Skeletal formula and ball-and-stick model of the cation in thiamine
|Synonyms||Vitamin B1, aneurine, thiamin|
|by mouth, IV, IM|
|Bioavailability||3.7% to 5.3%|
|Chemical and physical data|
|Molar mass||265.35 g mol−1|
|3D model (JSmol)|
Thiamine, also known as thiamin or vitamin B1, is a vitamin found in food, and manufactured as a dietary supplement and medication. Food sources of thiamine include whole grains, legumes, and some meats and fish. Grain processing removes much of the thiamine content, so in many countries cereals and flours are enriched with thiamine. Supplements and medications are available to treat and prevent thiamine deficiency and disorders that result from it, including beriberi and Wernicke encephalopathy. Other uses include the treatment of maple syrup urine disease and Leigh syndrome. They are typically taken by mouth, but may also be given by intravenous or intramuscular injection.
Thiamine supplements are generally well tolerated. Allergic reactions, including anaphylaxis, may occur when repeated doses are given by injection. Thiamine is in the B complex family. It is an essential micronutrient, which cannot be made in the body. Thiamine is required for metabolism including that of glucose, amino acids, and lipids.
Thiamine was discovered in 1897, was the first vitamin to be isolated in 1926, and was first made in 1936. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Thiamine is available as a generic medication, and as an over-the-counter drug. The wholesale cost in the developing world (as of 2016) is about 2.17 USD per one gm vial. In the United States a month's supply of a multivitamin containing thiamine is less than 25 USD.
- 1 Medical uses
- 2 Adverse effects
- 3 Chemistry
- 4 Biosynthesis
- 5 Nutrition
- 6 Absorption and transport
- 7 Function
- 8 History
- 9 See also
- 10 References
- 11 External links
Thiamine is used to treat thiamine deficiency which when severe can prove fatal. In less severe cases, non-specific signs include malaise, weight loss, irritability and confusion. Well-known disorders caused by thiamine deficiency include beriberi, Wernicke-Korsakoff syndrome, and optic neuropathy. In Western countries, thiamine deficiency is seen mainly in chronic alcoholism. Also at risk are older adults, persons with HIV/AIDS or diabetes, and persons who have had bariatric surgery. Varying degrees of thiamine deficiency have been associated with the long-term use of high doses of diuretics, particularly furosemide in the treatment of heart failure. Thiamine deficiency is often present in alcohol misuse disorder.
Thiamine is a colorless organosulfur compound with a chemical formula C12H17N4OS. Its structure consists of an aminopyrimidine and a thiazolium ring linked by a methylene bridge. The thiazole is substituted with methyl and hydroxyethyl side chains. Thiamine is soluble in water, methanol, and glycerol and practically insoluble in less polar organic solvents. It is stable at acidic pH, but is unstable in alkaline solutions. Thiamine, which is a persistent carbene, is used by enzymes to catalyze benzoin condensations in vivo. Thiamine is unstable to heat, but stable during frozen storage. It is unstable when exposed to ultraviolet light and gamma irradiation. Thiamine reacts strongly in Maillard-type reactions.
Complex thiamine biosynthesis occurs in bacteria, some protozoans, plants, and fungi. The thiazole and pyrimidine moieties are biosynthesized separately and then combined to form thiamine monophosphate (ThMP) by the action of thiamine-phosphate synthase (EC188.8.131.52). The biosynthetic pathways may differ among organisms. In E. coli and other enterobacteriaceae, ThMP may be phosphorylated to the cofactor thiamine diphospate (ThDP) by a thiamine-phosphate kinase (ThMP + ATP → ThDP + ADP, EC 184.108.40.206). In most bacteria and in eukaryotes, ThMP is hydrolyzed to thiamine, which may then be pyrophosphorylated to ThDP by thiamine diphosphokinase (thiamine + ATP → ThDP + AMP, EC 220.127.116.11).
The biosynthetic pathways are regulated by riboswitches. If there is sufficient thiamine present in the cell then the thiamine binds to the mRNAs for the enzymes that are required in the pathway and prevents their translation. If there is no thiamine present then there is no inhibition, and the enzymes required for the biosynthesis are produced. The specific riboswitch, the TPP riboswitch (or ThDP), is the only riboswitch identified in both eukaryotic and prokaryotic organisms.
Occurrence in foods
The salt thiamine mononitrate, rather than thiamine hydrochloride, is used for food fortification, as the mononitrate is more stable, and does not absorb water from natural humidity (is non-hygroscopic), whereas thiamine hydrochloride is hygroscopic. When thiamine mononitrate dissolves in water, it releases nitrate (about 19% of its weight) and is thereafter absorbed as the thiamine cation.
|Age group||RDA (mg/day)||Tolerable upper intake level|
|Infants 0–6 months||0.2*||ND|
|Infants 6–12 months||0.3*|
|Females 14–18 years||1.0|
|Males 14+ years||1.2|
|Females 19+ years||1.1|
|Pregnant/lactating females 14–50||1.4|
|* Adequate intake for infants, as an RDA has yet to be established|
|European Food Safety Authority|
|Age group||Adequate Intake (mg/MJ)||Tolerable upper limit|
|All persons 7 months+||0.1||ND|
In the U.S. the Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for thiamine were updated in 1998, by the Institute of Medicine now known as the National Academy of Medicine (NAM).
The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL defined the same as in United States. For women (including those pregnant or lactating), men and children the PRI is 0.1 mg thiamine per megajoule (MJ) of energy consumed. As the conversion is 1 MJ = 238.8 kcal, an adult consuming 2388 calories should be consuming 1.0 mg thiamine. This is slightly lower than the U.S. RDA. The EFSA reviewed the same safety question and also reached the conclusion that there was not sufficient evidence to set a UL for thiamine.
For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percentage of Daily Value (%DV). For thiamine labeling purposes 100% of the Daily Value was 1.5 mg, but as of May 27, 2016 it was revised to 1.2 mg to bring it into agreement with the RDA. A table of the old and new adult Daily Values is provided at Reference Daily Intake. The original deadline to be in compliance was July 28, 2018, but on September 29, 2017 the FDA released a proposed rule that extended the deadline to January 1, 2020 for large companies and January 1, 2021 for small companies.
Thiamine in foods can be degraded in a variety of ways. Sulfites, which are added to foods usually as a preservative, will attack thiamine at the methylene bridge in the structure, cleaving the pyrimidine ring from the thiazole ring. The rate of this reaction is increased under acidic conditions. Thiamine is degraded by thermolabile thiaminases (present in raw fish and shellfish). Some thiaminases are produced by bacteria. Bacterial thiaminases are cell surface enzymes that must dissociate from the membrane before being activated; the dissociation can occur in ruminants under acidotic conditions. Rumen bacteria also reduce sulfate to sulfite, therefore high dietary intakes of sulfate can have thiamine-antagonistic activities.
Plant thiamine antagonists are heat-stable and occur as both the ortho- and para-hydroxyphenols. Some examples of these antagonists are caffeic acid, chlorogenic acid, and tannic acid. These compounds interact with the thiamine to oxidize the thiazole ring, thus rendering it unable to be absorbed. Two flavonoids, quercetin and rutin, have also been implicated as thiamine antagonists.
Refining grain removes its bran and germ, and thus subtracts its naturally occurring vitamins and minerals. In the United States, B-vitamin deficiencies became common in the first half of the 20th century due to white flour consumption. The American Medical Association successfully lobbied for restoring these vitamins by enrichment of grain, which began in the US in 1939. The UK followed in 1940 and Denmark in 1953. As of 2016, about 85 countries had passed legislation mandating fortification of wheat flour with at least some nutrients, and 28% of industrially milled flour was fortified, often with thiamine and other B vitamins.
Absorption and transport
Thiamine is released by the action of phosphatase and pyrophosphatase in the upper small intestine. At low concentrations, the process is carrier-mediated. At higher concentrations, absorption also occurs via passive diffusion. Active transport is greatest in the jejunum and ileum, but it can be inhibited by alcohol consumption or by folate deficiency. Decline in thiamine absorption occurs at intakes above 5 mg/day. On the serosal side of the intestine, discharge of the vitamin by those cells is dependent on Na+-dependent ATPase.
Bound to serum proteins
The majority of thiamine in serum is bound to proteins, mainly albumin. Approximately 90% of total thiamine in blood is in erythrocytes. A specific binding protein called thiamine-binding protein (TBP) has been identified in rat serum and is believed to be a hormone-regulated carrier protein important for tissue distribution of thiamine.
Uptake of thiamine by cells of the blood and other tissues occurs via active transport and passive diffusion. About 80% of intracellular thiamine is phosphorylated and most is bound to proteins. In some tissues, thiamine uptake and secretion appears to be mediated by a soluble thiamine transporter that is dependent on Na+ and a transcellular proton gradient.
Human storage of thiamine is about 25 to 30 mg, with the greatest concentrations in skeletal muscle, heart, brain, liver, and kidneys. ThMP and free (unphosphorylated) thiamine is present in plasma, milk, cerebrospinal fluid, and, it is presumed, all extracellular fluid. Unlike the highly phosphorylated forms of thiamine, ThMP and free thiamine are capable of crossing cell membranes. Thiamine contents in human tissues are less than those of other species.
Thiamine and its acid metabolites (2-methyl-4-amino-5-pyrimidine carboxylic acid, 4-methyl-thiazole-5-acetic acid, and thiamine acetic acid) are excreted principally in the urine.
Its phosphate derivatives are involved in many cellular processes. The best-characterized form is thiamine pyrophosphate (TPP), a coenzyme in the catabolism of sugars and amino acids. In yeast, TPP is also required in the first step of alcoholic fermentation. All organisms use thiamine, but it is made only in bacteria, fungi, and plants. Animals must obtain it from their diet, and thus, for humans, it is an essential nutrient. Insufficient intake in birds produces a characteristic polyneuritis.
Thiamine is usually considered as the transport form of the vitamin. There are five known natural thiamine phosphate derivatives: thiamine monophosphate (ThMP), thiamine diphosphate (ThDP), also sometimes called thiamine pyrophosphate (TPP), thiamine triphosphate (ThTP), and the recently discovered adenosine thiamine triphosphate (AThTP), and adenosine thiamine diphosphate (AThDP). While the coenzyme role of thiamine diphosphate is well-known and extensively characterized, the non-coenzyme action of thiamine and derivatives may be realized through binding to a number of recently identified proteins which do not use the catalytic action of thiamine diphosphate 
No physiological role is known for thiamin monophosphate (ThMP); however, the diphosphate is physiologically relevant. The synthesis of thiamine diphosphate (ThDP), also known as thiamine pyrophosphate (TPP) or cocarboxylase, is catalyzed by an enzyme called thiamine diphosphokinase according to the reaction thiamine + ATP → ThDP + AMP (EC 18.104.22.168). ThDP is a coenzyme for several enzymes that catalyze the transfer of two-carbon units and in particular the dehydrogenation (decarboxylation and subsequent conjugation with coenzyme A) of 2-oxoacids (alpha-keto acids). Examples include:
- Present in most species
- Present in some species:
The enzymes transketolase, pyruvate dehydrogenase (PDH), and 2-oxoglutarate dehydrogenase (OGDH) are all important in carbohydrate metabolism. The cytosolic enzyme transketolase is a key player in the pentose phosphate pathway, a major route for the biosynthesis of the pentose sugars deoxyribose and ribose. The mitochondrial PDH and OGDH are part of biochemical pathways that result in the generation of adenosine triphosphate (ATP), which is a major form of energy for the cell. PDH links glycolysis to the citric acid cycle, while the reaction catalyzed by OGDH is a rate-limiting step in the citric acid cycle. In the nervous system, PDH is also involved in the production of acetylcholine, a neurotransmitter, and for myelin synthesis.
Thiamine triphosphate (ThTP) was long considered a specific neuroactive form of thiamine. However, recently it was shown that ThTP exists in bacteria, fungi, plants and animals suggesting a much more general cellular role. In particular in E. coli, it seems to play a role in response to amino acid starvation.
Adenosine thiamine triphosphate
Adenosine thiamine triphosphate (AThTP) or thiaminylated adenosine triphosphate has recently been discovered in Escherichia coli, where it accumulates as a result of carbon starvation. In E. coli, AThTP may account for up to 20% of total thiamine. It also exists in lesser amounts in yeast, roots of higher plants and animal tissue.
Adenosine thiamine diphosphate
In 1884, Takaki Kanehiro (1849–1920), a surgeon general in the Japanese navy, rejected the previous germ theory for beriberi and hypothesized that the disease was due to insufficiencies in the diet instead. Switching diets on a navy ship, he discovered that replacing a diet of white rice only with one also containing barley, meat, milk, bread, and vegetables, nearly eliminated beriberi on a nine-month sea voyage. However, Takaki had added many foods to the successful diet and he incorrectly attributed the benefit to increased nitrogen intake, as vitamins were unknown substances at the time. The Navy was not convinced of the need for so expensive a program of dietary improvement, and many men continued to die of beriberi, even during the Russo-Japanese war of 1904–5. Not until 1905, after the anti-beriberi factor had been discovered in rice bran (removed by polishing into white rice) and in barley bran, was Takaki's experiment rewarded by making him a baron in the Japanese peerage system, after which he was affectionately called "Barley Baron".
The specific connection to grain was made in 1897 by Christiaan Eijkman (1858–1930), a military doctor in the Dutch Indies, who discovered that fowl fed on a diet of cooked, polished rice developed paralysis, which could be reversed by discontinuing rice polishing. He attributed beriberi to the high levels of starch in rice being toxic. He believed that the toxicity was countered in a compound present in the rice polishings. An associate, Gerrit Grijns (1865–1944), correctly interpreted the connection between excessive consumption of polished rice and beriberi in 1901: He concluded that rice contains an essential nutrient in the outer layers of the grain that is removed by polishing. Eijkman was eventually awarded the Nobel Prize in Physiology and Medicine in 1929, because his observations led to the discovery of vitamins.
In 1910 a Japanese scientist Umetaro Suzuki first isolated the compound which he described as aberic acid. In translation from the Japanese paper in which it was claimed to be a new finding this claim was omitted. In 1911 a Polish biochemist Casimir Funk isolated the antineuritic substance from rice bran (the modern thiamine) that he called a "vitamine" (on account of its containing an amino group. However, Funk did not completely characterize its chemical structure. Dutch chemists, Barend Coenraad Petrus Jansen (1884–1962) and his closest collaborator Willem Frederik Donath (1889–1957), went on to isolate and crystallize the active agent in 1926, whose structure was determined by Robert Runnels Williams (1886–1965), a US chemist, in 1934. Thiamine was named by the Williams team as "thio" or “sulfur-containing vitamin”, with the term "vitamin" coming indirectly, by way of Funk, from the amine group of thiamine itself (by this time in 1936, vitamins were known to not always be amines, for example, vitamin C). Thiamine was synthesized in 1936 by the Williams group.
Thiamine was first named "aneurin" (for anti-neuritic vitamin). Sir Rudolph Peters, in Oxford, introduced thiamine-deprived pigeons as a model for understanding how thiamine deficiency can lead to the pathological-physiological symptoms of beriberi. Indeed, feeding the pigeons upon polished rice leads to an easily recognizable behavior of head retraction, a condition called opisthotonos. If not treated, the animals died after a few days. Administration of thiamine at the stage of opisthotonos led to a complete cure within 30 minutes. As no morphological modifications were observed in the brain of the pigeons before and after treatment with thiamine, Peters introduced the concept of a biochemical lesion.
When Lohman and Schuster (1937) showed that the diphosphorylated thiamine derivative (thiamine diphosphate, ThDP) was a cofactor required for the oxydative decarboxylation of pyruvate, a reaction now known to be catalyzed by pyruvate dehydrogenase, the mechanism of action of thiamine in the cellular metabolism seemed to be elucidated. At present, this view seems to be oversimplified: pyruvate dehydrogenase is only one of several enzymes requiring thiamine diphosphate as a cofactor; moreover, other thiamine phosphate derivatives have been discovered since then, and they may also contribute to the symptoms observed during thiamine deficiency. Lastly, the mechanism by which the thiamine moiety of ThDP exerts its coenzyme function by proton substitution on position 2 of the thiazole ring was elucidated by Ronald Breslow in 1958.
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