Biotin

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Biotin[1]
Skeletal formula of biotin
Ball-and-stick model of the Biotin molecule
Names
IUPAC name
5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanoic acid
Other names
Vitamin B7; Vitamin H; Coenzyme R; Biopeiderm
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.363
KEGG
UNII
Properties
C10H16N2O3S
Molar mass 244.31 g·mol−1
Appearance White crystalline needles
Melting point 232 to 233 °C (450 to 451 °F; 505 to 506 K)
22 mg/100 mL
Pharmacology
A11HA05 (WHO)
Hazards
NFPA 704
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g., canola oilHealth code 1: Exposure would cause irritation but only minor residual injury. E.g., turpentineReactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogenSpecial hazards (white): no codeNFPA 704 four-colored diamond
1
1
0
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☑Y verify (what is ☑Y‹See TfM›☒N ?)
Infobox references

Biotin is a water-soluble B vitamin,[2] also called vitamin B7 and formerly known as vitamin H or coenzyme R.[3] It is involved in a wide range of metabolic processes, both in humans and in other organisms, primarily related to the utilization of fats, carbohydrates, and amino acids.

Biotin deficiency can be caused by inadequate dietary intake or inheritance of one or more inborn genetic disorders that affect biotin metabolism.[2][3] Subclinical deficiency can cause mild symptoms, such as hair thinning or skin rash typically on the face.[2] Neonatal screening for biotinidase deficiency began in the United States in 1984, with many countries testing for this disorder at birth. Individuals born prior to 1984 are unlikely to have been screened, obscuring the true prevalence of the disorder.[2]

General[edit]

Dean Burk, American biochemist working on isolation of biotin.

Biotin is an important component of enzymes involved in metabolizing fats and carbohydrates, influencing cell growth, and affecting amino acids involved in protein synthesis.[2][3] Biotin assists in various metabolic reactions involving the transfer of carbon dioxide. It may also be helpful in maintaining a steady blood sugar level. Biotin is often recommended as a dietary supplement for strengthening hair and nails, though scientific data supporting these outcomes are weak.[3] Nevertheless, biotin is found in many cosmetics and health products for the hair and skin.[4][5]

Biotin deficiency is rare.[2] The amounts needed are small, a wide range of foods contain biotin, and intestinal bacteria synthesize biotin, which is then absorbed by the host animal. For that reason, statutory agencies in various countries, for example the USA[6] and Australia,[7] have not formally established a recommended daily intake of biotin. Instead, an adequate intake (AI) is identified based on the theory that average intake meets needs. Future research could result in biotin AIs with EARs and RDAs (see Dietary Reference Intake section).

A number of rare metabolic disorders exist in which an individual's metabolism of biotin is abnormal, such as deficiency in the holocarboxylase synthetase enzyme which covalently links biotin onto the carboxylase, where the biotin acts as a cofactor.[8]

Biotin is composed of a ureido ring fused with a tetrahydrothiophene ring. The ureido ring acts as the carbon dioxide carrier in carboxylation reactions.[9] A valeric acid substituent is attached to one of the carbon atoms of the tetrahydrothiophene ring. Biotin is a coenzyme for multiple carboxylase enzymes, which are involved in the digestion of carbohydrates, synthesis of fatty acids, and gluconeogenesis.[3] Biotin is also required for the catabolism and utilization of the three branched-chain amino acids: leucine, isoleucine, and valine.

Discovery[edit]

In 1916, W.G. Bateman observed that a diet high in raw egg whites caused toxic symptoms in dogs, cats, rabbits, and humans[10]. This study was followed in 1927 by Margaret Averil Boas, who found that a diet of only egg whites caused dermatitis, alopecia, and loss of muscular coordination in rats. [11] She called this syndrome "egg white injury". In 1939, six years after he began investigating the cause of egg white injury, Hungarian scientist Paul Gyorgy confirmed the existence of a protecting factor, which he called vitamin H.[12] By this point, many independent groups had isolated biotin. In 1936, Kögl and Tönnis isolated a growth factor from egg yolk they called bios.[13] After experiments performed with yeast and Rhizobium R, West and Wilson isolated a compound called co-enzyme R.[14] In 1940, Gyorgy proved that vitamin H and bios and coenzyme were the same substance; he called it biotin. [15]

Biosynthesis[edit]

Biotin has an unusual structure (above figure), with two rings fused together via one of their sides. The two rings are ureido and thiophene moieties. Biotin is a heterocyclic, S-containing monocarboxylic acid. It is made from two precursors, alanine and pimeloyl-CoA via three enzymes. 8-Amino-7-oxopelargonic acid synthase is a pyridoxal 5'-phosphate enzyme. The pimeloyl-CoA, could be produced by a modified fatty acid pathway involving a malonyl thioester as the starter. 7,8-Diaminopelargonic acid (DAPA) aminotransferase is unusual in using S-adenosyl methionine (SAM) as the NH2 donor. Dethiobiotin synthetase catalyzes the formation of the ureido ring via a DAPA carbamate activated with ATP. Biotin synthase reductively cleaves SAM into a deoxyadenosyl radical, which abstracts an H atom from dethiobiotin to give an intermediate that is trapped by the sulfur donor. This sulfur donor is an iron-sulfur cluster.[16]

Cofactor biochemistry[edit]

D-(+)-Biotin is a cofactor responsible for carbon dioxide transfer in several carboxylase enzymes:

Biotin is important in fatty acid synthesis, branched-chain amino acid catabolism, and gluconeogenesis.[2][3] It covalently attaches to the epsilon-amino group of specific lysine residues in these carboxylases. This biotinylation reaction requires ATP and is catalyzed by holocarboxylase synthetase.[17] In bacteria, biotin is attached to biotin carboxyl carrier protein (BCCP) by biotin protein ligase (BirA in E. coli).[18] The attachment of biotin to various molecules, biotinylation, is used as an important laboratory technique to study various processes, including protein localization, protein interactions, DNA transcription, and replication. Biotinidase itself is known to be able to biotinylate histone proteins,[19] but little biotin is found naturally attached to chromatin.

Biotin binds tightly to the tetrameric protein avidin (also streptavidin and neutravidin), with a dissociation constant Kd on the order of 10−15 M, which is one of the strongest known protein-ligand interactions.[20] This is often used in different biotechnological applications. Until 2005, very harsh conditions were thought to be required to break the biotin-streptavidin interaction.[21]

Dietary recommendations[edit]

The U.S. Institute of Medicine (IOM) updated Estimated Average Requirements (EARs), Recommended Dietary Allowances (RDAs) and Tolerable Upper Intake Levels (ULs) for many vitamins in 1998. At that time there was insufficient information to establish EARs and RDAs for biotin. In instances such as this, the IOM sets Adequate Intakes (AIs) with the understanding that at some later date, when the physiological effects of biotin are better understood, AIs will be replaced by more exact information. Collectively EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes (DRIs).[2][22]

The biotin AIs for males are: 5 μg/day of biotin for 0-6-month-old males, 6 μg/day of biotin for 7-12-month-old males, 8 μg/day of biotin for 1-3-year-old males, 12 μg/day of biotin for 4-8-year-old males, 20 μg/day of biotin for 9-13-year-old males, 25 μg/day of biotin for 14-18-year-old males, and 30 μg/day of biotin for males that are 19-years old and older.

The biotin AIs for females are: 5 μg/day of biotin for 0-6-month-old females, 6 μg/day of biotin for 7-12-month-old females, 8 μg/day of biotin for 1-3-year-old females, 12 μg/day of biotin for 4-8-year-old females, 20 μg/day of biotin for 9-13-year-old females, 25 μg/day of biotin for 14-18-year-old females, and 30 μg/day of biotin for females that are 19-years old and older. The biotin AIs for females who are either pregnant or lactating, respectively, are: 0 μg/day of biotin for pregnant females 14-50-years old; 35 μg/day of biotin for lactating females 14-50-years old.[2][3][22]

The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in United States. For women and men over age 18, the Adequate Intake is set at 40 μg/day. The AI for pregnancy is 40 μg/day per day, and 45 μg/day during breastfeeding. For children ages 1–17 years, the AIs increase with age from 20 to 35 μg/day.[23]

For the United States food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (DV). For biotin labeling purposes, 100% of the Daily Value was revised in 2016 to 30 μg/day to bring it into agreement with the AI.[24] 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 to make changes in product labeling.[25]

Safety[edit]

The U.S. Institute of Medicine estimates upper limits (ULs) for vitamins and minerals when evidence for a true limit is sufficient. For biotin, however, there is no UL because adverse effects of high biotin intake have not been determined.[22] EFSA also reviewed safety and reached the same conclusion as in United States that there is insufficient evidence to set a UL for biotin.[26]

Sources[edit]

Biotin is synthesized by intestinal bacteria, but there is a lack of good quality studies about how much biotin they provide.[3]

Biotin is stable at room temperature and is not destroyed by cooking. Sources with appreciable content are:[2][3]

  • Beef or pork liver, cooked: up to 35 μg per 3 ounce serving
  • Egg, cooked: up to 25 μg per large egg
  • Yeast, baker's, dried: up to 14 μg per 7 gram packet
  • Whole wheat bread: up to 6 μg per slice
  • Avocado: up to 6 μg per avocado
  • Salmon, cooked: up to 5 μg per 3 ounce serving
  • Cauliflower, raw: up to 4 μg per cup
  • Cheese, cheddar: up to 2 μg per ounce

Raw egg whites contain a protein (avidin) that blocks the absorption of biotin, so people who regularly consume a large number of raw eggs may become biotin-deficient.[22] The dietary biotin intake in Western populations has been estimated to be as high as 60 μg per day.[3] Biotin is also available in dietary supplements,[2] individually or as an ingredient in multivitamins.[3]

Bioavailability[edit]

Biotin is also called vitamin H (the H represents Haar und Haut, German words for "hair and skin") or vitamin B7. Studies on its bioavailability have been conducted in rats and in chicks. Based on these studies, biotin bioavailability may be low or variable, depending on the type of food being consumed. In general, biotin exists in food as protein-bound form or biocytin.[27] Proteolysis by protease is required prior to absorption. This process assists free biotin release from biocytin and protein-bound biotin. The biotin present in corn is readily available; however, most grains have about a 20-40% bioavailability of biotin.[28]

The wide variability in biotin bioavailability may be due to the ability of an organism to break various biotin-protein bonds from food. Whether an organism has an enzyme with that ability will determine the bioavailability of biotin from the foodstuff.[28]

Factors that affect biotin requirements[edit]

The frequency of marginal biotin status is not known, but the incidence of low circulating biotin levels in alcoholics has been found to be much greater than in the general population. Also, relatively low levels of biotin have been reported in the urine or plasma of patients who have had a partial gastrectomy or have other causes of achlorhydria, burn patients, epileptics, elderly individuals, and athletes.[28] Pregnancy and lactation may be associated with an increased demand for biotin. In pregnancy, this may be due to a possible acceleration of biotin catabolism, whereas, in lactation, the higher demand has yet to be elucidated. Recent studies have shown marginal biotin deficiency can be present in human gestation, as evidenced by increased urinary excretion of 3-hydroxyisovaleric acid, decreased urinary excretion of biotin and bisnorbiotin, and decreased plasma concentration of biotin. Additionally, smoking may further accelerate biotin catabolism in women.[29]

Deficiency[edit]

Biotin deficiency typically occurs from absence of the vitamin in the diet, particularly in breastfeeding mothers.[2] Daily consumption of raw egg whites for several months may result in biotin deficiency,[30] due to their avidin content.

Deficiency can be addressed with nutritional supplementation.[30]

Deficiency symptoms include:[2]

  • Brittle and thin fingernails
  • Hair loss (alopecia)
  • Conjunctivitis
  • Dermatitis in the form of a scaly, red rash around the eyes, nose, mouth, and genital area.
  • Neurological symptoms in adults, such as depression, lethargy, hallucination, and numbness and tingling of the extremities[30]

The neurological and psychological symptoms can occur with only mild deficiencies. Dermatitis, conjunctivitis, and hair loss will generally occur only when deficiency becomes more severe.[30] Individuals with hereditary disorders of biotin deficiency have evidence of impaired immune system function, including increased susceptibility to bacterial and fungal infections.[3] Pregnant women tend to have a higher risk of biotin deficiency. Nearly half of pregnant women have abnormal increases of 3-hydroxyisovaleric acid, which reflects reduced status of biotin.[3]

Metabolic disorders[edit]

Inherited metabolic disorders characterized by deficient activities of biotin-dependent carboxylases are termed multiple carboxylase deficiency. These include deficiencies in the enzymes holocarboxylase synthetase or biotinidase.[2] Holocarboxylase synthetase deficiency prevents the body's cells from using biotin effectively, and thus interferes with multiple carboxylase reactions.[31] Biochemical and clinical manifestations include: ketolactic acidosis, organic aciduria, hyperammonemia, skin rash, feeding problems, hypotonia, seizures, developmental delay, alopecia, and coma.

Biotinidase deficiency is not due to inadequate biotin, but rather to a deficiency in the enzymes that process it.[2] Biotinidase catalyzes the cleavage of biotin from biocytin and biotinyl-peptides (the proteolytic degradation products of each holocarboxylase) and thereby recycles biotin. It is also important in freeing biotin from dietary protein-bound biotin.[31] General symptoms include decreased appetite and growth. Dermatologic symptoms include dermatitis, alopecia, and achromotrichia (absence or loss of pigment in the hair). Perosis (a shortening and thickening of bones) is seen in the skeleton. Fatty liver and kidney syndrome and hepatic steatosis also can occur.[28]

Use in biotechnology[edit]

Biotin is widely used throughout the biotechnology industry to conjugate proteins for biochemical assays.[32] Biotin's small size means the biological activity of the protein will most likely be unaffected. This process is called biotinylation. Because both streptavidin and avidin bind biotin with high affinity (Kd of 10−14 to 10−15 M) and specificity, biotinylated proteins of interest can be isolated from a sample by exploiting this highly stable interaction. The sample is incubated with streptavidin/avidin beads, allowing capture of the biotinylated protein of interest. Any other proteins binding to the biotinylated molecule will also stay with the bead and all other unbound proteins can be washed away. However, due to the extremely strong streptavidin-biotin interaction, very harsh conditions are needed to elute the biotinylated protein from the beads (typically 6 M guanidine HCl at pH 1.5), which often will denature the protein of interest. To circumvent this problem, beads conjugated to monomeric avidin can be used, which has a decreased biotin-binding affinity of ~10−8 M, allowing the biotinylated protein of interest to be eluted with excess free biotin.

As one of the strongest non-covalent interactions, the binding of biotin to streptavidin is commonly used as the target molecular interaction in the research of biosensors and cell sorting.[33][34]

ELISAs often make use of biotinylated detection antibodies against the antigen of interest, followed by a detection step using streptavidin conjugated to a reporter molecule, such as horseradish peroxidase or alkaline phosphatase.

Medical laboratory testing[edit]

Biotin in samples taken from people ingesting high levels of biotin in dietary supplements may affect diagnostic test results.[2][35]

See also[edit]

References[edit]

  1. ^ Merck Index, 11th Edition, 1244.
  2. ^ a b c d e f g h i j k l m n o p "Biotin – Fact Sheet for Health Professionals". Office of Dietary Supplements, US National Institutes of Health. 8 December 2017. Retrieved 25 February 2018.
  3. ^ a b c d e f g h i j k l m "Biotin". Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis, OR. 21 October 2015. Retrieved 16 January 2018.
  4. ^ Fiume MZ (2001). "Final report on the safety assessment of biotin". International Journal of Toxicology. 20 Suppl 4: 1–12. PMID 11800048.
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  10. ^ Bateman, W.G. (June 1916). "The Digestibility and Utilization of Egg Proteins". Journal of Biological Chemistry. 26: 263–291.
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  12. ^ Gyorgy, Paul (December 1939). "The Curative Factor (vitamin H) for Egg White Injury, with Particular Reference to Its Presence in Different Foodstuffs and in Yeast". Journal of Biological Chemistry. 131: 733–744.
  13. ^ Kögl and Tönnis (1936). "Ueber das Bios Problem. Darstellung von kristallisiertem Bios aus Eigelb". Zschr. f. Phys. Chem. 242: 43.
  14. ^ West PM, Wilson PW (June 1939). "The Relation of "coenzyme R" to Biotin". Science. 89 (2322): 607–8. doi:10.1126/science.89.2322.607. PMID 17751623.
  15. ^ György P, Rose CS, Eakin RE, Snell EE, Williams RJ (May 1941). "Egg-White Injury as the Result of Nonabsorption or Inactivation of Biotin". Science. 93 (2420): 477–8. doi:10.1126/science.93.2420.477. PMID 17757050.
  16. ^ Marquet A, Bui BT, Florentin D (2001). "Biosynthesis of biotin and lipoic acid". Vitamins and Hormones. Vitamins & Hormones. 61: 51–101. doi:10.1016/S0083-6729(01)61002-1. ISBN 978-0-12-709861-6. PMID 11153271.
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  21. ^ Holmberg A, Blomstergren A, Nord O, Lukacs M, Lundeberg J, Uhlén M (February 2005). "The biotin-streptavidin interaction can be reversibly broken using water at elevated temperatures". Electrophoresis. 26 (3): 501–10. doi:10.1002/elps.200410070. PMID 15690449.
  22. ^ a b c d Institute of Medicine (1998). "Biotin". Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. pp. 374–389. ISBN 0-309-06554-2. Retrieved 2017-08-29.
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  25. ^ "Changes to the Nutrition Facts Panel - Compliance Date"
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  35. ^ "The FDA Warns that Biotin May Interfere with Lab Tests: FDA Safety Communication". US Food and Drug Administration. 28 November 2017. Retrieved 11 December 2017.