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| Names | |
|---|---|
| IUPAC name
5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanoic acid
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| Other names
Vitamin B7; Vitamin H; Coenzyme R; Biopeiderm
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| Identifiers | |
3D model (JSmol)
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| ChEBI | |
| ChEMBL | |
| ChemSpider | |
| DrugBank | |
| ECHA InfoCard | 100.000.363 |
| KEGG | |
PubChem CID
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| UNII | |
CompTox Dashboard (EPA)
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| 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 | |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Biotin is a water-soluble B vitamin, also called vitamin B7 and formerly known as vitamin H or coenzyme R. 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. Subclinical deficiency can cause mild symptoms, such as hair thinning or skin rash typically on the face. 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.
General
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. 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. Nevertheless, biotin is found in many cosmetics and health products for the hair and skin.
Biotin deficiency is rare.
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 and Australia,
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.
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.
Biotin is composed of a ureido ring fused with a tetrahydrothiophene ring. The ureido ring acts as the carbon dioxide carrier in carboxylation reactions. 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. Biotin is also required for the catabolism and utilization of the three branched-chain amino acids: leucine, isoleucine, and valine.
Discovery
In 1916, W.G. Bateman observed that a diet high in raw egg whites caused toxic symptoms in dogs, cats, rabbits, and humans.
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.
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.
By this point, many independent groups had isolated biotin. In 1936,
Kögl and Tönnis isolated a growth factor from egg yolk they called bios. After experiments performed with yeast and Rhizobium R, West and Wilson isolated a compound called co-enzyme R. In 1940, Gyorgy proved that vitamin H and bios and coenzyme were the same substance; he called it biotin.
Biosynthesis
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.
Cofactor biochemistry
- Acetyl-CoA carboxylase alpha
- Acetyl-CoA carboxylase beta
- Methylcrotonyl-CoA carboxylase
- Propionyl-CoA carboxylase
- Pyruvate carboxylase
Biotin is important in fatty acid synthesis, branched-chain amino acid catabolism, and gluconeogenesis. 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. In bacteria, biotin is attached to biotin carboxyl carrier protein (BCCP) by biotin protein ligase (BirA in E. coli). 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, 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.
This is often used in different biotechnological applications. Until
2005, very harsh conditions were thought to be required to break the
biotin-streptavidin interaction.
Dietary recommendations
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).
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: 30 μg/day of
biotin for pregnant females 14-50-years old; 35 μg/day of biotin for
lactating females 14-50-years old.
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.
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. The deadline to be in compliance was set at January 1, 2020 for large companies and January 1, 2021 for small companies.
Safety
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.
EFSA also reviewed safety and reached the same conclusion as in United
States that there is insufficient evidence to set a UL for biotin.
Sources
Biotin is synthesized by intestinal bacteria, but there is a lack of good quality studies about how much biotin they provide.
Biotin is stable at room temperature and is not destroyed by cooking. Sources with appreciable content are:
- Chicken liver, cooked: 138 μg per 74g serving
- 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
- Avocado: up to 6 μg per avocado
- Peanuts, roasted, salted: can vary between 5 μg and 28 μg per 28g serving
- Salmon, cooked: up to 5 μg per 3 ounce serving
- Sunflower seeds, roasted, salted: 2.4 μg per 31g serving
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. The dietary biotin intake in Western populations has been estimated to be as high as 60 μg per day. Biotin is also available in dietary supplements, individually or as an ingredient in multivitamins.
Bioavailability
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.
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.
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.
Factors that affect biotin requirements
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. 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.
Deficiency
Biotin deficiency typically occurs from absence of the vitamin in the diet, particularly in breastfeeding mothers. Daily consumption of raw egg whites for several months may result in biotin deficiency, due to their avidin content.
Deficiency can be addressed with nutritional supplementation.
Deficiency symptoms include:
- 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
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.
Individuals with hereditary disorders of biotin deficiency have
evidence of impaired immune system function, including increased
susceptibility to bacterial and fungal infections.
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.
Metabolic disorders
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. Holocarboxylase synthetase deficiency prevents the body's cells from using biotin effectively, and thus interferes with multiple carboxylase reactions. 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. 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. 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.
Use in biotechnology
Biotin is widely used throughout the biotechnology industry to conjugate proteins for biochemical assays. 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.
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
Biotin in samples taken from people ingesting high levels of biotin in dietary supplements may affect diagnostic test results.
