Biotin Vitamin H

Biotin was originally discovered as part of the complex called bios, which promoted the growth of yeast, and separately, as vitamin H, the protective or curative factor in egg white injury - the disease caused by diets containing large amounts of uncooked egg white. The glycoprotein avidin in egg white binds biotin with high affinity. This has been exploited to provide a variety of extremely sensitive assay systems.

Dietary deficiency of biotin sufficient to cause clinical signs is extremely rare in human beings, although it may be a problem in intensively reared poultry. However, there is increasing evidence that suboptimal biotin status may be relatively common, despite the fact that the vitamin is widely distributed in many foods, is synthesized by intestinal flora, and there is an efficient mechanism for conserving biotin after the catabolism of biotin-containing enzymes.

Metabolically, biotin is of central importance in lipogenesis, gluconeogen-esis, and the catabolism of branched-chain (and other) amino acids. There are two well-characterized biotin-responsive inborn errors of metabolism, which are fatal if untreated: holocarboxylase synthetase deficiency and biotinidase deficiency. In addition, biotin induces a number of enzymes, including glu-cokinase and other key enzymes of glycolysis. Biotinylation of histones may be important in regulation of the cell cycle.

11.1 METABOLISM OF BIOTIN

As shown in Figure 11.1, biotin is a bicyclic compound with fused ureido (im-idazolidone) and thiophene rings, and an aliphatic carboxylate side chain. It is bound covalently to enzymes by the formation of a peptide bond between the carboxyl group of the side chain and the e- amino group of a lysine residue forming biocytin (biotinyl-lysine).

Biotin Protein Ligase
Figure 11.1. Metabolism of biotin. Holocarboxylase synthetase (biotin protein ligase), EC 6.3.4.10; andbiotinidase (biotinamide amidohydrolase),EC 3.5.1.12. Relative molecular mass (Mr): biotin, 244.3; and biocytin, 372.5.

Most biotin in foods is present as biocytin, incorporated into enzymes, which is released on proteolysis, then hydrolyzed by biotinidase in the pancreatic juice and intestinal mucosal secretions to yield free biotin. Biocytin is not absorbed to any significant extent.

Biotin uptake into enterocytes is by a sodium-dependent carrier, which also transports pantothenic acid (Section 12.2) and lipoic acid, but is inhibited by biocytin and dethiobiotin. The carrier is found in both the small intestine and the colon, so both biotin and pantothenic acid synthesized by intestinal bacteria can be absorbed (Chatterjee etal., 1999; Ramaswamy, 1999; Said, 1999; Prasad and Ganapathy, 2000). Even at relatively high intakes (up to 80 ^mol), biotin is more-or-less completely absorbed (Zempleni and Mock, 1999b).

Most biotin circulates in the bloodstream bound to a serum glycoprotein, biotinidase (Section 11.2.3), which not only acts as a transport protein, but also catalyzes the hydrolysis of biocytin, and the transfer of biotin from biocytin

biotin sulfone

Figure 11.2. Biotin metabolites. Relative molecular masses (Mr): biotin, 244.3; biotin sulfoxide, 260.3; biotin sulfone, 276.3; bisnorbiotin, 212.3; tetranorbiotin, 180.3; and bisnorbiotin sulfoxide, 228.3.

biotin sulfone

Figure 11.2. Biotin metabolites. Relative molecular masses (Mr): biotin, 244.3; biotin sulfoxide, 260.3; biotin sulfone, 276.3; bisnorbiotin, 212.3; tetranorbiotin, 180.3; and bisnorbiotin sulfoxide, 228.3.

onto sulfhydryl groups ofhistones and other proteins (Section 11.2.5). Some biotin is also nonspecifically bound to albumin and a- and f-globulins.

Dietary biotin bound to avidin (Section 11.6) is unavailable, but intravenously administered avidin-biotin is biologically active. Cells in culture are not inhibited by the addition of avidin to the culture medium, and can take up the avidin-biotin complex by pinocytosis followed by lysosomal hydrolysis, releasing free biotin. Unlike other B vitamins, for which concentrative uptake into tissues is achieved by facilitated diffusion, followed by metabolic trapping, the incorporation of biotin into enzymes is slow and cannot be considered part of the uptake process.

As discussed in Section 11.2.2, biotin is incorporated covalently into biotin-dependent enzymes as the e-amino-lysine peptide, biocytin. On catabolism of the enzymes, biocytin is hydrolyzed by biotinidase, permitting reutilization of the biotin.

As shown in Figure 11.2, the side chain of biotin can undergo mitochondrial or peroxisomal f-oxidation to yield bisnorbiotin and tetranorbiotin. In the microsomes, both biotin and bisnorbiotin undergo S-oxidation to the sulfoxides, and biotin sulfoxide can undergo further oxidation to the sulfone. At physiological levels of intake, about 30% of biotin is excreted unchanged, and 50% to 60% as bisnorbiotin and bisnorbiotin methyl ketone; sulfoxides and biotin sulfone make up the remainder (Zempleni and Mock, 1999a).

The brush border of the kidney cortex has a sodium-biotin cotransport system similar to that in the intestinal mucosa, thus providing for reabsorption of free biotin filtered into the urine. It is only when this mechanism is saturated (it has a relatively low Km) that there will be a significant excretion of biotin.

As a result of this resorption and the protein binding of plasma biotin, which reduces filtration at the glomerulus, renal clearance of biotin is only 40% of that of creatinine. This efficient conservation of biotin, together with the recycling of biocytin released from the catabolism of biotin-containing enzymes, may be as important as intestinal bacterial synthesis of the vitamin in explaining the rarity of deficiency.

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