Biotin is a hydrophilic (water-soluble) vitamin of the B group and bears the historical names coenzyme R, vitamin BW, vitamin B7, and vitamin H (effect on skin). In the early 20th century, Wildiers discovered a specific factor required for growth in experiments on yeasts, which was named “Bios” and was a mixture of Bios I (later identified as meso-inositol), Bios II A (later pantothenic acid (vitamin B5)), and Bios II B, the actual biotin. In 1936, Kögl and Tönnis isolated biotin from egg yolk. Between 1940 and 1943, the structure was elucidated by the working groups around Kögl in Europe and Vigneaud in the USA. During the same period, animal experiments showed that regular ingestion of raw eggs was associated with severe skin changes due to the basic glycoprotein avidin. Avidin is a biotin antagonist that impairs biotin absorption by forming a complex – 1 molecule of avidin binds 4 molecules of biotin – and thus can cause biotin deficiencies in the long term. Administration of a heat-stable factor from yeast or liver resulted in remission (temporary or permanent attenuation of symptoms) of such skin lesions. The biochemical functions of biotin as a coenzyme, for example in amino acid metabolism, fatty acid biosynthesis, and gluconeogenesis (new synthesis of glucose from organic non-carbohydrate precursors, such as pyruvate), were not recognized until the second half of the 20th century. Biotin is a heterocyclic urea derivative (derivative of urea) consisting of an imidazolidone ring and a tetrahydrothiophene ring to which valeric acid is coupled [1, 2, 4-6, 14]. According to the IUPAC (International Union of Pure and Applied Chemistry) classification, the chemical name of biotin is cis-hexahydro-2-oxo-1H-thieno(3,4-d)-imidazol-4-yl-valeric acid (molecular formula: C10H16O3N2S). The 3 asymmetric C (carbon) atoms of biotin allow the formation of 8 stereoisomers, of which only D-(+)-biotin occurs in nature and is biologically active. While biotin is highly stable against air, daylight, and heat, the vitamin is sensitive to UV light. Accordingly, biotin should be stored away from light.
Synthesis
Biotin can be synthesized (formed) by most bacteria as well as by many fungal and plant species. Accordingly, the vitamin is widely distributed in nature, but their concentration in food is very low. In the human organism, the bacteria of the colon (large intestine) are capable of biotin synthesis. Both the extent of enteric self-synthesis (formation of biotin in the intestine) and its contribution to biotin metabolism are not precisely known. Since the vitamin is predominantly absorbed (taken up) in the proximal (upper) small intestine, microbially produced biotin cannot be adequately utilized and is largely lost in the feces (stool). Finally, bacterial biotin synthesis is thought to play only a minor role in meeting requirements.
Absorption
In the diet, biotin is present in free form but mostly bound to proteins. To be absorbed, biotin must be released from its binding protein, to which it is covalently attached (by means of a tight atomic bond) to the ε (epsilon)-amino (NH2) group of a lysine residue (biotinyl-ε-NH2-lysyl<[protein]). During food passage, gastric acid and peptidases (protein-cleaving enzymes) of the gastrointestinal (GI) tract, such as pepsin and trypsin, lead to degradation (breakdown) of dietary protein with release of biotin-containing peptides and biocytin (compound of biotin and the amino acid lysine – biotinyl-ε-lysine). Biotinyl peptides and especially biocytin are hydrolytically (by reaction with water) cleaved into free biotin and lysine in the upper part of the small intestine by the enzyme biotinidase, which is synthesized in the pancreas (pancreas). Deficiency of biotinidase can be treated by pharmacological amounts of free biotin (5-10 mg/day). Without therapeutic action, there is a dramatic drop in serum biotin levels within a week and, in the long term, the manifestation (expression) of biotin deficiency.Absorption of free biotin in the proximal (upper) small intestine, especially in the jejunum (empty intestine), occurs actively at low or normal intakes by means of sodium-dependent carrier-mediated transport – carrier (transport protein)-biotin-sodium complex – according to saturation kinetics. After higher doses, the uptake of biotin into enterocytes (cells of the small intestinal epithelium) by passive diffusion predominates. The rate of absorption from food-primarily protein-bound biotin-is estimated to be around 50%, whereas bioavailability after therapeutic doses-free biotin-is around 100%.
Transport and distribution in the body
Absorbed biotin enters the bloodstream via a carrier mechanism, where it is mostly in free form (81%) and, to a lesser extent, covalently bound to serum biotinidase (12%) and nonspecifically bound to plasma albumin and globulins (7%). Erythrocytes (red blood cells) contain about 10% of the serum biotin concentration. The uptake of biotin into the cells of the target tissues probably occurs – similar to intestinal absorption (uptake via the intestine) – via a specific energy-consuming sodium-dependent carrier mechanism. Proliferation processes (cell division and growth) lead to an increase in the expression of biotin transport proteins, whereas an increase in biotin serum levels is accompanied by a decrease in the cellular expression of biotin carriers. Transport of biotin across the placentra to the fetus is mediated by an actively working sodium-dependent carrier that also transports lipoic acid (antioxidant coenzyme) and pantothenic acid (vitamin B5). In the 18th-24th week of pregnancy, the biotin concentration in fetal blood is 3 to 17 times higher than in maternal blood. In target cells, biotin functions as a coenzyme in a series of carboxylase reactions in which carboxy (COOH) groups are inserted into organic compounds. Covalent binding of biotin to the ε-amino group of lysine of apocarboxylases is catalyzed (accelerated) by the enzyme holocarboxylase synthetase in the following two steps.
- Biotin + ATP (adenosine triphosphate) → biotinyl 5′-adenylate + PP (pyrophosphate).
- Biotinyl 5′-adenylate + lysine residue of apocarboxylase → biotinyl-ε-NH2-lysyl<[apocarboxylase] (biologically active holocarboxylase) + AMP (adenosine monophosphate).
As part of physiological cell turnover, holocarboxylases are proteolytically degraded (by protein-cleaving enzymes), producing biocytin in addition to biotin-containing peptides, which is hydrolyzed (cleaved by reaction with water) to free biotin and lysine by the action of intracellular biotinidase. Thus, biotin is available for further carboxylation reactions (enzymatic insertion of COOH groups into organic compounds).
Excretion
Biotin is excreted predominantly by the kidneys in free and metabolized (metabolized) forms. During biotin degradation, beta-oxidation (fatty acid degradation) of the valeric acid chain yields bisnorbiotin and bisnorbiotin methyl ketone, whereas oxidation of sulfur in the tetrahydrothiophene ring yields biotin d,1-sulfoxide and biotin sulfone. The listed biotin metabolites have no vitamin activity and are detectable in both blood plasma and urine. In addition, other biotin metabolites are excreted renally (via the kidneys), some of which have not yet been identified. Under physiological intake, urinary biotin excretion varies between 6 and 90 µg/24 hours. In the deficiency state, renal biotin excretion (excretion) decreases to 5 µg/24 hours, while urinary 3-hydroxyisovaleric acid concentration increases as a result of decreased activity of biotin-dependent 3-methylcrotonyl-CoA carboxylase (enzyme that catalyzes the carboxylation (insertion of a COOH group) of methylcrotonyl-CoA to beta-methylglutaconyl-CoA). During gravidity (pregnancy), a significant decrease in renal biotin elimination and an increase in urinary 3-hydroxyisovaleric acid excretion were observed in 50% of women, despite higher serum biotin levels in early pregnancy than in non-pregnant controls. Supplementation (supplemental intake) of 300 µg biotin/day results in reduction of 3-hydroxyisovaleric acid excretion. Due to microbial biotin synthesis in the colon (large intestine), the amount of biotin excreted in urine and feces usually exceeds the alimentary (dietary) biotin intake.The elimination or plasma half-life (the time that elapses between the maximum concentration of a substance in the blood plasma and the fall to half this value) depends on the biotin dose supplied and the individual biotin status. It is about 26 hours for oral intake of 100 µg/kg body weight biotin. In biotinidase deficiency, the elimination half-life is reduced to 10-14 hours at the same dosage.