449. PMC 296435. PMID 2298912. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[4] Davidson, RT (1998). "Conversion of Dietary Phylloquinone to Tissue Menaquinone-4 in Rats is Not Dependent on Gut Bacteria1". Journal of Nutrition. 128 (2): 220–223. PMID 9446847. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[5] Ronden, JE (1998). "Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat". Biochimica et Biophysica Acta (BBA) - General Subjects. 1379 (1): 69–75. doi:10.1016/S0304-4165(97)00089-5. PMID 9468334. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

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[94] Saxena SP, Israels ED, Israels LG (2001). "Novel vitamin K-dependent pathways regulating cell survival". Apoptosis. 6 (1–2): 57–68. doi:10.1023/A:1009624111275. PMID 11321042.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[95] Nimptsch K, Rohrmann S, Linseisen J (2008). "Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition. (EPIC-Heidelberg)" (PDF). Am. J. Clin. Nutr. 87 (4): 985–92. PMID 18400723. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[MacCorquodale-96] MacCorquodale, D. W. (1939). "On the constitution of Vitamin K1". Journal of the American Chemical Society. 61 (7): 1928–1929. doi:10.1021/ja01876a510. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[Fieser-97] Fieser, L. F. (1939). "Synthesis of Vitamin K1". Journal of the American Chemical Society. 61 (12): 3467–3475. doi:10.1021/ja01267a072. {{cite journal}}: Cite has empty unknown parameter: |coauthors= (help)

[dam-nobel-98] Dam, Henrik (December 12, 1946). The discovery of vitamin K, its biological functions and therapeutical application. Nobel Prize lecture

[Warner-99] Warner, E. D. (1938). Proceedings of the Society of Experimental Biology and Medicine. 37: 628. {{cite journal}}: Missing or empty |title= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)

[Stenflo-100] Stenflo J, Fernlund P, Egan W, Roepstorff P (1974). "Vitamin K Dependent Modifications of Glutamic Acid Residues in Prothrombin". Proc. Natl. Acad. Sci. U.S.A. 71 (7): 2730–3. doi:10.1073/pnas.71.7.2730. PMC 388542. PMID 4528109. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[Nelsestuen-101] Nelsestuen GL, Zytkovicz TH, Howard JB (1974). "The mode of action of vitamin K. Identification of gamma-carboxyglutamic acid as a component of prothrombin" (PDF). J. Biol. Chem. 249 (19): 6347–50. PMID 4214105. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[Magnusson-102] Magnusson S, Sottrup-Jensen L, Petersen TE, Morris HR, Dell A (1974). "Primary structure of the vitamin K-dependent part of prothrombin". FEBS Lett. 44 (2): 189–93. doi:10.1016/0014-5793(74)80723-4. PMID 4472513. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

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@@ Line 1: / Line 1: @@
 {{Dablink|"Vitamin K" has also been used as a slang term for [[ketamine]], an unrelated anaesthetic.}}
-[[Image:Phylloquinone structure.svg|thumb|right|250px|Vitamin K<sub>1</sub> (phylloquinone).  Both forms of the vitamin contain a functional [[naphthoquinone]] ring and an aliphatic side chain.  Phylloquinone has a [[Phytane|phytyl]] side chain.]]
+[[Image:Phylloquinone structure.svg|thumb|right|250px|Vitamin K<sub>1</sub> (phylloquinone). Both forms of the vitamin contain a functional [[naphthoquinone]] ring and an aliphatic side chain. Phylloquinone has a [[Phytane|phytyl]] side chain.]]
-[[Image:Menaquinone.svg|thumb||right|250px|Vitamin K<sub>2</sub> (menaquinone).  In menaquinone the side chain is composed of a varying number of [[isoprenoid]] residues.]]
+[[Image:Menaquinone.svg|thumb||right|250px|Vitamin K<sub>2</sub> (menaquinone). In menaquinone the side chain is composed of a varying number of [[isoprenoid]] residues.]]
-'''Vitamin K''' is a group of structurally similar, fat soluble vitamins that are needed for the [[posttranslational modification]] of certain proteins required for blood coagulation and in metabolic pathways in bone and other tissue.  They are 2-[[methyl]]-[[1,4-naphthoquinone]] (3-)derivatives.  This group of vitamins includes two natural [[vitamer]]s: vitamin K<sub>1</sub> and vitamin K<sub>2</sub>.
+'''Vitamin K''' is a group of structurally similar, fat soluble vitamins that are needed for the [[posttranslational modification]] of certain proteins required for blood coagulation and in metabolic pathways in bone and other tissue. They are 2-[[methyl]]-[[1,4-naphthoquinone]] (3-)derivatives. This group of vitamins includes two natural [[vitamer]]s: vitamin K<sub>1</sub> and vitamin K<sub>2</sub>.
 Vitamin K<sub>1</sub> is also known as vitamin K<sub>j</sub>, [[phylloquinone]] or phytomenadione (also called phytonadione).
 Vitamin K<sub>1</sub> is required for [[Coagulation|blood coagulation]] and is synthesized by plants, is found in green leafy vegetables, and can be found in soybean oil.
-Vitamin K<sub>2</sub> is involved in bone metabolism. Vitamin K<sub>2</sub> homologs (menaquinones) are characterized by the number of isoprenoid residues comprising the side chain.  Menaquinones are abbreviated MK-n, where n represents the number of isoprenoid side chains. Thus, [[Menatetrenone|menaquinone-4]] abbreviated MK-4, has 4 isoprene residues in the side chain.  Bacteria can produce a range of vitamin K<sub>2</sub> forms, including the conversion of K<sub>1</sub> to K<sub>2</sub> (MK-7) by bacteria in the small intestines.  No known toxicity exists for vitamins K<sub>1</sub> and K<sub>2</sub>.
+Vitamin K<sub>2</sub> is involved in bone metabolism. Vitamin K<sub>2</sub> homologs (menaquinones) are characterized by the number of isoprenoid residues comprising the side chain. Menaquinones are abbreviated MK-n, where n represents the number of isoprenoid side chains. Thus, [[Menatetrenone|menaquinone-4]] abbreviated MK-4, has 4 isoprene residues in the side chain. Bacteria can produce a range of vitamin K<sub>2</sub> forms, including the conversion of K<sub>1</sub> to K<sub>2</sub> (MK-7) by bacteria in the small intestines. No known toxicity exists for vitamins K<sub>1</sub> and K<sub>2</sub>.
-Three synthetic types of vitamin K are known: vitamins K<sub>3</sub>, K<sub>4</sub>, and K<sub>5</sub>.  Although the natural K<sub>1</sub> and K<sub>2</sub> forms are nontoxic, the synthetic form K<sub>3</sub> (menadione) has shown toxicity.<ref name=Higdon>{{cite web|last=Higdon|title=Vitamin K|publisher=Linus Pauling Institute, Oregon State University|date=February 2008|url=http://lpi.oregonstate.edu/infocenter/vitamins/vitaminK/|accessdate=2008-04-12}}</ref>
+Three synthetic types of vitamin K are known: vitamins K<sub>3</sub>, K<sub>4</sub>, and K<sub>5</sub>. Although the natural K<sub>1</sub> and K<sub>2</sub> forms are nontoxic, the synthetic form K<sub>3</sub> (menadione) has shown toxicity.<ref name=Higdon>{{cite web|last=Higdon|title=Vitamin K|publisher=Linus Pauling Institute, Oregon State University|date=February 2008|url=http://lpi.oregonstate.edu/infocenter/vitamins/vitaminK/|accessdate=2008-04-12}}</ref>
-Vitamin K was identified in 1929 by [[Denmark|Danish]] scientist [[Henrik Dam]] when he investigated the role of [[cholesterol]] by feeding chickens a cholesterol-depleted diet.<ref name="Dam">{{cite journal|last=Dam|first=H.|authorlink=|coauthors=|year=1935|title=The Antihæmorrhagic Vitamin of the Chick.: Occurrence And Chemical Nature|journal=Nature|volume=135|issue=3417|pages=652–653|doi=10.1038/135652b0|url=|accessdate=|quote= }}</ref>  After several weeks, the animals developed hemorrhages and started bleeding.  These defects could not be restored by adding purified cholesterol to the diet.  It appeared that—together with the cholesterol—a second compound had been extracted from the food, and this compound was called the coagulation vitamin.  The new vitamin received the letter '''K''' because the initial discoveries were reported in a German journal, in which it was designated as ''Koagulationsvitamin''.
+Vitamin K was identified in 1929 by [[Denmark|Danish]] scientist [[Henrik Dam]] when he investigated the role of [[cholesterol]] by feeding chickens a cholesterol-depleted diet.<ref name="Dam">{{cite journal|last=Dam|first=H.|authorlink=|coauthors=|year=1935|title=The Antihæmorrhagic Vitamin of the Chick.: Occurrence And Chemical Nature|journal=Nature|volume=135|issue=3417|pages=652–653|doi=10.1038/135652b0 }}</ref> After several weeks, the animals developed hemorrhages and started bleeding. These defects could not be restored by adding purified cholesterol to the diet. It appeared that—together with the cholesterol—a second compound had been extracted from the food, and this compound was called the coagulation vitamin. The new vitamin received the letter '''K''' because the initial discoveries were reported in a German journal, in which it was designated as ''Koagulationsvitamin''.
 ==Subtypes of vitamin K<sub>2</sub>==
-Vitamin K<sub>2</sub> (menaquinone), is itself a category of vitamin K that includes many types of vitamin K<sub>2</sub>.  The two subtypes of vitamin K<sub>2</sub> that have been most studied are menaquinone-4 ([[menatetrenone]], MK4) and menaquinone-7 (MK7).
+Vitamin K<sub>2</sub> (menaquinone), is itself a category of vitamin K that includes many types of vitamin K<sub>2</sub>. The two subtypes of vitamin K<sub>2</sub> that have been most studied are menaquinone-4 ([[menatetrenone]], MK4) and menaquinone-7 (MK7).
-MK4 is produced via conversion of vitamin K<sub>1</sub> in the body, in the testes, pancreas and arterial walls.<ref>{{cite journal|last=Sell|first=DR|coauthors=Monnier VM|title=End-stage renal disease and diabetes catalyze the formation of a pentose-derived crosslink from aging human collagen|journal=Journal of Clinical Investigation|year=1990|volume=85|issue=2|pages=380–384|pmid=2298912|doi=10.1172/JCI114449|pmc=296435}}</ref>  While major questions still surround the biochemical pathway for the transformation of vitamin K<sub>1</sub> to MK4, studies demonstrate that the conversion is not dependent on gut bacteria, occurring in germ-free rats<ref>{{cite journal|last=Davidson|first=RT|coauthors=Foley AL, Engelke JA, Suttie JW|title=Conversion of Dietary Phylloquinone to Tissue Menaquinone-4 in Rats is Not Dependent on Gut Bacteria1|journal=Journal of Nutrition|year=1998|volume=128|issue=2|pages=220–223|pmid=9446847}}</ref><ref>{{cite journal|last=Ronden|first=JE|coauthors=Drittij-Reijnders M-J, Vermeer C, Thijssen HHW.|title=Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat|journal=Biochimica et Biophysica Acta (BBA) - General Subjects|year=1998|volume=1379|issue=1|pages=69–75|pmid=9468334|doi=10.1016/S0304-4165(97)00089-5}}</ref> and in parenterally-administered K<sub>1</sub> in rats.<ref>{{cite journal|last=Thijssen|first=HHW|coauthors=Drittij-Reijnders MJ|title=Vitamin K distribution in rat tissues: dietary phylloquinone is a source of tissue menaquinone-4|journal=British Journal of Nutrition|year=1994|volume=72|issue=3|pages=415–425|pmid=7947656|doi=10.1079/BJN19940043}}</ref><ref>{{cite journal|last=Will|first=BH|coauthors=Usui Y, Suttie JW|title=Comparative Metabolism and Requirement of Vitamin K in Chicks and Rats|journal=Journal of Nutrition|year=1992|volume=122|issue=12|pages=2354–2360|pmid=1453219}}</ref>  In fact, tissues that accumulate high amounts of MK4 have a remarkable capacity to convert up to 90% of the available K<sub>1</sub> into MK4.<ref>{{cite journal|last=Davidson|first=RT|coauthors=Foley AL, Engelke JA, Suttie JW|title=Conversion of Dietary Phylloquinone to Tissue Menaquinone-4 in Rats is Not Dependent on Gut Bacteria|journal=Journal of Nutrition|year=1998|volume=128|issue=2|pages=220–223|pmid=9446847}}</ref><ref>{{cite journal|last=Ronden|first=JE|coauthors=Drittij-Reijnders M-J, Vermeer C, Thijssen HHW|title=Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat|journal=Biochimica et Biophysica Acta (BBA) - General Subjects|year=1998|volume=1379|issue=1|pages=69–75|pmid=9468334|doi=10.1016/S0304-4165(97)00089-5}}</ref>
+MK4 is produced via conversion of vitamin K<sub>1</sub> in the body, in the testes, pancreas and arterial walls.<ref>{{cite journal|last=Sell|first=DR|coauthors=Monnier VM|title=End-stage renal disease and diabetes catalyze the formation of a pentose-derived crosslink from aging human collagen|journal=Journal of Clinical Investigation|year=1990|volume=85|issue=2|pages=380–384|pmid=2298912|doi=10.1172/JCI114449|pmc=296435}}</ref> While major questions still surround the biochemical pathway for the transformation of vitamin K<sub>1</sub> to MK4, studies demonstrate that the conversion is not dependent on gut bacteria, occurring in germ-free rats<ref>{{cite journal|last=Davidson|first=RT|coauthors=Foley AL, Engelke JA, Suttie JW|title=Conversion of Dietary Phylloquinone to Tissue Menaquinone-4 in Rats is Not Dependent on Gut Bacteria1|journal=Journal of Nutrition|year=1998|volume=128|issue=2|pages=220–223|pmid=9446847}}</ref><ref>{{cite journal|last=Ronden|first=JE|coauthors=Drittij-Reijnders M-J, Vermeer C, Thijssen HHW.|title=Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat|journal=Biochimica et Biophysica Acta (BBA) - General Subjects|year=1998|volume=1379|issue=1|pages=69–75|pmid=9468334|doi=10.1016/S0304-4165(97)00089-5}}</ref> and in parenterally-administered K<sub>1</sub> in rats.<ref>{{cite journal|last=Thijssen|first=HHW|coauthors=Drittij-Reijnders MJ|title=Vitamin K distribution in rat tissues: dietary phylloquinone is a source of tissue menaquinone-4|journal=British Journal of Nutrition|year=1994|volume=72|issue=3|pages=415–425|pmid=7947656|doi=10.1079/BJN19940043}}</ref><ref>{{cite journal|last=Will|first=BH|coauthors=Usui Y, Suttie JW|title=Comparative Metabolism and Requirement of Vitamin K in Chicks and Rats|journal=Journal of Nutrition|year=1992|volume=122|issue=12|pages=2354–2360|pmid=1453219}}</ref> In fact, tissues that accumulate high amounts of MK4 have a remarkable capacity to convert up to 90% of the available K<sub>1</sub> into MK4.<ref>{{cite journal|last=Davidson|first=RT|coauthors=Foley AL, Engelke JA, Suttie JW|title=Conversion of Dietary Phylloquinone to Tissue Menaquinone-4 in Rats is Not Dependent on Gut Bacteria|journal=Journal of Nutrition|year=1998|volume=128|issue=2|pages=220–223|pmid=9446847}}</ref><ref>{{cite journal|last=Ronden|first=JE|coauthors=Drittij-Reijnders M-J, Vermeer C, Thijssen HHW|title=Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat|journal=Biochimica et Biophysica Acta (BBA) - General Subjects|year=1998|volume=1379|issue=1|pages=69–75|pmid=9468334|doi=10.1016/S0304-4165(97)00089-5}}</ref>
-In contrast to MK4, menaquinone-7 (MK7) is not produced by humans but is converted from phylloquinone in the intestines by gut bacteria.<ref>{{cite journal|last=Vermeer|first=C|coauthors=Braam L|title=Role of K vitamins in the regulation of tissue calcification|journal=Journal of bone and mineral metabolism|year=2001|volume=19|issue=4|pages=201–206|pmid=11448011|doi=10.1007/s007740170021}}</ref>  However, bacteria-derived menaquinones (MK7) appear to contribute minimally to overall vitamin K status.<ref>{{cite journal|last=Suttie|first=JW|title=The importance of menaquinones in human nutrition|journal=Annual Review of Nutrition|year=1995|volume=15|pages=399–417|pmid=8527227|doi=10.1146/annurev.nu.15.070195.002151}}</ref><ref>{{cite journal|last=Weber|first=P|title=Vitamin K and bone health|journal=Nutrition|year=2001|volume=17|pages=880–887|doi=10.1016/S0899-9007(01)00709-2|pmid=11684396|issue=10}}</ref>  MK4 and MK7 are both found in the United States in dietary supplements for bone health.
+In contrast to MK4, menaquinone-7 (MK7) is not produced by humans but is converted from phylloquinone in the intestines by gut bacteria.<ref>{{cite journal|last=Vermeer|first=C|coauthors=Braam L|title=Role of K vitamins in the regulation of tissue calcification|journal=Journal of bone and mineral metabolism|year=2001|volume=19|issue=4|pages=201–206|pmid=11448011|doi=10.1007/s007740170021}}</ref> However, bacteria-derived menaquinones (MK7) appear to contribute minimally to overall vitamin K status.<ref>{{cite journal|last=Suttie|first=JW|title=The importance of menaquinones in human nutrition|journal=Annual Review of Nutrition|year=1995|volume=15|pages=399–417|pmid=8527227|doi=10.1146/annurev.nu.15.070195.002151}}</ref><ref>{{cite journal|last=Weber|first=P|title=Vitamin K and bone health|journal=Nutrition|year=2001|volume=17|pages=880–887|doi=10.1016/S0899-9007(01)00709-2|pmid=11684396|issue=10}}</ref> MK4 and MK7 are both found in the United States in dietary supplements for bone health.
-The US FDA has not approved any form of vitamin K for the prevention or treatment of [[osteoporosis]]; however, MK4 has been shown to decrease fractures up to 87%.<ref name="Sato 2005">{{cite journal|last=Sato|first=Y|coauthors=Kanoko T, Satoh K, Iwamoto J|title=Menatetrenone and vitamin D2 with calcium supplements prevent nonvertebral fracture in elderly women with Alzheimer's disease|journal=Bone|year=2005|volume=36|issue=1|pmid=15664003|doi=10.1016/j.bone.2004.09.018|pages=61–8}}</ref>  In the amount of 45&nbsp;mg daily MK4 has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of [[osteoporosis]].<ref name="Iwamoto 1999 161–164">{{cite journal|last=Iwamoto|first=I|coauthors=Kosha S, Noguchi S-i|title=A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal women a comparative study with vitamin D3 and estrogen-progestin therapy|journal=Maturitas|year=1999|volume=31|issue=2|pages=161–164|pmid=10227010|doi=10.1016/S0378-5122(98)00114-5}}</ref>
+The US FDA has not approved any form of vitamin K for the prevention or treatment of [[osteoporosis]]; however, MK4 has been shown to decrease fractures up to 87%.<ref name="Sato 2005">{{cite journal|last=Sato|first=Y|coauthors=Kanoko T, Satoh K, Iwamoto J|title=Menatetrenone and vitamin D2 with calcium supplements prevent nonvertebral fracture in elderly women with Alzheimer's disease|journal=Bone|year=2005|volume=36|issue=1|pmid=15664003|doi=10.1016/j.bone.2004.09.018|pages=61–8}}</ref> In the amount of 45&nbsp;mg daily MK4 has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of [[osteoporosis]].<ref name="Iwamoto 1999 161–164">{{cite journal|last=Iwamoto|first=I|coauthors=Kosha S, Noguchi S-i|title=A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal women a comparative study with vitamin D3 and estrogen-progestin therapy|journal=Maturitas|year=1999|volume=31|issue=2|pages=161–164|pmid=10227010|doi=10.1016/S0378-5122(98)00114-5}}</ref>
 Vitamin K<sub>2</sub> (MK4, but not MK7 or vitamin K<sub>1</sub>) has also been shown to prevent bone loss and/or fractures in the following circumstances:
 * caused by corticosteroids (e.g., prednisone, dexamethasone, prednisolone),<ref name="Inoue 2001 11–18">{{cite journal|last=Inoue|first=T|coauthors=Sugiyama T, Matsubara T, Kawai S, Furukawa S|title=Inverse correlation between the changes of lumbar bone mineral density and serum undercarboxylated osteocalcin after vitamin K2 (menatetrenone) treatment in children treated with glucocorticoid and alfacalcidol|journal=Endocrine Journal|year=2001|volume=48|issue=1|pages=11–18|pmid=11403096|doi=10.1507/endocrj.48.11}}</ref><ref name="Sasaki 2005 41–47">{{cite journal|last=Sasaki|first=N, Kusano E, Takahashi H, Ando Y, Yano K, Tsuda E, Asano Y|coauthors=Kusano E, Takahashi H, Ando Y, Yano K, Tsuda E, Asano Y|title=Vitamin K2 inhibits glucocorticoid-induced bone loss partly by preventing the reduction of osteoprotegerin (OPG)|journal=Journal of bone and mineral metabolism|year=2005|volume=23|issue=1|pages=41–47|pmid=15616893|doi=10.1007/s00774-004-0539-6}}</ref><ref name="Yonemura 2004 53–60">{{cite journal|last=Yonemura|first=K|coauthors=Fukasawa H, Fujigaki Y, Hishida A.|title=Protective effect of vitamins K2 and D3 on prednisolone-induced loss of bone mineral density in the lumbar spine|journal=American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation|year=2004|volume=43|issue=1|pages=53–60|pmid=14712427}}</ref><ref name="Yonemura 2000 123–128">{{cite journal|last=Yonemura|first=K|coauthors=Kimura M, Miyaji T, Hishida A|title=Short-term effect of vitamin K administration on prednisolone-induced loss of bone mineral density in patients with chronic glomerulonephritis|journal=Calcified Tissue International|year=2000|volume=66|issue=2|pages=123–128|pmid=10652960|doi=10.1007/PL00005832}}</ref>
 * anorexia nervosa,<ref name="Iketani 2003 259–269">{{cite journal|last=Iketani|first=T|coauthors=Kiriike N, B. Stein M|title=Effect of menatetrenone (vitamin K2) treatment on bone loss in patients with anorexia nervosa|journal=Psychiatry Research|year=2003|volume=117|issue=3|pages=259–269|pmid=12686368|doi=10.1016/S0165-1781(03)00024-6}}</ref>
@@ Line 29: / Line 29: @@
 * postmenopausal osteoporosis,<ref name="Cockayne 2006 1256–1261">{{cite journal|last=Cockayne|first=S|coauthors=Adamson J, Lanham-New S, Shearer MJ, Gilbody S, Torgerson DJ|title=Vitamin K and the Prevention of Fractures: Systematic Review and Meta-analysis of Randomized Controlled Trials|journal=Archives of Internal Medicine|year=2006|volume=166|issue=12|pages=1256–1261|pmid=16801507|doi=10.1001/archinte.166.12.1256}}</ref><ref name="ReferenceA">{{cite journal|last=Iwamoto|first=I|coauthors=Kosha S, Noguchi S-i|title=A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal women a comparative study with vitamin D3 and estrogen-progestin therapy|journal=Maturitas|year=1999|volume=31|issue=2|pages=161–164|pmid=10227010|doi=10.1016/S0378-5122(98)00114-5}}</ref><ref name="Iwamoto 2000 546–551">{{cite journal|last=Iwamoto|first=J|coauthors=Takeda T, Ichimura S|title=Effect of combined administration of vitamin D3 and vitamin K2 on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis|journal=Journal of Orthopaedic Science|year=2000|volume=5|issue=6|pages=546–551|pmid=11180916|doi=10.1007/s007760070003}}</ref><ref name="Purwosunu 2006 230–234">{{cite journal|last=Purwosunu|first=Y|coauthors=Muharram, Rachman IA, Reksoprodjo S, Sekizawa A|title=Vitamin K2 treatment for postmenopausal osteoporosis in Indonesia|journal=The journal of obstetrics and gynaecology research|year=2006|volume=32|issue=2|pages=230–234|pmid=16594930|doi=10.1111/j.1447-0756.2006.00386.x}}</ref><ref name="Shiraki 2000 515–522">{{cite journal|last=Shiraki|first=M|coauthors=Shiraki Y, Aoki C, Miura M|title=Vitamin K2 (Menatetrenone) Effectively Prevents Fractures and Sustains Lumbar Bone Mineral Density in Osteoporosis|journal=Journal of Bone and Mineral Research|year=2000|volume=15|issue=3|pages=515–522|pmid=10750566|doi=10.1359/jbmr.2000.15.3.515}}</ref><ref name="Ushiroyama 2002 211–221">{{cite journal|last=Ushiroyama|first=T|coauthors=Ikeda A, Ueki M|title=Effect of continuous combined therapy with vitamin K2 and vitamin D3 on bone mineral density and coagulofibrinolysis function in postmenopausal women|journal=Maturitas|year=2002|volume=41|issue=3|pages=211–221|pmid=11886767|doi=10.1016/S0378-5122(01)00275-4}}</ref>
 * disuse from stroke,<ref name="Sato 1998 291–296">{{cite journal|last=Sato|first=Y|coauthors=Honda Y, Kuno H, Oizumi K|title=Menatetrenone ameliorates osteopenia in disuse-affected limbs of vitamin D- and K-deficient stroke patients|journal=Bone|year=1998|volume=23|issue=3|pages=291–296|pmid=9737352|doi=10.1016/S8756-3282(98)00108-2}}</ref>
-* [[Alzheimer’s disease]],<ref name="Sato 2005 61–68">{{cite journal|last=Sato|first=Y|coauthors=Kanoko T, Satoh K, Iwamoto J|title=Menatetrenone and vitamin D2 with calcium supplements prevent nonvertebral fracture in elderly women with Alzheimer's disease|journal=Bone|year=2005|volume=36|issue=1|pages=61–68|pmid=15664003|doi=10.1016/j.bone.2004.09.018}}</ref>
+* [[Alzheimer's disease]],<ref name="Sato 2005 61–68">{{cite journal|last=Sato|first=Y|coauthors=Kanoko T, Satoh K, Iwamoto J|title=Menatetrenone and vitamin D2 with calcium supplements prevent nonvertebral fracture in elderly women with Alzheimer's disease|journal=Bone|year=2005|volume=36|issue=1|pages=61–68|pmid=15664003|doi=10.1016/j.bone.2004.09.018}}</ref>
 * [[Parkinson disease]],<ref name="Sato 2002 114–118">{{cite journal|last=Sato|first=Y|coauthors=Honda Y, Kaji M|title=Amelioration of osteoporosis by menatetrenone in elderly female Parkinson's disease patients with vitamin D deficiency|journal=Bone|year=2002|volume=31|issue=1|pages=114–118|pmid=12110423|doi=10.1016/S8756-3282(02)00783-4}}</ref>
 * [[primary biliary cirrhosis]]<ref name="Nishiguchi 2001 543–545">{{cite journal|last=Nishiguchi|first=S|coauthors=Shimoi S, Kurooka H|title=Randomized pilot trial of vitamin K2 for bone loss in patients with primary biliary cirrhosis|journal=Journal of Hepatology|year=2001|volume=35|issue=4|pages=543–545|pmid=11682046|doi=10.1016/S0168-8278(01)00133-7}}</ref>
@@ Line 36: / Line 36: @@
 ==Vitamin K absorption and dietary need==
-Previous theory held that dietary deficiency is extremely rare unless the intestine (small bowel) was heavily damaged, resulting in [[malabsorption]] of the molecule.  The other at-risk group for deficiency were those subject to decreased production of K<sub>2</sub> by normal flora, as seen in [[broad spectrum antibiotic]] use.<ref>{{cite web| title=Vitamin K| accessdate=2009-05-26|url= http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-vitamink.html}}</ref>  Taking broad-spectrum antibiotics can reduce vitamin K production in the gut by nearly 74% in people compared to those not taking these antibiotics.<ref>{{cite journal|last=Conly|first=J|coauthors=Stein K|title=Reduction of vitamin K2 concentrations in human liver associated with the use of broad spectrum antimicrobials|journal=Clinical and investigative medicine.  Médecine clinique et experimentale|year=1994|volume=17|issue=6|pages=531–539|pmid=7895417}}</ref>  Diets low in vitamin K also decrease the body's vitamin K concentration.<ref>{{cite journal |author=Ferland G, Sadowski JA, O'Brien ME |title=Dietary induced subclinical vitamin K deficiency in normal human subjects |journal=J. Clin. Invest. |volume=91 |issue=4 |pages=1761–8 |year=1993 |month=April |pmid=8473516 |pmc=288156 |doi=10.1172/JCI116386 }}</ref>  Additionally, in the elderly there is a reduction in vitamin K<sub>2</sub> production.<ref>{{cite journal |author=Hodges SJ, Pilkington MJ, Shearer MJ, Bitensky L, Chayen J |title=Age-related changes in the circulating levels of congeners of vitamin K2, menaquinone-7 and menaquinone-8 |journal=Clin. Sci. |volume=78 |issue=1 |pages=63–6 |year=1990 |month=January |pmid=2153497 }}</ref>
+Previous theory held that dietary deficiency is extremely rare unless the intestine (small bowel) was heavily damaged, resulting in [[malabsorption]] of the molecule. The other at-risk group for deficiency were those subject to decreased production of K<sub>2</sub> by normal flora, as seen in [[broad spectrum antibiotic]] use.<ref>{{cite web| title=Vitamin K| accessdate=2009-05-26|url= http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-vitamink.html}}</ref> Taking broad-spectrum antibiotics can reduce vitamin K production in the gut by nearly 74% in people compared with those not taking these antibiotics.<ref>{{cite journal|last=Conly|first=J|coauthors=Stein K|title=Reduction of vitamin K2 concentrations in human liver associated with the use of broad spectrum antimicrobials|journal=Clinical and investigative medicine. Médecine clinique et experimentale|year=1994|volume=17|issue=6|pages=531–539|pmid=7895417}}</ref> Diets low in vitamin K also decrease the body's vitamin K concentration.<ref>{{cite journal |author=Ferland G, Sadowski JA, O'Brien ME |title=Dietary induced subclinical vitamin K deficiency in normal human subjects |journal=The Journal of Clinical Investigation |volume=91 |issue=4 |pages=1761–8 |year=1993 |month=April |pmid=8473516 |pmc=288156 |doi=10.1172/JCI116386 }}</ref> Additionally, in the elderly there is a reduction in vitamin K<sub>2</sub> production.<ref>{{cite journal |author=Hodges SJ, Pilkington MJ, Shearer MJ, Bitensky L, Chayen J |title=Age-related changes in the circulating levels of congeners of vitamin K2, menaquinone-7 and menaquinone-8 |journal=Clinical Science |volume=78 |issue=1 |pages=63–6 |year=1990 |month=January |pmid=2153497 }}</ref>
-Recent research results also demonstrate that the small intestine and large intestine (colon) seem to be inefficient at absorbing vitamins K.<ref name=Groenen>{{cite journal |author=Groenen-van Dooren MM, Ronden JE, Soute BA, Vermeer C |title=Bioavailability of phylloquinone and menaquinones after oral and colorectal administration in vitamin K-deficient rats |journal=Biochem. Pharmacol. |volume=50 |issue=6 |pages=797–801 |year=1995 |month=September |pmid=7575640 |url=http://linkinghub.elsevier.com/retrieve/pii/0006-2952(95)00202-B |doi=10.1016/0006-2952(95)00202-B}}</ref><ref name=Komai>{{cite journal |author=Komai M, Shirakawa H |title=[Vitamin K metabolism. Menaquinone-4 (MK-4) formation from ingested VK analogues and its potent relation to bone function] |language=Japanese |journal=Clin Calcium |volume=17 |issue=11 |pages=1663–72 |year=2007 |month=November |pmid=17982185 |doi=CliCa071116631672 }}</ref>  These results are reinforced by human cohort studies, where a majority of the subjects showed inadequate vitamins K amounts in the body.  This was revealed by the presence of large amounts of incomplete [[carboxylation#Carboxylation in biochemistry|gamma-carboxylated protein]]s in the blood, an indirect test for vitamins K deficiency.<ref name=Geleijnse>{{cite journal |author=Geleijnse JM, Vermeer C, Grobbee DE, ''et al.'' |title=Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study |journal=J. Nutr. |volume=134 |issue=11 |pages=3100–5 |year=2004 |month=November |pmid=15514282 |url=http://jn.nutrition.org/cgi/pmidlookup?view=long&pmid=15514282}}</ref><ref name=Beulens>{{cite journal |author=Beulens JW, Bots ML, Atsma F, ''et al.'' |title=High dietary menaquinone intake is associated with reduced coronary calcification |journal=Atherosclerosis |volume=203 |issue=2 |pages=489–93 |year=2009 |month=April |pmid=18722618 |doi=10.1016/j.atherosclerosis.2008.07.010 |url=http://linkinghub.elsevier.com/retrieve/pii/S0021-9150(08)00507-8}}</ref><ref name=Nimptsch>{{cite journal |author=Nimptsch K, Rohrmann S, Kaaks R, Linseisen J |title=Dietary vitamin K intake in relation to cancer incidence and mortality: results from the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg) |journal=Am. J. Clin. Nutr. |volume=91 |issue=5 |pages=1348–58 |year=2010 |month=May |pmid=20335553 |doi=10.3945/ajcn.2009.28691 |url=http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=20335553}}</ref>  And in an animal model MK4 was shown to prevent arterial calcifications, pointing to its potential role in cardiovascular disease prevention.<ref>{{cite journal|last=Spronk|first=HMH|coauthors=Soute BAM, Schurgers LJ, Thijssen HHW, De Mey JGR, Vermeer C|title=Tissue-Specific Utilization of Menaquinone-4 Results in the Prevention of Arterial Calcification in Warfarin-Treated Rats|journal=Journal of vascular research|year=2003|volume=40|issue=6|pages=531–537|pmid=14654717|doi=10.1159/000075344}}</ref>  In this study vitamin K<sub>1</sub> was also tested and shown to not prevent arterial calcifications.
+Recent research results also demonstrate that the small intestine and large intestine (colon) seem to be inefficient at absorbing vitamins K.<ref name=Groenen>{{cite journal |author=Groenen-van Dooren MM, Ronden JE, Soute BA, Vermeer C |title=Bioavailability of phylloquinone and menaquinones after oral and colorectal administration in vitamin K-deficient rats |journal=Biochem. Pharmacol. |volume=50 |issue=6 |pages=797–801 |year=1995 |month=September |pmid=7575640 |url=http://linkinghub.elsevier.com/retrieve/pii/0006-2952(95)00202-B |doi=10.1016/0006-2952(95)00202-B}}</ref><ref name=Komai>{{cite journal |author=Komai M, Shirakawa H |title=[Vitamin K metabolism. Menaquinone-4 (MK-4) formation from ingested VK analogues and its potent relation to bone function] |language=Japanese |journal=Clin Calcium |volume=17 |issue=11 |pages=1663–72 |year=2007 |month=November |pmid=17982185 |doi=CliCa071116631672 }}</ref> These results are reinforced by human cohort studies, where a majority of the subjects showed inadequate vitamins K amounts in the body. This was revealed by the presence of large amounts of incomplete [[carboxylation#Carboxylation in biochemistry|gamma-carboxylated protein]]s in the blood, an indirect test for vitamins K deficiency.<ref name=Geleijnse>{{cite journal |author=Geleijnse JM, Vermeer C, Grobbee DE, ''et al.'' |title=Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study |journal=J. Nutr. |volume=134 |issue=11 |pages=3100–5 |year=2004 |month=November |pmid=15514282 |url=http://jn.nutrition.org/content/134/11/3100.full.pdf }}</ref><ref name=Beulens>{{cite journal |author=Beulens JW, Bots ML, Atsma F, ''et al.'' |title=High dietary menaquinone intake is associated with reduced coronary calcification |journal=Atherosclerosis |volume=203 |issue=2 |pages=489–93 |year=2009 |month=April |pmid=18722618 |doi=10.1016/j.atherosclerosis.2008.07.010 |url=http://linkinghub.elsevier.com/retrieve/pii/S0021-9150(08)00507-8}}</ref><ref name=Nimptsch>{{cite journal |author=Nimptsch K, Rohrmann S, Kaaks R, Linseisen J |title=Dietary vitamin K intake in relation to cancer incidence and mortality: results from the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg) |journal=Am. J. Clin. Nutr. |volume=91 |issue=5 |pages=1348–58 |year=2010 |month=May |pmid=20335553 |doi=10.3945/ajcn.2009.28691 |url=http://www.ajcn.org/content/91/5/1348.full.pdf }}</ref> And in an animal model MK4 was shown to prevent arterial calcifications, pointing to its potential role in cardiovascular disease prevention.<ref>{{cite journal|last=Spronk|first=HMH|coauthors=Soute BAM, Schurgers LJ, Thijssen HHW, De Mey JGR, Vermeer C|title=Tissue-Specific Utilization of Menaquinone-4 Results in the Prevention of Arterial Calcification in Warfarin-Treated Rats|journal=Journal of vascular research|year=2003|volume=40|issue=6|pages=531–537|pmid=14654717|doi=10.1159/000075344}}</ref> In this study vitamin K<sub>1</sub> was also tested and shown to not prevent arterial calcifications.
 ==Chemical structure==
-All members of the vitamin K group of vitamins share a [[methylation|methylated]] [[naphthoquinone]] ring structure ([[menadione]]), and vary in the [[aliphatic]] [[side chain]] attached at the 3-position (see figure 1).  [[Phylloquinone]] (also known as vitamin K<sub>1</sub>) invariably contains in its side chain four [[isoprene|isoprenoid]]  residues, one of which is unsaturated.
+All members of the vitamin K group of vitamins share a [[methylation|methylated]] [[naphthoquinone]] ring structure ([[menadione]]), and vary in the [[aliphatic]] [[side chain]] attached at the 3-position (see figure 1). [[Phylloquinone]] (also known as vitamin K<sub>1</sub>) invariably contains in its side chain four [[isoprene|isoprenoid]] residues, one of which is unsaturated.
 Menaquinones have side chains composed of a variable number of unsaturated isoprenoid residues; generally they are designated as MK-n, where n specifies the number of isoprenoids.
-It is generally accepted that the naphthoquinone is the functional group, so that the mechanism of action is similar for all K-vitamins.  Substantial differences may be expected, however, with respect to intestinal absorption, transport, tissue distribution, and bio-availability.  These differences are caused by the different lipophilicity of the various side chains, and by the different food matrices in which they occur.
+It is generally accepted that the naphthoquinone is the functional group, so that the mechanism of action is similar for all K-vitamins. Substantial differences may be expected, however, with respect to intestinal absorption, transport, tissue distribution, and bio-availability. These differences are caused by the different lipophilicity of the various side chains, and by the different food matrices in which they occur.
 There are three synthetic forms of vitamin K, vitamins K<sub>3</sub>, K<sub>4</sub>, and K<sub>5</sub>, which are used in many areas including the pet food industry (vitamin K<sub>3</sub>) and to inhibit fungal growth (vitamin K<sub>5</sub>).<ref>{{cite web|last=McGee|first=W |publisher=[[MedlinePlus]]|title=Vitamin K|date=2007-02-01|accessdate=2009-04-02|url=http://www.nlm.nih.gov/medlineplus/ency/article/002407.htm}}</ref>
 ==Physiology==
-Vitamin K is involved in the [[carboxylation]] of certain [[glutamate]] residues in proteins to form [[gamma-carboxyglutamate]] residues (abbreviated Gla residues).  The modified residues are often (but not always) situated within specific [[protein domains]] called [[Gla domain]]s.  Gla residues are usually involved in binding [[calcium in biology|calcium]].  The Gla residues are essential for the biological activity of all known [[Gla domain#Human proteins containing this domain|Gla-proteins]].<ref name=Furie>{{cite journal|author=Furie B, Bouchard BA, Furie BC|title=Vitamin K-dependent biosynthesis of gamma-carboxyglutamic acid|journal=Blood|volume=93|issue=6|pages=1798–808|date=15 March 1999|pmid=10068650|url=http://bloodjournal.hematologylibrary.org/cgi/content/full/93/6/1798}}</ref>
+Vitamin K is involved in the [[carboxylation]] of certain [[glutamate]] residues in proteins to form [[gamma-carboxyglutamate]] residues (abbreviated Gla residues). The modified residues are often (but not always) situated within specific [[protein domains]] called [[Gla domain]]s. Gla residues are usually involved in binding [[calcium in biology|calcium]]. The Gla residues are essential for the biological activity of all known [[Gla domain#Human proteins containing this domain|Gla-proteins]].<ref name=Furie>{{cite journal|author=Furie B, Bouchard BA, Furie BC|title=Vitamin K-dependent biosynthesis of gamma-carboxyglutamic acid|journal=Blood|volume=93|issue=6|pages=1798–808|date=15 March 1999|pmid=10068650|url=http://bloodjournal.hematologylibrary.org/cgi/content/full/93/6/1798}}</ref>
 {{As of|2007|alt=At this time}} 15 human proteins with [[Gla domain]]s have been discovered, and they play key roles in the regulation of three physiological processes:
@@ Line 61: / Line 61: @@
 ==Recommended amounts==
-The U.S. [[Dietary Reference Intake]] (DRI) for an Adequate Intake (AI) of vitamin K for a 25-year old [[male]] is 120 [[micrograms]]/day.  The Adequate Intake (AI) for adult women is 90 micrograms/day, for infants is 10–20 micrograms/day, for children and adolescents 15–100 micrograms/day.  In 2002 it was found that to get maximum [[carboxylation]] of [[osteocalcin]], one may have to take up to 1000 μg of vitamin K<sub>1</sub>.<ref>{{cite journal |author=Binkley NC, Krueger DC, Kawahara TN, Engelke JA, Chappell RJ, Suttie JW |title=A high phylloquinone intake is required to achieve maximal osteocalcin gamma-carboxylation |journal=Am. J. Clin. Nutr. |volume=76 |issue=5 |pages=1055–60 |year=2002 |month=November |pmid=12399278 |url=http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=12399278}}</ref>
+The U.S. [[Dietary Reference Intake]] (DRI) for an Adequate Intake (AI) of vitamin K for a 25-year old [[male]] is 120 [[micrograms]]/day. The Adequate Intake (AI) for adult women is 90 micrograms/day, for infants is 10–20 micrograms/day, for children and adolescents 15–100 micrograms/day. In 2002 it was found that to get maximum [[carboxylation]] of [[osteocalcin]], one may have to take up to 1000 μg of vitamin K<sub>1</sub>.<ref>{{cite journal |author=Binkley NC, Krueger DC, Kawahara TN, Engelke JA, Chappell RJ, Suttie JW |title=A high phylloquinone intake is required to achieve maximal osteocalcin gamma-carboxylation |journal=Am. J. Clin. Nutr. |volume=76 |issue=5 |pages=1055–60 |year=2002 |month=November |pmid=12399278 |url=http://www.ajcn.org/content/76/5/1055.full.pdf }}</ref>
 ==Toxicity==
 Although [[allergic reaction]] from supplementation is possible, there is no known toxicity associated with high doses of the phylloquinone (vitamin K<sub>1</sub>) or menaquinone (vitamin K<sub>2</sub>) forms of vitamin K and therefore no [[Tolerable_upper_intake_level#Current_recommendations|tolerable upper intake level]] (UL) has been set.{{Citation needed|date=April 2010}}
-Blood clotting ([[coagulation]]) studies in humans using 45&nbsp;mg per day of vitamin K<sub>2</sub> (as MK4)<ref name="Ushiroyama 2002 211–221"/> and even up to 135&nbsp;mg/day (45&nbsp;mg three times daily) of K2 (as MK4),<ref>{{cite journal|last=Asakura|first=H|coauthors=Myou S, Ontachi Y, Mizutani T, Kato M, Saito M, Morishita E, Yamazaki M, Nakao S|title=Vitamin K administration to elderly patients with osteoporosis induces no hemostatic activation, even in those with suspected vitamin K deficiency|journal=Osteoporosis International|year=2001|volume=12|issue=12|pages=996–1000|pmid=11846334|doi=10.1007/s001980170007}}</ref> showed no increase in blood clot risk.  Even doses in rats as high as 250&nbsp;mg/kg body weight did not alter the tendency for blood-clot formation to occur.<ref>{{cite journal|last=Ronden|first=JE|coauthors=Groenen-van Dooren MMCL, Hornstra G, Vermeer C|title=Modulation of arterial thrombosis tendency in rats by vitamin K and its side chains|journal=Atherosclerosis|year=1997|volume=132|issue=1|pages=61–67|pmid=9247360|doi=10.1016/S0021-9150(97)00087-7}}</ref>
+Blood clotting ([[coagulation]]) studies in humans using 45&nbsp;mg per day of vitamin K<sub>2</sub> (as MK4)<ref name="Ushiroyama 2002 211–221"/> and even up to 135&nbsp;mg/day (45&nbsp;mg three times daily) of K2 (as MK4),<ref>{{cite journal|last=Asakura|first=H|coauthors=Myou S, Ontachi Y, Mizutani T, Kato M, Saito M, Morishita E, Yamazaki M, Nakao S|title=Vitamin K administration to elderly patients with osteoporosis induces no hemostatic activation, even in those with suspected vitamin K deficiency|journal=Osteoporosis International|year=2001|volume=12|issue=12|pages=996–1000|pmid=11846334|doi=10.1007/s001980170007}}</ref> showed no increase in blood clot risk. Even doses in rats as high as 250&nbsp;mg/kg body weight did not alter the tendency for blood-clot formation to occur.<ref>{{cite journal|last=Ronden|first=JE|coauthors=Groenen-van Dooren MMCL, Hornstra G, Vermeer C|title=Modulation of arterial thrombosis tendency in rats by vitamin K and its side chains|journal=Atherosclerosis|year=1997|volume=132|issue=1|pages=61–67|pmid=9247360|doi=10.1016/S0021-9150(97)00087-7}}</ref>
-However, a synthetic form of vitamin K, vitamin K<sub>3</sub> (menadione), is demonstrably toxic.  In fact, the FDA has banned this synthetic form of the vitamin from over-the-counter supplements because large doses have been shown to cause allergic reactions, [[hemolytic anemia]], and cytotoxicity in liver cells.<ref name=Higdon/>
+However, a synthetic form of vitamin K, vitamin K<sub>3</sub> (menadione), is demonstrably toxic. In fact, the FDA has banned this synthetic form of the vitamin from over-the-counter supplements because large doses have been shown to cause allergic reactions, [[hemolytic anemia]], and cytotoxicity in liver cells.<ref name=Higdon/>
 ==Drug interactions==
-Phylloquinone (K<sub>1</sub>)<ref name="pmid15383473">{{cite journal |author=Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E |title=The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy |journal=Chest |volume=126 |issue=3 Suppl |pages=204S–233S |year=2004 |pmid=15383473 |doi=10.1378/chest.126.3_suppl.204S |url=http://www.chestjournal.org/cgi/content/full/126/3_suppl/204S}} ([http://www.chestjournal.org/cgi/content/full/126/3_suppl/204S/T6 summary])</ref><ref name="pmid12186515">{{cite journal |author=Crowther MA, Douketis JD, Schnurr T, ''et al.'' |title=Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of [[warfarin]]-associated coagulopathy.  A randomized, controlled trial |journal=Ann. Intern. Med. |volume=137 |issue=4 |pages=251–4 |year=2002 |pmid=12186515 |url=http://www.annals.org/cgi/reprint/137/4/251| format=PDF}}</ref> or menaquinone (K<sub>2</sub>) are capable of blocking the blood thinning action of anticoagulants like [[warfarin]], which work by interfering with the action of vitamin K.  They also reverse the tendency of these drugs to cause arterial calcification in the long term.
+Phylloquinone (K<sub>1</sub>)<ref name="pmid15383473">{{cite journal |author=Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E |title=The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy |journal=Chest |volume=126 |issue=3 Suppl |pages=204S–233S |year=2004 |pmid=15383473 |doi=10.1378/chest.126.3_suppl.204S |url=http://chestjournal.chestpubs.org/content/126/3_suppl/204S.full.pdf }}</ref><ref name="pmid12186515">{{cite journal |author=Crowther MA, Douketis JD, Schnurr T, ''et al.'' |title=Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of [[warfarin]]-associated coagulopathy. A randomized, controlled trial |journal=Ann. Intern. Med. |volume=137 |issue=4 |pages=251–4 |year=2002 |pmid=12186515 |url=http://www.annals.org/content/137/4/251.full.pdf }}</ref> or menaquinone (K<sub>2</sub>) are capable of blocking the blood thinning action of anticoagulants like [[warfarin]], which work by interfering with the action of vitamin K. They also reverse the tendency of these drugs to cause arterial calcification in the long term.
 ==Sources==
-Vitamin K<sub>1</sub> is found chiefly in leafy green vegetables such as [[spinach]], [[swiss chard]], and  ''[[Brassica]]'' (''e.g.'' [[cabbage]], [[kale]], [[cauliflower]], [[broccoli]], and [[brussels sprout]]s); some [[fruit]]s such as [[avocado]], [[kiwifruit]] and [[grapes]] are also high in vitamin K.  By way of reference, two tablespoons of [[parsley]] contain 153% of the recommended daily amount of vitamin K.<ref>[http://www.nutritiondata.com/facts-C00001-01c20eX.html Nutrition Facts and Information for Parsley, raw<!-- Bot generated title -->]</ref>  Some vegetable oils, notably soybean, contain vitamin K, but at levels that would require relatively large calorific consumption to meet the [[USDA]] recommended levels.<ref>[http://www.nutritiondata.com Nutrition facts, calories in food, labels, nutritional information and analysis – NutritionData.com<!-- Bot generated title -->]</ref>
+Vitamin K<sub>1</sub> is found chiefly in leafy green vegetables such as [[spinach]], [[swiss chard]], and ''[[Brassica]]'' (''e.g.'' [[cabbage]], [[kale]], [[cauliflower]], [[broccoli]], and [[brussels sprout]]s); some [[fruit]]s such as [[avocado]], [[kiwifruit]] and [[grapes]] are also high in vitamin K. By way of reference, two tablespoons of [[parsley]] contain 153% of the recommended daily amount of vitamin K.<ref>[http://www.nutritiondata.com/facts-C00001-01c20eX.html Nutrition Facts and Information for Parsley, raw<!-- Bot generated title -->]</ref> Some vegetable oils, notably soybean, contain vitamin K, but at levels that would require relatively large calorific consumption to meet the [[USDA]] recommended levels.<ref>[http://www.nutritiondata.com Nutrition facts, calories in food, labels, nutritional information and analysis – NutritionData.com<!-- Bot generated title -->]</ref>
 Colonic bacteria synthesize a significant portion of humans' vitamin K needs; this is one of the reasons why newborns often receive a vitamin K shot at birth - in order to tide them over until day 5-7 when their colon becomes colonized.
-It is believed that phylloquinone's tight binding to the thylakoid membranes in the chloroplasts is the reason behind the poor bioavailability of vitamin K in green plants.  For example, cooked spinach has a 5% bioavailability of phylloquinone.  However when one adds fat to the spinach, the bioavailability increases to 13% due to the increased solubility of vitamin K in fat.<ref>[http://www.vivo.colostate.edu/hbooks/pathphys/misc_topics/vitamink.html NutritionData.com<!-- Bot generated title -->]</ref>
+It is believed{{by whom}} that phylloquinone's tight binding to the thylakoid membranes in the chloroplasts is the reason behind the poor bioavailability of vitamin K in green plants. For example, cooked spinach has a 5% bioavailability of phylloquinone. However when one adds fat to the spinach, the bioavailability increases to 13% due to the increased solubility of vitamin K in fat.<ref>[http://www.vivo.colostate.edu/hbooks/pathphys/misc_topics/vitamink.html NutritionData.com<!-- Bot generated title -->]</ref>
-Vitamin K<sub>2</sub> (Menaquinone-4) is synthesized by animal tissues and is found in meat, eggs, and dairy products.<ref name="pmid16417305">{{cite journal|author=Elder SJ, Haytowitz DB, Howe J, Peterson JW, Booth SL|title=Vitamin k contents of meat, dairy, and fast food in the U.S. Diet|journal=J. Agric. Food Chem.|volume=54|issue=2|pages=463–7|year=2006|month=January|pmid=16417305|doi=10.1021/jf052400h|url=}}</ref> Menaquinone-7 is synthesized by bacteria during fermentation and is found in fermented soybeans ([[natto]]).<ref name="pmid10874601">{{cite journal|author=Tsukamoto Y, Ichise H, Kakuda H, Yamaguchi M|title=Intake of fermented soybean (natto) increases circulating vitamin K<sub>2</sub> (menaquinone-7) and gamma-carboxylated osteocalcin concentration in normal individuals|journal=J. Bone Miner. Metab.|volume=18|issue=4|pages=216–22|year=2000|pmid=10874601|doi= 10.1007/s007740070023|url=http://link.springer.de/link/service/journals/00774/bibs/0018004/00180216.htm}}</ref> In natto 0% of vitamin K is from MK-4 and in cheese 2–7%.<ref name="urlOn the Trail of the Elusive X-Factor: Vitamin K2 Revealed">{{cite web|url=http://www.westonaprice.org/abcs-of-nutrition/175#fig4|title=On the Trail of the Elusive X-Factor: Vitamin K2 Revealed|format=|work=|accessdate=}}</ref>
+Vitamin K<sub>2</sub> (Menaquinone-4) is synthesized by animal tissues and is found in meat, eggs, and dairy products.<ref name="pmid16417305">{{cite journal|author=Elder SJ, Haytowitz DB, Howe J, Peterson JW, Booth SL|title=Vitamin k contents of meat, dairy, and fast food in the U.S. Diet|journal=J. Agric. Food Chem.|volume=54|issue=2|pages=463–7|year=2006|month=January|pmid=16417305|doi=10.1021/jf052400h }}</ref> Menaquinone-7 is synthesized by bacteria during fermentation and is found in fermented soybeans ([[natto]]).<ref name="pmid10874601">{{cite journal|author=Tsukamoto Y, Ichise H, Kakuda H, Yamaguchi M|title=Intake of fermented soybean (natto) increases circulating vitamin K<sub>2</sub> (menaquinone-7) and gamma-carboxylated osteocalcin concentration in normal individuals|journal=J. Bone Miner. Metab.|volume=18|issue=4|pages=216–22|year=2000|pmid=10874601|doi= 10.1007/s007740070023|url=http://link.springer.de/link/service/journals/00774/bibs/0018004/00180216.htm}}</ref> In natto 0% of vitamin K is from MK-4 and in cheese 2–7%.<ref name="urlOn the Trail of the Elusive X-Factor: Vitamin K2 Revealed">{{cite web|url=http://www.westonaprice.org/fat-soluble-activators/x-factor-is-vitamin-k2#fig4|title=On the Trail of the Elusive X-Factor: Vitamin K2 Revealed }}{{verify source}}</ref>
 ==Deficiency==
 {{Main|Vitamin K deficiency}}
-Average diets are usually not lacking in vitamin K and primary vitamin K deficiency is rare in healthy adults.  Newborn infants are at an increased risk of deficiency.  Other populations with an increased prevalence of vitamin K deficiency include individuals who suffer from liver damage or disease (e.g. alcoholics), people with cystic fibrosis, inflammatory bowel diseases or those who have recently had abdominal surgeries.  Groups that may suffer from secondary vitamin K deficiency include bulimics, those on stringent diets, and those taking anticoagulants.  Other drugs that have been associated with vitamin K deficiency include salicylates, barbiturates, and cefamandole, although the mechanism is still unknown.  There is no difference between the sexes as both males and females are affected equally.  Symptoms of deficiency include heavy menstrual bleeding in women, anemia, bruising, and bleeding of the gums or nose.  They could also have disorders such as [[coagulopathy]].<ref name="urlOn the Trail of the Elusive X-Factor: Vitamin K2 Revealed">{{cite web|url=http://lpi.oregonstate.edu/infocenter/vitamins/vitaminK/|title=Micronutrient Data Centre: Vitamin K|format=|work=|accessdate=}}</ref>
+Average diets are usually not lacking in vitamin K and primary vitamin K deficiency is rare in healthy adults. Newborn infants are at an increased risk of deficiency. Other populations with an increased prevalence of vitamin K deficiency include individuals who suffer from liver damage or disease (e.g. alcoholics), people with cystic fibrosis, inflammatory bowel diseases or those who have recently had abdominal surgeries. Groups that may suffer from secondary vitamin K deficiency include bulimics, those on stringent diets, and those taking anticoagulants. Other drugs that have been associated with vitamin K deficiency include salicylates, barbiturates, and cefamandole, although the mechanism is still unknown. There is no difference between the sexes as both males and females are affected equally. Symptoms of deficiency include heavy menstrual bleeding in women, anemia, bruising, and bleeding of the gums or nose. They could also have disorders such as [[coagulopathy]].<ref name="urlOn the Trail of the Elusive X-Factor: Vitamin K2 Revealed">{{cite web|url=http://lpi.oregonstate.edu/infocenter/vitamins/vitaminK/|title=Micronutrient Data Centre: Vitamin K }}</ref>
-Osteoporosis<ref>{{cite journal |pmid=16614424 |year=2006 |author1=Ikeda |first2=M |first3=A |first4=E |first5=S |first6=Y |first7=H |title=Intake of fermented soybeans, natto, is associated with reduced bone loss in postmenopausal women: Japanese Population-Based Osteoporosis (JPOS) Study |volume=136 |issue=5 |pages=1323–8 |journal=The Journal of nutrition |last2=Iki |last3=Morita |last4=Kajita |last5=Kagamimori |last6=Kagawa |last7=Yoneshima}}</ref><ref>{{cite journal |pmid=12350079 |year=2002 |author1=Katsuyama |first2=S |first3=M |first4=K |first5=S |title=Usual dietary intake of fermented soybeans (Natto) is associated with bone mineral density in premenopausal women |volume=48 |issue=3 |pages=207–15 |journal=Journal of nutritional science and vitaminology |last2=Ideguchi |last3=Fukunaga |last4=Saijoh |last5=Sunami |doi=10.3177/jnsv.48.207}}</ref> and coronary heart disease<ref>{{cite journal |pmid=10737225 |year=1999 |author1=Sano |first2=H |first3=I |first4=H |first5=S |title=Vitamin K2 (menatetrenone) induces iNOS in bovine vascular smooth muscle cells: no relationship between nitric oxide production and gamma-carboxylation |volume=45 |issue=6 |pages=711–23 |journal=Journal of nutritional science and vitaminology |last2=Fujita |last3=Morita |last4=Uematsu |last5=Murota |doi=10.3177/jnsv.45.711}}</ref><ref>http://www.npicenter.com/anm/templates/newsATemp.aspx?articleid=23259</ref> are strongly associated with lower levels of K<sub>2</sub> (menaquinone).  Menaquinone is not inhibited by salicylates as happens with K<sub>1</sub>, so menaquinone supplementation can alleviate the chronic vitamin K deficiency caused by long term aspirin use.{{Citation needed|date=July 2009}}
+Osteoporosis<ref>{{cite journal |pmid=16614424 |year=2006 |author1=Ikeda |first2=M |first3=A |first4=E |first5=S |first6=Y |first7=H |title=Intake of fermented soybeans, natto, is associated with reduced bone loss in postmenopausal women: Japanese Population-Based Osteoporosis (JPOS) Study |volume=136 |issue=5 |pages=1323–8 |journal=The Journal of nutrition |last2=Iki |last3=Morita |last4=Kajita |last5=Kagamimori |last6=Kagawa |last7=Yoneshima}}</ref><ref>{{cite journal |pmid=12350079 |year=2002 |author1=Katsuyama |first2=S |first3=M |first4=K |first5=S |title=Usual dietary intake of fermented soybeans (Natto) is associated with bone mineral density in premenopausal women |volume=48 |issue=3 |pages=207–15 |journal=Journal of nutritional science and vitaminology |last2=Ideguchi |last3=Fukunaga |last4=Saijoh |last5=Sunami |doi=10.3177/jnsv.48.207}}</ref> and coronary heart disease<ref>{{cite journal |pmid=10737225 |year=1999 |author1=Sano |first2=H |first3=I |first4=H |first5=S |title=Vitamin K2 (menatetrenone) induces iNOS in bovine vascular smooth muscle cells: no relationship between nitric oxide production and gamma-carboxylation |volume=45 |issue=6 |pages=711–23 |journal=Journal of nutritional science and vitaminology |last2=Fujita |last3=Morita |last4=Uematsu |last5=Murota |doi=10.3177/jnsv.45.711}}</ref><ref>[http://www.npicenter.com/anm/templates/newsATemp.aspx?articleid=23259]</ref> are strongly associated with lower levels of K<sub>2</sub> (menaquinone). Menaquinone is not inhibited by salicylates as happens with K<sub>1</sub>, so menaquinone supplementation can alleviate the chronic vitamin K deficiency caused by long term aspirin use.{{Citation needed|date=July 2009}}
 ==Biochemistry==
@@ Line 91: / Line 91: @@
 The function of vitamin K in the cell is to convert [[glutamate]] in proteins to [[gamma-carboxyglutamate]] (Gla).
-Within the cell, vitamin K undergoes electron [[Redox|reduction]] to a reduced form of vitamin K (called vitamin K hydroquinone) by the enzyme [[vitamin K epoxide reductase]] (or VKOR).<ref name="Oldenburg">{{cite journal|author=Oldenburg J, Bevans CG, Müller CR, Watzka M|title=Vitamin K epoxide reductase complex subunit 1 (VKORC1): the key protein of the vitamin K cycle|journal=Antioxid. Redox Signal.|volume=8|issue=3–4|pages=347–53|year=2006|pmid=16677080|doi=10.1089/ars.2006.8.347|url=}}</ref>  Another enzyme then oxidizes vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called the [[gamma-glutamyl carboxylase]]<ref name="Suttie">{{cite journal|author=Suttie JW|title=Vitamin K-dependent carboxylase|journal=Annu. Rev. Biochem.|volume=54|issue=|pages=459–77|year=1985|pmid=3896125|doi=10.1146/annurev.bi.54.070185.002331|url=}}</ref><ref name="Presnell">{{cite journal|author=Presnell SR, Stafford DW|title=The vitamin K-dependent carboxylase|journal=Thromb. Haemost.|volume=87|issue=6|pages=937–46|year=2002|month=June|pmid=12083499|doi=|url=}}</ref> or the vitamin K-dependent carboxylase.  The carboxylation reaction will only proceed if the carboxylase enzyme is able to oxidize vitamin K hydroquinone to vitamin K epoxide at the same time; the carboxylation and epoxidation reactions are said to be coupled reactions.  Vitamin K epoxide is then re-converted to vitamin K by [[vitamin K epoxide reductase]].  The reduction and subsequent re-oxidation of vitamin K coupled with carboxylation of Glu is called the vitamin K cycle.<ref name=Stafford>{{cite journal|author=Stafford DW|title=The vitamin K cycle|journal=J. Thromb. Haemost.|volume=3|issue=8|pages=1873–8|year=2005|month=August|pmid=16102054|doi=10.1111/j.1538-7836.2005.01419.x|url=}}</ref>  One of the reasons humans are rarely deficient in vitamin K is that vitamin K is continually recycled in cells.
+Within the cell, vitamin K undergoes electron [[Redox|reduction]] to a reduced form of vitamin K (called vitamin K hydroquinone) by the enzyme [[vitamin K epoxide reductase]] (or VKOR).<ref name="Oldenburg">{{cite journal|author=Oldenburg J, Bevans CG, Müller CR, Watzka M|title=Vitamin K epoxide reductase complex subunit 1 (VKORC1): the key protein of the vitamin K cycle|journal=Antioxid. Redox Signal.|volume=8|issue=3–4|pages=347–53|year=2006|pmid=16677080|doi=10.1089/ars.2006.8.347 }}</ref> Another enzyme then oxidizes vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called the [[gamma-glutamyl carboxylase]]<ref name="Suttie">{{cite journal|author=Suttie JW|title=Vitamin K-dependent carboxylase|journal=Annu. Rev. Biochem.|volume=54|issue=|pages=459–77|year=1985|pmid=3896125|doi=10.1146/annurev.bi.54.070185.002331 }}</ref><ref name="Presnell">{{cite journal|author=Presnell SR, Stafford DW|title=The vitamin K-dependent carboxylase|journal=Thromb. Haemost.|volume=87|issue=6|pages=937–46|year=2002|month=June|pmid=12083499|doi= }}</ref> or the vitamin K-dependent carboxylase. The carboxylation reaction will only proceed if the carboxylase enzyme is able to oxidize vitamin K hydroquinone to vitamin K epoxide at the same time; the carboxylation and epoxidation reactions are said to be coupled reactions. Vitamin K epoxide is then re-converted to vitamin K by [[vitamin K epoxide reductase]]. The reduction and subsequent re-oxidation of vitamin K coupled with carboxylation of Glu is called the vitamin K cycle.<ref name=Stafford>{{cite journal|author=Stafford DW|title=The vitamin K cycle|journal=J. Thromb. Haemost.|volume=3|issue=8|pages=1873–8|year=2005|month=August|pmid=16102054|doi=10.1111/j.1538-7836.2005.01419.x }}</ref> One of the reasons humans are rarely deficient in vitamin K is that vitamin K is continually recycled in cells.
-[[Warfarin]] and other [[coumarin]] drugs block the action of the [[vitamin K epoxide reductase]].<ref name="Whitlon">{{cite journal|author=Whitlon DS, Sadowski JA, Suttie JW|title=Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition|journal=Biochemistry|volume=17|issue=8|pages=1371–7|year=1978|month=April|pmid=646989|doi= 10.1021/bi00601a003|url=}}</ref>  This results in decreased concentrations of vitamin K and vitamin K hydroquinone in the tissues, such that the carboxylation reaction catalyzed by the glutamyl carboxylase is inefficient.  This results in the production of clotting factors with inadequate Gla.  Without Gla on the amino termini of these factors, they no longer bind stably to the blood vessel [[endothelium]] and cannot activate clotting to allow formation of a clot during tissue injury.  As it is impossible to predict what dose of warfarin will give the desired degree of suppression of the clotting, warfarin treatment must be carefully monitored to avoid over-dosing. (See the [[warfarin]] article.)
+[[Warfarin]] and other [[coumarin]] drugs block the action of the [[vitamin K epoxide reductase]].<ref name="Whitlon">{{cite journal|author=Whitlon DS, Sadowski JA, Suttie JW|title=Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition|journal=Biochemistry|volume=17|issue=8|pages=1371–7|year=1978|month=April|pmid=646989|doi= 10.1021/bi00601a003 }}</ref> This results in decreased concentrations of vitamin K and vitamin K hydroquinone in the tissues, such that the carboxylation reaction catalyzed by the glutamyl carboxylase is inefficient. This results in the production of clotting factors with inadequate Gla. Without Gla on the amino termini of these factors, they no longer bind stably to the blood vessel [[endothelium]] and cannot activate clotting to allow formation of a clot during tissue injury. As it is impossible to predict what dose of warfarin will give the desired degree of suppression of the clotting, warfarin treatment must be carefully monitored to avoid over-dosing. (See the [[warfarin]] article.)
 ===Gamma-carboxyglutamate proteins, or Gla-proteins===
-At present, the following human Gla-containing proteins have been characterized to the level of primary structure: the blood coagulation factors II (prothrombin), VII, IX, and X, the anticoagulant proteins C and S, and the Factor X-targeting [[protein Z]].  The bone Gla-protein [[osteocalcin]], the calcification inhibiting [[matrix Gla protein]] (MGP), the [[cell growth]] regulating growth arrest specific gene 6 protein (Gas6), and the four transmembrane Gla proteins (TMGPs) the function of which is at present unknown.  Gas6 can function as a [[growth factor]] that activates the Axl [[receptor (biochemistry)|receptor]] [[tyrosine kinase]] and stimulates cell proliferation or prevents [[apoptosis]] in some cells.  In all cases in which their function was known, the presence of the Gla residues in these proteins turned out to be essential for functional activity.
+At present, the following human Gla-containing proteins have been characterized to the level of primary structure: the blood coagulation factors II (prothrombin), VII, IX, and X, the anticoagulant proteins C and S, and the Factor X-targeting [[protein Z]]. The bone Gla-protein [[osteocalcin]], the calcification inhibiting [[matrix Gla protein]] (MGP), the [[cell growth]] regulating growth arrest specific gene 6 protein (Gas6), and the four transmembrane Gla proteins (TMGPs) the function of which is at present unknown. Gas6 can function as a [[growth factor]] that activates the Axl [[receptor (biochemistry)|receptor]] [[tyrosine kinase]] and stimulates cell proliferation or prevents [[apoptosis]] in some cells. In all cases in which their function was known, the presence of the Gla residues in these proteins turned out to be essential for functional activity.
-Gla-proteins are known to occur in a wide variety of vertebrates: mammals, birds, reptiles, and fish.  The [[venom]] of a number of Australian snakes acts by activating the human blood clotting system.  Remarkably, in some cases activation is accomplished by snake Gla-containing enzymes that bind to the endothelium of human blood vessels and catalyze the conversion of procoagulant clotting factors into activated ones, leading to unwanted and potentially deadly clotting.
+Gla-proteins are known to occur in a wide variety of vertebrates: mammals, birds, reptiles, and fish. The [[venom]] of a number of Australian snakes acts by activating the human blood clotting system. Remarkably, in some cases activation is accomplished by snake Gla-containing enzymes that bind to the endothelium of human blood vessels and catalyze the conversion of procoagulant clotting factors into activated ones, leading to unwanted and potentially deadly clotting.
-Another interesting class of invertebrate Gla-containing proteins is synthesized by the fish-hunting snail ''[[Conus geographus]]''.<ref name="Terlau">{{cite journal|author=Terlau H, Olivera BM|title=Conus venoms: a rich source of novel ion channel-targeted peptides|journal=Physiol. Rev.|volume=84|issue=1|pages=41–68|year=2004|month=January|pmid=14715910|doi=10.1152/physrev.00020.2003|url=}}</ref>  These snails produce a venom containing hundreds of neuro-active peptides, or conotoxins,  which is sufficiently toxic to kill an adult human.  Several of the conotoxins contain 2–5 Gla residues.<ref name="Buczek">{{cite journal|author=Buczek O, Bulaj G, Olivera BM|title=Conotoxins and the posttranslational modification of secreted gene products|journal=Cell. Mol. Life Sci.|volume=62|issue=24|pages=3067–79|year=2005|month=December|pmid=16314929|doi=10.1007/s00018-005-5283-0|url=}}</ref>
+Another interesting class of invertebrate Gla-containing proteins is synthesized by the fish-hunting snail ''[[Conus geographus]]''.<ref name="Terlau">{{cite journal|author=Terlau H, Olivera BM|title=Conus venoms: a rich source of novel ion channel-targeted peptides|journal=Physiol. Rev.|volume=84|issue=1|pages=41–68|year=2004|month=January|pmid=14715910|doi=10.1152/physrev.00020.2003 }}</ref> These snails produce a venom containing hundreds of neuro-active peptides, or conotoxins, which is sufficiently toxic to kill an adult human. Several of the conotoxins contain 2–5 Gla residues.<ref name="Buczek">{{cite journal|author=Buczek O, Bulaj G, Olivera BM|title=Conotoxins and the posttranslational modification of secreted gene products|journal=Cell. Mol. Life Sci.|volume=62|issue=24|pages=3067–79|year=2005|month=December|pmid=16314929|doi=10.1007/s00018-005-5283-0 }}</ref>
 ===Methods of assessment===
@@ Line 110: / Line 110: @@
 Plasma Phylloquinone:
-:Was found to be positively correlated with phylloquinone intake in elderly British women, but not men <ref>{{cite journal|author=Thane CW, Bates CJ, Shearer MJ, ''et al''|title=Plasma phylloquinone (vitamin K1) concentration and its relationship to intake in a national sample of British elderly people|journal=Br. J. Nutr.|volume=87|issue=6|pages=615–22|year=2002|month=June|pmid=12067432|doi=10.1079/BJNBJN2002582|url=}}</ref>
+:Was found to be positively correlated with phylloquinone intake in elderly British women, but not men <ref>{{cite journal|author=Thane CW, Bates CJ, Shearer MJ, ''et al''|title=Plasma phylloquinone (vitamin K1) concentration and its relationship to intake in a national sample of British elderly people|journal=Br. J. Nutr.|volume=87|issue=6|pages=615–22|year=2002|month=June|pmid=12067432|doi=10.1079/BJNBJN2002582 }}</ref>
-However an article by Schurges et al. reported no correlation between FFQ and plasma phylloquinone <ref>{{cite journal|author=McKeown NM, Jacques PF, Gundberg CM, ''et al''|title=Dietary and nondietary determinants of vitamin K biochemical measures in men and women|journal=J. Nutr.|volume=132|issue=6|pages=1329–34|year=2002|month=June|pmid=12042454|doi=|url=http://jn.nutrition.org/cgi/pmidlookup?view=long&pmid=12042454}}</ref>
+However an article by Schurges et al. reported no correlation between FFQ and plasma phylloquinone <ref>{{cite journal|author=McKeown NM, Jacques PF, Gundberg CM, ''et al''|title=Dietary and nondietary determinants of vitamin K biochemical measures in men and women|journal=J. Nutr.|volume=132|issue=6|pages=1329–34|year=2002|month=June|pmid=12042454|doi=|url=http://jn.nutrition.org/content/132/6/1329.full.pdf }}</ref>
 Urinary γ-carboxyglutamic acid:
 :Urinary Gla responds to changes in dietary vitamin K intake.
-:Several days are required  before any change can be observed.
+:Several days are required before any change can be observed.
 In a study by Booth et al. increases of phylloquinone intakes from 100 μg to between 377–417 μg for 5 days did ''not'' induce a significant change
-Response may be age-specific <ref>{{cite journal|author=Yamano M, Yamanaka Y, Yasunaga K, Uchida K|title=Effect of vitamin K deficiency on urinary gamma-carboxyglutamic acid excretion in rats|journal=Nippon Ketsueki Gakkai Zasshi|volume=52|issue=6|pages=1078–86|year=1989|month=September|pmid=2588957|doi=|url=}}</ref>
+Response may be age-specific <ref>{{cite journal|author=Yamano M, Yamanaka Y, Yasunaga K, Uchida K|title=Effect of vitamin K deficiency on urinary gamma-carboxyglutamic acid excretion in rats|journal=Nippon Ketsueki Gakkai Zasshi|volume=52|issue=6|pages=1078–86|year=1989|month=September|pmid=2588957|doi= }}</ref>
 ===Function in bacteria===
-Many bacteria, such as ''[[Escherichia coli]]'' found in the [[large intestine]], can synthesize vitamin K<sub>2</sub> (menaquinone-7),<ref name="Bentley">{{cite journal|author=Bentley R, Meganathan R|title=Biosynthesis of vitamin K (menaquinone) in bacteria|journal=Microbiol. Rev.|volume=46|issue=3|pages=241–80|year=1982|month=September|pmid=6127606|pmc=281544|doi=|url=http://mmbr.asm.org/cgi/pmidlookup?view=long&pmid=6127606}}</ref> but not vitamin K<sub>1</sub> (phylloquinone).  In these bacteria, menaquinone will transfer two [[electrons]] between two different small  molecules, in a process called [[anaerobic respiration]].<ref name="Haddock">{{cite journal|author=Haddock BA, Jones CW|title=Bacterial respiration|journal=Bacteriol Rev|volume=41|issue=1|pages=47–99|year=1977|month=March|pmid=140652|pmc=413996|doi=|url=http://mmbr.asm.org/cgi/pmidlookup?view=long&pmid=140652}}</ref>  For example, a small molecule with an excess of electrons (also called an electron donor) such as [[lactic acid|lactate]], [[formate]], or [[NADH]], with the help of an enzyme, will pass two electrons to a menaquinone.  The menaquinone, with the help of another enzyme, will in turn transfer these 2 electrons to a suitable oxidant, such [[fumarate]] or [[nitrate]] (also called an electron acceptor).  Adding two electrons to [[fumarate]] or [[nitrate]] will convert the molecule to [[succinate]] or [[nitrite]] + [[water]], respectively.  Some of these reactions generate a cellular energy source, [[adenosine triphosphate|ATP]], in a manner similar to [[eukaryotic]] cell [[aerobic respiration]], except that the final electron acceptor is not [[molecular oxygen]], but say [[fumarate]] or [[nitrate]] (In [[aerobic respiration]],  the final oxidant is [[molecular oxygen]] (O<sub>2</sub>) , which accepts four electrons from an electron donor such as [[NADH]] to be converted to [[water]].)  ''[[Escherichia coli]]'' can carry out [[aerobic respiration]] and menaquinone-mediated [[anaerobic respiration]].
+Many bacteria, such as ''[[Escherichia coli]]'' found in the [[large intestine]], can synthesize vitamin K<sub>2</sub> (menaquinone-7),<ref name="Bentley">{{cite journal|author=Bentley R, Meganathan R|title=Biosynthesis of vitamin K (menaquinone) in bacteria|journal=Microbiol. Rev.|volume=46|issue=3|pages=241–80|year=1982|month=September|pmid=6127606|pmc=281544|doi=|url=http://mmbr.asm.org/content/46/3/241.full.pdf }}</ref> but not vitamin K<sub>1</sub> (phylloquinone). In these bacteria, menaquinone will transfer two [[electrons]] between two different small molecules, in a process called [[anaerobic respiration]].<ref name="Haddock">{{cite journal|author=Haddock BA, Jones CW|title=Bacterial respiration|journal=Bacteriol Rev|volume=41|issue=1|pages=47–99|year=1977|month=March|pmid=140652|pmc=413996|doi=|url=http://mmbr.asm.org/content/41/1/47.full.pdf }}</ref> For example, a small molecule with an excess of electrons (also called an electron donor) such as [[lactic acid|lactate]], [[formate]], or [[NADH]], with the help of an enzyme, will pass two electrons to a menaquinone. The menaquinone, with the help of another enzyme, will in turn transfer these 2 electrons to a suitable oxidant, such [[fumarate]] or [[nitrate]] (also called an electron acceptor). Adding two electrons to [[fumarate]] or [[nitrate]] will convert the molecule to [[succinate]] or [[nitrite]] + [[water]], respectively. Some of these reactions generate a cellular energy source, [[adenosine triphosphate|ATP]], in a manner similar to [[eukaryotic]] cell [[aerobic respiration]], except that the final electron acceptor is not [[molecular oxygen]], but say [[fumarate]] or [[nitrate]] (In [[aerobic respiration]], the final oxidant is [[molecular oxygen]] (O<sub>2</sub>) , which accepts four electrons from an electron donor such as [[NADH]] to be converted to [[water]].) ''[[Escherichia coli]]'' can carry out [[aerobic respiration]] and menaquinone-mediated [[anaerobic respiration]].
 ==Vitamin K injection in newborns==
-The blood clotting factors of newborn babies are roughly 30 to 60% that of adult values; this may be due to the reduced synthesis of precursor proteins and the sterility of their guts.  Human milk contains between 1 and 4 micrograms/litre of vitamin K<sub>1</sub>, while formula derived milk can contain up to 100 micrograms/litre in supplemented formulas.  Vitamin K<sub>2</sub> concentrations in human milk appear to be much lower than those of vitamin K<sub>1</sub>.
+The blood clotting factors of newborn babies are roughly 30 to 60% that of adult values; this may be due to the reduced synthesis of precursor proteins and the sterility of their guts. Human milk contains between 1 and 4 micrograms/litre of vitamin K<sub>1</sub>, while formula derived milk can contain up to 100 micrograms/litre in supplemented formulas. Vitamin K<sub>2</sub> concentrations in human milk appear to be much lower than those of vitamin K<sub>1</sub>.
-It is estimated that there is a 0.25 to 1.7% occurrence of vitamin K deficiency bleeding in the first week of the infant's life with a prevalence of 2-10 cases per 100,000 births.<ref>{{cite journal|author=Shearer MJ|title=Vitamin K|journal=Lancet|volume=345|issue=8944|pages=229–34|year=1995|month=January|pmid=7823718|doi= 10.1016/S0140-6736(95)90227-9|url=}}</ref>  Premature babies have even lower levels of the vitamin and are at a higher risk from this deficiency.
+It is estimated that there is a 0.25 to 1.7% occurrence of vitamin K deficiency bleeding in the first week of the infant's life with a prevalence of 2-10 cases per 100,000 births.<ref>{{cite journal|author=Shearer MJ|title=Vitamin K|journal=Lancet|volume=345|issue=8944|pages=229–34|year=1995|month=January|pmid=7823718|doi= 10.1016/S0140-6736(95)90227-9 }}</ref> Premature babies have even lower levels of the vitamin and are at a higher risk from this deficiency.
-Bleeding in infants due to vitamin K deficiency can be severe, leading to hospitalizations, blood transfusions, brain damage and death.  Supplementation with vitamin K can prevent most cases of vitamin K deficiency bleeding in the newborn.  Intramuscular administration of vitamin K is more effective in preventing late vitamin K deficiency bleeding than oral administration.<ref>''Wintrobe's Clinical Hematology'', 11th Edition. J.P. Greer, Foerster J., Lukens, J.N., Rodgers, G.M., Paraskevas, F., and Glader, B., editor. Philadelphia, PA, USA: Lippincott Williams and Wilkens.</ref><ref name="pediatrics.aappublications.org">{{cite journal|author=|title=Controversies concerning vitamin K and the newborn.  American Academy of Pediatrics Committee on Fetus and Newborn|journal=Pediatrics|volume=112|issue=1 Pt 1|pages=191–2|year=2003|month=July|pmid=12837888|doi=|url=http://pediatrics.aappublications.org/cgi/pmidlookup?view=long&pmid=12837888|author1=American Academy of Pediatrics Committee on Fetus and Newborn}}</ref>
+Bleeding in infants due to vitamin K deficiency can be severe, leading to hospitalizations, blood transfusions, brain damage and death. Supplementation with vitamin K can prevent most cases of vitamin K deficiency bleeding in the newborn. Intramuscular administration of vitamin K is more effective in preventing late vitamin K deficiency bleeding than oral administration.<ref>''Wintrobe's Clinical Hematology'', 11th Edition. J.P. Greer, Foerster J., Lukens, J.N., Rodgers, G.M., Paraskevas, F., and Glader, B., editor. Philadelphia, PA, USA: Lippincott Williams and Wilkens.</ref><ref name="pediatrics.aappublications.org">{{cite journal|author=|title=Controversies concerning vitamin K and the newborn. American Academy of Pediatrics Committee on Fetus and Newborn|journal=Pediatrics|volume=112|issue=1 Pt 1|pages=191–2|year=2003|month=July|pmid=12837888|doi=|url=http://pediatrics.aappublications.org/content/112/1/191.full.pdf |author1=American Academy of Pediatrics Committee on Fetus and Newborn}}</ref>
 ===USA===
@@ Line 132: / Line 132: @@
 ===UK===
+{{unreferenced section}}
 In the UK, vitamin K is administered to newborns as either a single injection at birth or three orally administered doses given at birth and then over the baby's first month.
 ===Controversy===
-Controversy arose in the early 1990s regarding this practice when two studies were shown suggesting a relationship between [[parenteral]] administration of vitamin K and childhood cancer (14){{Verify source|date=July 2010}}{{Citation needed|date=July 2010}}.  However, poor methods and small sample sizes led to the discrediting of these studies and a review of the evidence published in 2000 by Ross and Davies found no link between the two.<ref>{{cite journal |author=McMillan DD |title=Routine administration of vitamin K to newborns |journal=Paediatr Child Health |volume=2 |issue=6 |pages=429–31 |year=1997 |doi= |url=http://www.pulsus.com/journals/abstract.jsp?sCurrPg=abstract&jnlKy=5&atlKy=105&isuKy=378&isArt=t&fromfold=}}</ref>{{Verify source|date=July 2010}}
+Controversy arose in the early 1990s regarding this practice when two studies were shown suggesting a relationship between [[parenteral]] administration of vitamin K and childhood cancer (14){{Verify source|date=July 2010}}{{Citation needed|date=July 2010}}. However, poor methods and small sample sizes led to the discrediting of these studies and a review of the evidence published in 2000 by Ross and Davies found no link between the two.<ref>{{cite journal |author=McMillan DD |title=Routine administration of vitamin K to newborns |journal=Paediatr Child Health |volume=2 |issue=6 |pages=429–31 |year=1997 |doi= |url=http://www.pulsus.com/journals/abstract.jsp?sCurrPg=abstract&jnlKy=5&atlKy=105&isuKy=378&isArt=t&fromfold=}}</ref>{{Verify source|date=July 2010}}
 ==Vitamin K and bone health==
 There is physiological and observational evidence that vitamin K plays a role in bone growth and the maintenance of bone density, but efforts to delay the onset of osteoporosis by vitamin K supplementation have proven ineffective.
-Vitamin K takes part in the post translational modification as a cofactor in γ-carboxylation of vitamin K dependant proteins (VKDPs).  VKDPs have glutamate residues (Glu).  Biophysical studies have suggested that supplemental vitamin K promotes [[Osteoblast|osteotrophic]] processes and slows [[osteoclast]]ic processes via calcium bonding.  Study of Atkins et al.<ref>{{cite journal | author = Gerald JA, Katie JW, Asiri R W, et al. | year = 2009 | title = Vitamin K promotes mineralization, osteoblast‐to‐osteocyte transition, and an anticatabolic phenotype by γ‐carboxylation‐dependent and independent mechanisms | journal = Am J Physiol Cell Physiol | volume = 297 | pages = C1358–C1367 | doi = 10.1152/ajpcell.00216.2009 | pmid = 19675304 | issue = 6}}</ref> revealed that [[phylloquinone]], [[menatetrenone]] (MK4) and [[menadione]] promote ''in vitro'' mineralisaton by human primary osteoblasts.  Other studies have shown that [[vitamin K antagonists]] (usually a class of anticoagulants) lead to early calcification of the [[epiphysis]] and epiphysial line in mice and other animals, causing seriously decreased bone growth.  This is due to defects in [[osteocalcin]] and [[matrix Gla protein]].  Their primary function is to prevent overcalcification of the bone and cartilage.  Vitamin K is important in the process of carboxylating glutamic acid (Glu) in these proteins to gamma-carboxyglutamic acid (Gla), which is necessary for their function.<ref>Drenckhahn, D. & Kugler, P (2003), "Knochengewebe".  In Benninhoff & D. Drenhahn, ''Anatomie Band'' 1:147. Munich, Germany: Urban & Fisher</ref><ref name="womentowomen">{{cite web |url= http://www.womentowomen.com/bonehealth/keynutrients-vitamink.aspx |title= Key vitamins for bone health — vitamins K1 and K2 |author= Dr. Susan E. Brown, PhD |date= |work= |publisher= womentowomen.com |accessdate=11 August 2010}}</ref>  Vitamin D is reported to regulate the OC transcription by osteoblast thereby showing that vitamin K and vitamin D work in tandem for the bone metabolism and development.  Lian and his group discovered two nucleotide substitution regions which they named "osteocalcin box" in the rat and human osteocalcin genes.<ref>{{cite journal | author = Lian J, Stewart C, Puchacz E, Mackowiak S, Shalhoub V, Collart D, Zambetti G & Stein G | year = 1989 | title = Structure of the rat osteocalcin gene and regulation of vitamin D-dependent expression | journal = Proc Natl Acad Sci | volume = 86 | pages = 1143–1147 | doi = 10.1073/pnas.86.4.1143 | pmid = 2784002 | issue = 4 | pmc = 286642}}</ref>  They found a region 600 nucleotides immediately upstream from the transcription start site that support a 10-fold stimulated transcription of the gene by 1,25-dihydroxy vitamin D.
+Vitamin K takes part in the post translational modification as a cofactor in γ-carboxylation of vitamin K dependant proteins (VKDPs). VKDPs have glutamate residues (Glu). Biophysical studies have suggested that supplemental vitamin K promotes [[Osteoblast|osteotrophic]] processes and slows [[osteoclast]]ic processes via calcium bonding. Study of Atkins et al.<ref>{{cite journal | author = Gerald JA, Katie JW, Asiri R W, et al. | year = 2009 | title = Vitamin K promotes mineralization, osteoblast‐to‐osteocyte transition, and an anticatabolic phenotype by γ‐carboxylation‐dependent and independent mechanisms | journal = Am J Physiol Cell Physiol | volume = 297 | pages = C1358–C1367 | doi = 10.1152/ajpcell.00216.2009 | pmid = 19675304 | issue = 6}}</ref> revealed that [[phylloquinone]], [[menatetrenone]] (MK4) and [[menadione]] promote ''in vitro'' mineralisaton by human primary osteoblasts. Other studies have shown that [[vitamin K antagonists]] (usually a class of anticoagulants) lead to early calcification of the [[epiphysis]] and epiphysial line in mice and other animals, causing seriously decreased bone growth. This is due to defects in [[osteocalcin]] and [[matrix Gla protein]]. Their primary function is to prevent overcalcification of the bone and cartilage. Vitamin K is important in the process of carboxylating glutamic acid (Glu) in these proteins to gamma-carboxyglutamic acid (Gla), which is necessary for their function.<ref>Drenckhahn, D. & Kugler, P (2003), "Knochengewebe". In Benninhoff & D. Drenhahn, ''Anatomie Band'' 1:147. Munich, Germany: Urban & Fisher</ref><ref name="womentowomen">{{cite web |url= http://www.womentowomen.com/bonehealth/keynutrients-vitamink.aspx |title= Key vitamins for bone health — vitamins K1 and K2 |author= Dr. Susan E. Brown, PhD |date= |work= |publisher= womentowomen.com |accessdate=11 August 2010}}</ref> Vitamin D is reported to regulate the OC transcription by osteoblast thereby showing that vitamin K and vitamin D work in tandem for the bone metabolism and development. Lian and his group discovered two nucleotide substitution regions which they named "osteocalcin box" in the rat and human osteocalcin genes.<ref>{{cite journal | author = Lian J, Stewart C, Puchacz E, Mackowiak S, Shalhoub V, Collart D, Zambetti G & Stein G | year = 1989 | title = Structure of the rat osteocalcin gene and regulation of vitamin D-dependent expression | journal = Proc Natl Acad Sci | volume = 86 | pages = 1143–1147 | doi = 10.1073/pnas.86.4.1143 | pmid = 2784002 | issue = 4 | pmc = 286642}}</ref> They found a region 600 nucleotides immediately upstream from the transcription start site that support a 10-fold stimulated transcription of the gene by 1,25-dihydroxy vitamin D.
 ===Vitamin K<sub>1</sub> and bone health===
-Data from the 1998 Nurses Health Study, an [[observational study]], indicated an inverse relationship between dietary vitamin K<sub>1</sub> and the risk of [[hip fracture]].  After being given 110 micrograms/day of vitamin K, women who consumed [[lettuce]] one or more times per day had a significantly lower risk of hip fracture than women who consumed lettuce one or fewer times per week.  In addition to this, high intakes of [[vitamin D]] but low intakes of vitamin K were suggested to pose an increased risk of hip fracture.<ref name="womentowomen" /><ref name=Kanai1997/> The Framingham Heart Study<ref>{{cite journal | author = Booth SL, Tucker K, Chen H, et al. | year = 2000 | title = Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women | journal = Am J Clin Nutr | volume = 71 | pages = 1201–1208 | pmid = 10799384 | issue = 5}}</ref> is another study that showed the similar result.  Subjects in the highest quartile of vitamin K<sub>1</sub> intake (median K<sub>1</sub> intake of 254 μg/ day) has 35% lower risk of hip fracture than those in the lowest quartile.  Comparing with the daily recommended intake (DRI) of 90 and 120 μg/ day, both the above intakes are higher than existing DRI.
+Data from the 1998 Nurses Health Study, an [[observational study]], indicated an inverse relationship between dietary vitamin K<sub>1</sub> and the risk of [[hip fracture]]. After being given 110 micrograms/day of vitamin K, women who consumed [[lettuce]] one or more times per day had a significantly lower risk of hip fracture than women who consumed lettuce one or fewer times per week. In addition to this, high intakes of [[vitamin D]] but low intakes of vitamin K were suggested to pose an increased risk of hip fracture.<ref name="womentowomen" /><ref name=Kanai1997/> The Framingham Heart Study<ref>{{cite journal | author = Booth SL, Tucker K, Chen H, et al. | year = 2000 | title = Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women | journal = Am J Clin Nutr | volume = 71 | pages = 1201–1208 | pmid = 10799384 | issue = 5}}</ref> is another study that showed the similar result. Subjects in the highest quartile of vitamin K<sub>1</sub> intake (median K<sub>1</sub> intake of 254 μg/ day) has 35% lower risk of hip fracture than those in the lowest quartile. Comparing with the daily recommended intake (DRI) of 90 and 120 μg/ day, both the above intakes are higher than existing DRI.
-In the face of this evidence, a large multicentre randomized placebo-controlled trial was performed to test the supplementation of vitamin K in post-menopausal women with osteopenia.  Despite heavy doses of vitamin K<sub>1</sub>, no differences were found in bone density between the supplemented and placebo groups.<ref>{{cite journal |doi=10.1371/journal.pmed.0050196 |pmc=2566998 |pmid=18922041 |url=http://www.ncbi.nlm.nih.gov/pubmed/18922041?dopt=Abstract |journal=PLoS Med. |title=Vitamin K Supplementation in Postmenopausal Women with Osteopenia (ECKO Trial): A Randomized Controlled Trial |first9=L |last9=Thompson |first8=R |last8=Vieth |first7=H |last7=Hu |first6=GA |last6=Colditz |first5=SL |last5=Booth |first4=H |last4=Rockett |first3=WC |last3=Willett |first2=P |volume=5 |last2=Weber |issue=10 |pages=e196 |author=Cheung, AM|year=2008 |editor1-last=Torgerson |editor1-first=David}}</ref>
+In the face of this evidence, a large multicentre randomized placebo-controlled trial was performed to test the supplementation of vitamin K in post-menopausal women with osteopenia. Despite heavy doses of vitamin K<sub>1</sub>, no differences were found in bone density between the supplemented and placebo groups.<ref>{{cite journal |doi=10.1371/journal.pmed.0050196 |pmc=2566998 |pmid=18922041 |url=http://www.ncbi.nlm.nih.gov/pubmed/18922041?dopt=Abstract |journal=PLoS Med. |title=Vitamin K Supplementation in Postmenopausal Women with Osteopenia (ECKO Trial): A Randomized Controlled Trial |first9=L |last9=Thompson |first8=R |last8=Vieth |first7=H |last7=Hu |first6=GA |last6=Colditz |first5=SL |last5=Booth |first4=H |last4=Rockett |first3=WC |last3=Willett |first2=P |volume=5 |last2=Weber |issue=10 |pages=e196 |author=Cheung, AM|year=2008 |editor1-last=Torgerson |editor1-first=David}}</ref>
 ===Vitamin K<sub>2</sub> (MK4) and bone health===
-In contrast, MK4 has been shown in numerous studies to reduce fracture risk, stop and reverse bone loss.  In Japan, MK4 in the dose of 45&nbsp;mg daily is recognized as a treatment for [[osteoporosis]].<ref name=Kanai1997>{{cite journal |doi=10.1016/S0020-7292(96)02790-7 |title=Serum vitamin K level and bone mineral density in post-menopausal women |year=1997 |last1=Kanai |first1=T |journal=International Journal of Gynecology & Obstetrics |volume=56 |pages=25}}</ref><ref>{{cite journal |pmid=9925126 |url=http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=9925126 |journal=American Journal of Clinical Nutrition |title=Vitamin K intake and hip fractures in women: a prospective study |volume=69 |issue=1 |pages=74–9 |author=Feskanich, Diane |first2=P |first3=W |first4=H |first5=S |first6=G |year=1999 |last2=Weber |last3=Willett |last4=Rockett |last5=Booth |last6=Colditz}}</ref>  MK4 has been shown to decrease fractures up to 87%.<ref name="Sato 2005"/>  In the amount of 45&nbsp;mg daily MK4 has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of [[osteoporosis]].<ref name="Iwamoto 1999 161–164"/>
+In contrast, MK4 has been shown in numerous studies to reduce fracture risk, stop and reverse bone loss. In Japan, MK4 in the dose of 45&nbsp;mg daily is recognized as a treatment for [[osteoporosis]].<ref name=Kanai1997>{{cite journal |doi=10.1016/S0020-7292(96)02790-7 |title=Serum vitamin K level and bone mineral density in post-menopausal women |year=1997 |last1=Kanai |first1=T |journal=International Journal of Gynecology & Obstetrics |volume=56 |pages=25}}</ref><ref>{{cite journal |pmid=9925126 |url=http://www.ajcn.org/content/69/1/74.full.pdf |journal=American Journal of Clinical Nutrition |title=Vitamin K intake and hip fractures in women: a prospective study |volume=69 |issue=1 |pages=74–9 |author=Feskanich, Diane |first2=P |first3=W |first4=H |first5=S |first6=G |year=1999 |last2=Weber |last3=Willett |last4=Rockett |last5=Booth |last6=Colditz}}</ref> MK4 has been shown to decrease fractures up to 87%.<ref name="Sato 2005"/> In the amount of 45&nbsp;mg daily MK4 has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of [[osteoporosis]].<ref name="Iwamoto 1999 161–164"/>
 MK4 (but not MK7 or vitamin K<sub>1</sub>) prevented bone loss and/or fractures in the following circumstances:
@@ Line 156: / Line 157: @@
 * postmenopausal osteoporosis,<ref name="Cockayne 2006 1256–1261"/><ref name="ReferenceA"/><ref name="Iwamoto 2000 546–551"/><ref name="Purwosunu 2006 230–234"/><ref name="Shiraki 2000 515–522"/><ref name="Ushiroyama 2002 211–221"/>
 * disuse from stroke,<ref name="Sato 1998 291–296"/>
-* [[Alzheimer’s disease]],<ref name="Sato 2005 61–68"/>
+* [[Alzheimer's disease]],<ref name="Sato 2005 61–68"/>
 * [[Parkinson disease]],<ref name="Sato 2002 114–118"/>
 * [[primary biliary cirrhosis]]<ref name="Nishiguchi 2001 543–545"/> and
@@ Line 162: / Line 163: @@
 ===Vitamin K<sub>2</sub> (MK7) and bone health===
-Menaquinone-7 (MK7), which is abundant in fermented soybeans (natto), has been demonstrated to stimulate osteoblastic bone formation and to inhibit osteoclastic bone resorption.<ref>{{cite journal |author=Yamaguchi M |title=Regulatory mechanism of food factors in bone metabolism and prevention of osteoporosis |journal=Yakugaku Zasshi |volume=126 |issue=11 |pages=1117–37 |year=2006 |month=November |pmid=17077614 |url=http://www.jstage.jst.go.jp/article/yakushi/126/11/126_1117/_article}}</ref> In another study, use of MK-7 caused significant elevations of serum Y-carboxylated [[osteocalcin]] concentration, a biomarker of bone formation.  MK-7 also completely inhibited a decrease in the calcium content of bone tissue by inhibiting the bone-resorbing factors [[parathyroid hormone]] and prostaglandin E<sub>2</sub>.<ref>{{cite journal |author=Tsukamoto Y |title=Studies on action of menaquinone-7 in regulation of bone metabolism and its preventive role of osteoporosis |journal=BioFactors |volume=22 |issue=1-4 |pages=5–19 |year=2004 |pmid=15630245 |doi=10.1002/biof.5520220102 |url=http://onlinelibrary.wiley.com/doi/10.1002/biof.5520220102/abstract}}</ref>
+Menaquinone-7 (MK7), which is abundant in fermented soybeans (natto), has been demonstrated to stimulate osteoblastic bone formation and to inhibit osteoclastic bone resorption.<ref>{{cite journal |author=Yamaguchi M |title=Regulatory mechanism of food factors in bone metabolism and prevention of osteoporosis |journal=Yakugaku Zasshi |volume=126 |issue=11 |pages=1117–37 |year=2006 |month=November |pmid=17077614 |url=http://www.jstage.jst.go.jp/article/yakushi/126/11/126_1117/_article}}</ref> In another study, use of MK-7 caused significant elevations of serum Y-carboxylated [[osteocalcin]] concentration, a biomarker of bone formation. MK-7 also completely inhibited a decrease in the calcium content of bone tissue by inhibiting the bone-resorbing factors [[parathyroid hormone]] and prostaglandin E<sub>2</sub>.<ref>{{cite journal |author=Tsukamoto Y |title=Studies on action of menaquinone-7 in regulation of bone metabolism and its preventive role of osteoporosis |journal=BioFactors |volume=22 |issue=1-4 |pages=5–19 |year=2004 |pmid=15630245 |doi=10.1002/biof.5520220102 |url=http://onlinelibrary.wiley.com/doi/10.1002/biof.5520220102/abstract}}</ref>
-On 19 February 2011, HSA (Singapore) approved a health supplement which contains vitamin K<sub>2</sub> (MK7) and vitamin D<sub>3</sub> for increasing bone mineral density.<ref>http://iabpi.com/fitness-natto-essence Ref. no. HPRG (HSU) 2011-02-0016</ref>
+On 19 February 2011, HSA (Singapore) approved a health supplement which contains vitamin K<sub>2</sub> (MK7) and vitamin D<sub>3</sub> for increasing bone mineral density.<ref>[http://iabpi.com/fitness-natto-essence Ref. no. HPRG (HSU) 2011-02-0016]</ref>
 ==Vitamin K and Alzheimer's disease==
-Research into the antioxidant properties of vitamin K indicates that the concentration of vitamin K is lower in the circulation of carriers of the [[Apolipoprotein E|APOE4]] gene, and recent studies have shown its ability to inhibit [[Neuron|nerve cell]] death due to [[oxidative stress]].  It has been hypothesized that vitamin K may reduce neuronal damage and that supplementation may hold benefits to treating [[Alzheimer's disease]], although more research is necessary in this area.<ref>{{cite journal |doi=10.1054/mehy.2001.1307 |pmid=11461163 |year=2001 |author1=Allison |title=The possible role of vitamin K deficiency in the pathogenesis of Alzheimer's disease and in augmenting brain damage associated with cardiovascular disease |volume=57 |issue=2 |pages=151–5 |journal=Medical hypotheses}}</ref>
+Research into the antioxidant properties of vitamin K indicates that the concentration of vitamin K is lower in the circulation of carriers of the [[Apolipoprotein E|APOE4]] gene, and recent studies have shown its ability to inhibit [[Neuron|nerve cell]] death due to [[oxidative stress]]. It has been hypothesized that vitamin K may reduce neuronal damage and that supplementation may hold benefits to treating [[Alzheimer's disease]], although more research is necessary in this area.<ref>{{cite journal |doi=10.1054/mehy.2001.1307 |pmid=11461163 |year=2001 |author1=Allison |title=The possible role of vitamin K deficiency in the pathogenesis of Alzheimer's disease and in augmenting brain damage associated with cardiovascular disease |volume=57 |issue=2 |pages=151–5 |journal=Medical hypotheses}}</ref>
 ==Vitamin K used topically==
@@ Line 172: / Line 173: @@
 ==Vitamin K and cancer==
-While researchers in Japan were studying the role of vitamin K<sub>2</sub> as the menaquinone-4 (MK-4) form in the prevention of bone loss in females with liver disease, they discovered another possible effect.  This two year study which involved 21 women with viral [[liver cirrhosis]] found that women in the supplement group were 90% less likely to develop [[liver cancer]].<ref>"[http://www.nutraingredients.com/Research/Vitamin-K-found-to-protect-against-liver-cancer Vitamin K Found to Protect Against Liver Cancer]"</ref><ref>{{cite journal|author=Saxena SP, Israels ED, Israels LG|title=Novel vitamin K-dependent pathways regulating cell survival|journal=Apoptosis|volume=6|issue=1–2|pages=57–68|year=2001|pmid=11321042|doi=10.1023/A:1009624111275|url=}}</ref>  A German study performed on men with [[prostate cancer]] found a significant inverse relationship between vitamin K<sub>2</sub> consumption and advanced prostate cancer.<ref>{{cite journal|author=Nimptsch K, Rohrmann S, Linseisen J|title=Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition. (EPIC-Heidelberg)|journal=Am. J. Clin. Nutr.|volume=87|issue=4|pages=985–92|year=2008|month=April|pmid=18400723|doi=|url=http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=18400723}}</ref>
+While researchers in Japan were studying the role of vitamin K<sub>2</sub> as the menaquinone-4 (MK-4) form in the prevention of bone loss in females with liver disease, they discovered another possible effect. This two year study which involved 21 women with viral [[liver cirrhosis]] found that women in the supplement group were 90% less likely to develop [[liver cancer]].<ref>"[http://www.nutraingredients.com/Research/Vitamin-K-found-to-protect-against-liver-cancer Vitamin K Found to Protect Against Liver Cancer]"</ref><ref>{{cite journal|author=Saxena SP, Israels ED, Israels LG|title=Novel vitamin K-dependent pathways regulating cell survival|journal=Apoptosis|volume=6|issue=1–2|pages=57–68|year=2001|pmid=11321042|doi=10.1023/A:1009624111275 }}</ref> A German study performed on men with [[prostate cancer]] found a significant inverse relationship between vitamin K<sub>2</sub> consumption and advanced prostate cancer.<ref>{{cite journal|author=Nimptsch K, Rohrmann S, Linseisen J|title=Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition. (EPIC-Heidelberg)|journal=Am. J. Clin. Nutr.|volume=87|issue=4|pages=985–92|year=2008|month=April|pmid=18400723|url=http://www.ajcn.org/content/87/4/985.full.pdf }}</ref>
 ==Vitamin K as antidote for poisoning by 4-hydroxcoumarin drugs==
-Vitamin K is a true [[antidote]] for poisoning by [[4-hydroxycoumarin]] anticoagulant drugs (sometimes loosely referred to as [[coumarin]]s).  These include the pharmaceutical [[warfarin]], and also anticoagulant-mechanism poisons such as [[bromadiolone]], which are commonly found in [[rodenticides]].  4-Hydroxycoumarin drugs possess [[anticoagulant|anticoagulatory]] and rodenticidal properties because they inhibit vitamin K-dependent synthesis of some clotting factors by the liver.  Death is usually a result of internal hemorrhage.  Treatment usually consists of repeated intravenous doses of vitamin K, followed by doses in pill form for a period of at least two weeks, though possibly up to 2 months, afterwards (in the case of the more potent 4-hydoxycoumarins used as rodenticides).  If caught early, prognosis is good, even when great amounts of the drug or poison are ingested.
+Vitamin K is a true [[antidote]] for poisoning by [[4-hydroxycoumarin]] anticoagulant drugs (sometimes loosely referred to as [[coumarin]]s). These include the pharmaceutical [[warfarin]], and also anticoagulant-mechanism poisons such as [[bromadiolone]], which are commonly found in [[rodenticides]]. 4-Hydroxycoumarin drugs possess [[anticoagulant|anticoagulatory]] and rodenticidal properties because they inhibit vitamin K-dependent synthesis of some clotting factors by the liver. Death is usually a result of internal hemorrhage. Treatment usually consists of repeated intravenous doses of vitamin K, followed by doses in pill form for a period of at least two weeks, though possibly up to 2 months, afterwards (in the case of the more potent 4-hydoxycoumarins used as rodenticides). If caught early, prognosis is good, even when great amounts of the drug or poison are ingested.
 ==History of discovery==
-In 1929, [[Denmark|Danish]] scientist [[Carl Peter Henrik Dam|Henrik Dam]] investigated the role of [[cholesterol]] by feeding chickens a cholesterol-depleted diet.<ref name="Dam"/>  After several weeks, the animals developed hemorrhages and started bleeding.  These defects could not be restored by adding purified cholesterol to the diet.  It appeared that—together with the cholesterol—a second compound had been extracted from the food, and this compound was called the coagulation vitamin.  The new vitamin received the letter K because the initial discoveries were reported in a German journal, in which it was designated as ''Koagulationsvitamin''.  [[Edward Adelbert Doisy]] of [[Saint Louis University]] did much of the research that led to the discovery of the structure and chemical nature of vitamin K.<ref name="MacCorquodale">{{cite journal|last=MacCorquodale|first=D. W.|authorlink=|coauthors=Binkley, S. B.; Thayer, S. A.; Doisy, E. A.|year=1939|title=On the constitution of Vitamin K1|journal=Journal of the American Chemical Society|volume=61|issue=7|pages=1928–1929|id=|url=|accessdate=|quote=|doi=10.1021/ja01876a510 }}
+In 1929, [[Denmark|Danish]] scientist [[Carl Peter Henrik Dam|Henrik Dam]] investigated the role of [[cholesterol]] by feeding chickens a cholesterol-depleted diet.<ref name="Dam"/> After several weeks, the animals developed hemorrhages and started bleeding. These defects could not be restored by adding purified cholesterol to the diet. It appeared that—together with the cholesterol—a second compound had been extracted from the food, and this compound was called the coagulation vitamin. The new vitamin received the letter K because the initial discoveries were reported in a German journal, in which it was designated as ''Koagulationsvitamin''. [[Edward Adelbert Doisy]] of [[Saint Louis University]] did much of the research that led to the discovery of the structure and chemical nature of vitamin K.<ref name="MacCorquodale">{{cite journal|last=MacCorquodale|first=D. W.|authorlink=|coauthors=Binkley, S. B.; Thayer, S. A.; Doisy, E. A.|year=1939|title=On the constitution of Vitamin K1|journal=Journal of the American Chemical Society|volume=61|issue=7|pages=1928–1929|id=|url=|accessdate=|quote=|doi=10.1021/ja01876a510 }}
-</ref>  Dam and Doisy shared the 1943 [[Nobel Prize]] for medicine for their work on vitamin K (K<sub>1</sub> and K<sub>2</sub>) published in 1939.  Several laboratories synthesized the compound(s) in 1939.<ref name="Fieser">{{cite journal|last=Fieser|first=L. F.|authorlink=|coauthors=|year=1939|title=Synthesis of Vitamin K1|journal=Journal of the American Chemical Society|volume=61|issue=12|pages=3467–3475|id=|url=|accessdate=|quote=|doi=10.1021/ja01267a072 }}</ref>
+</ref> Dam and Doisy shared the 1943 [[Nobel Prize]] for medicine for their work on vitamin K (K<sub>1</sub> and K<sub>2</sub>) published in 1939. Several laboratories synthesized the compound(s) in 1939.<ref name="Fieser">{{cite journal|last=Fieser|first=L. F.|authorlink=|coauthors=|year=1939|title=Synthesis of Vitamin K1|journal=Journal of the American Chemical Society|volume=61|issue=12|pages=3467–3475|id=|url=|accessdate=|quote=|doi=10.1021/ja01267a072 }}</ref>
-For several decades the vitamin K-deficient chick model was the only method of quantifying vitamin K in various foods: the chicks were made vitamin K-deficient and subsequently fed with known amounts of vitamin K-containing food.  The extent to which blood coagulation was restored by the diet was taken as a measure for its vitamin K content.  Three groups of physicians independently found this: Biochemical Institute, University of Copenhagen (Dam and [[Johannes Glavind]]), [[University of Iowa]] Department of Pathology ([[Emory Warner]], [[Kenneth Brinkhous]], and [[Harry Pratt Smith]]), and the [[Mayo Clinic]] ([[Hugh Butt]], [[Albert Snell]], and [[Arnold Osterberg]]).<ref name="dam-nobel">Dam, Henrik (December 12, 1946). [http://nobelprize.org/nobel_prizes/medicine/laureates/1943/dam-lecture.pdf The discovery of vitamin K, its biological functions and therapeutical application.] Nobel Prize lecture</ref>
+For several decades the vitamin K-deficient chick model was the only method of quantifying vitamin K in various foods: the chicks were made vitamin K-deficient and subsequently fed with known amounts of vitamin K-containing food. The extent to which blood coagulation was restored by the diet was taken as a measure for its vitamin K content. Three groups of physicians independently found this: Biochemical Institute, University of Copenhagen (Dam and [[Johannes Glavind]]), [[University of Iowa]] Department of Pathology ([[Emory Warner]], [[Kenneth Brinkhous]], and [[Harry Pratt Smith]]), and the [[Mayo Clinic]] ([[Hugh Butt]], [[Albert Snell]], and [[Arnold Osterberg]]).<ref name="dam-nobel">Dam, Henrik (December 12, 1946). [http://nobelprize.org/nobel_prizes/medicine/laureates/1943/dam-lecture.pdf The discovery of vitamin K, its biological functions and therapeutical application.] Nobel Prize lecture</ref>
-The first published report of successful treatment with vitamin K of life-threatening hemorrhage in a jaundiced patient with prothrombin deficiency was made in 1938 by Smith, Warner, and Brinkhous.<ref name="Warner">{{cite journal|last=Warner|first=E. D.|authorlink=|coauthors=Brinkhous, K. M.; Smith, H. P.|year=1938|title=|journal=Proceedings of the Society of Experimental Biology and Medicine|volume=37|issue=|pages=628|id=|url=|accessdate=|quote= }}</ref>
+The first published report of successful treatment with vitamin K of life-threatening hemorrhage in a jaundiced patient with prothrombin deficiency was made in 1938 by Smith, Warner, and Brinkhous.<ref name="Warner">{{cite journal|last=Warner|first=E. D.|authorlink=|coauthors=Brinkhous, K. M.; Smith, H. P.|year=1938|title=|journal=Proceedings of the Society of Experimental Biology and Medicine|volume=37|issue=|pages=628|id= }}</ref>
-The precise function of vitamin K was not discovered until 1974, when three laboratories (Stenflo ''et al.'',<ref name=Stenflo>{{cite journal|author=Stenflo J, Fernlund P, Egan W, Roepstorff P|title=Vitamin K Dependent Modifications of Glutamic Acid Residues in Prothrombin|journal=Proc. Natl. Acad. Sci. U.S.A.|volume=71|issue=7|pages=2730–3|year=1974|month=July|pmid=4528109|pmc=388542|doi= 10.1073/pnas.71.7.2730|url=}}</ref> Nelsestuen ''et al.'',<ref name=Nelsestuen>{{cite journal|author=Nelsestuen GL, Zytkovicz TH, Howard JB|title=The mode of action of vitamin K.  Identification of gamma-carboxyglutamic acid as a component of prothrombin|journal=J. Biol. Chem.|volume=249|issue=19|pages=6347–50|year=1974|month=October|pmid=4214105|doi=|url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=4214105}}</ref> and Magnusson ''et al.''<ref name=Magnusson>{{cite journal|author=Magnusson S, Sottrup-Jensen L, Petersen TE, Morris HR, Dell A|title=Primary structure of the vitamin K-dependent part of prothrombin|journal=FEBS Lett.|volume=44|issue=2|pages=189–93|year=1974|month=August|pmid=4472513|doi=10.1016/0014-5793(74)80723-4|url=}}</ref>) isolated the vitamin K-dependent coagulation factor [[prothrombin|prothrombin (Factor II)]] from cows that received a high dose of a vitamin K antagonist, [[warfarin]].  It was shown that while [[warfarin]]-treated cows had a form of [[prothrombin]] that contained 10 [[glutamate]] [[amino acid]] residues near the amino terminus of this protein, the normal (untreated) cows contained 10 unusual residues that were chemically identified as gamma-carboxyglutamate, or Gla.  The extra carboxyl group in Gla made clear that vitamin K plays a role in a carboxylation reaction during which Glu is converted into Gla.
+The precise function of vitamin K was not discovered until 1974, when three laboratories (Stenflo ''et al.'',<ref name=Stenflo>{{cite journal|author=Stenflo J, Fernlund P, Egan W, Roepstorff P|title=Vitamin K Dependent Modifications of Glutamic Acid Residues in Prothrombin|journal=Proc. Natl. Acad. Sci. U.S.A.|volume=71|issue=7|pages=2730–3|year=1974|month=July|pmid=4528109|pmc=388542|doi= 10.1073/pnas.71.7.2730 }}</ref> Nelsestuen ''et al.'',<ref name=Nelsestuen>{{cite journal|author=Nelsestuen GL, Zytkovicz TH, Howard JB|title=The mode of action of vitamin K. Identification of gamma-carboxyglutamic acid as a component of prothrombin|journal=J. Biol. Chem.|volume=249|issue=19|pages=6347–50|year=1974|month=October|pmid=4214105|doi=|url=http://www.jbc.org/content/249/19/6347.full.pdf }}</ref> and Magnusson ''et al.''<ref name=Magnusson>{{cite journal|author=Magnusson S, Sottrup-Jensen L, Petersen TE, Morris HR, Dell A|title=Primary structure of the vitamin K-dependent part of prothrombin|journal=FEBS Lett.|volume=44|issue=2|pages=189–93|year=1974|month=August|pmid=4472513|doi=10.1016/0014-5793(74)80723-4 }}</ref>) isolated the vitamin K-dependent coagulation factor [[prothrombin|prothrombin (Factor II)]] from cows that received a high dose of a vitamin K antagonist, [[warfarin]]. It was shown that while [[warfarin]]-treated cows had a form of [[prothrombin]] that contained 10 [[glutamate]] [[amino acid]] residues near the amino terminus of this protein, the normal (untreated) cows contained 10 unusual residues that were chemically identified as gamma-carboxyglutamate, or Gla. The extra carboxyl group in Gla made clear that vitamin K plays a role in a carboxylation reaction during which Glu is converted into Gla.
 The biochemistry of how vitamin K is used to convert Glu to Gla has been elucidated over the past thirty years in academic laboratories throughout the world.
 ==References==
-{{Reflist|2}}
+{{Reflist|30em}}
 ==External links==
@@ Line 205: / Line 206: @@
 {{Antihemorrhagics}}
+[[Category:Antihemorrhagics]]
 [[Category:Naphthoquinones]]
 [[Category:Terpenes and terpenoids]]
-[[Category:Antihemorrhagics]]
 [[Category:Vitamers]]
 [[Category:Vitamin K]]