Bacterial Synthesis of Biotin

Biotin is synthesized in microorganisms from pimelate by the pathway shown in Figure 11.3 (Marquet et al., 2001; Schneider and Lindqvist, 2001). The first committed stepis the condensation of pimeloyl CoA with alanine, with release of the carboxyl group of alanine, catalyzed by keto-aminopelargonic acid synthase. It is a pyridoxal phosphate-dependent reaction, similar to the condensation of succinyl CoA and glycine to form S -aminolevulinic acid in porphyrin synthesis. There is a considerable degree of structural homology between keto-aminopelargonic acid and S-aminolevulinic acid synthases.

The second nitrogen of biotin is incorporated by transamination of keto-aminopelargonic acid, with S-adenosylmethionine - an apparently unique metabolic role for this amino acid derivative that is normally a methyl donor. The immediate product of the deamination of S-adenosylmethionine, S-adenosyl-2-oxo-4-methylthiobutyric acid, is unstable and decomposes non-enzymically to 2-oxo-3-butenoic acid and 5-methyl thioadenosine.

Completion of the ureido ring of biotin, yielding dethiobiotin, is by a car-boxylation reaction using CO2 and ATP. The reaction proceeds by the formation of a monocarbamate by reaction between diaminopelargonic acid and CO2, followed by formation of a substituted carbamyl phosphate, which then

dethiobiotin

Figure 11.3. Biosynthesis of biotin. Keto-aminopelargonic acid synthase, EC 2.3.1.47; diaminopelargonic acid synthase (aminotransferase), EC 2.6.1.62; dethiobiotin synthase, EC 6.3.3.3; and biotin synthase, EC 2.8.1.6.

dethiobiotin

Figure 11.3. Biosynthesis of biotin. Keto-aminopelargonic acid synthase, EC 2.3.1.47; diaminopelargonic acid synthase (aminotransferase), EC 2.6.1.62; dethiobiotin synthase, EC 6.3.3.3; and biotin synthase, EC 2.8.1.6.

cyclizes by elimination of the phosphate group. The two amide bonds are thus formed using a single mole of ATP ^ ADP + Pj.

The final reaction, catalyzed by biotin synthase, involves the insertion of sulfur between the unreactive methyl and methylene carbons of dethiobiotin. The enzyme has an iron-sulfur box, and requires NADPH and a ferredoxin or flavo-doxin reducing system. S-Adenosylmethionine is also required, and is cleaved to yield methionine and a 5-deoxyadenosyl radical during the reaction. Biotin synthase is a member of the radical SAM family of enzymes, in which the catalytic 5 -deoxyadenosyl radical is formed from S-adenosylmethionine, rather than from adenosylcobalamin as in methylmalonyl CoA mutase and similar vitamin B12-dependent enzymes (Section 10.8.2). Two moles of S-adenosylmethionine are required: one 5-deoxyadenosyl radical abstracts hydrogen from the methyl group of dethiobiotin and the other from the methylene group.

It is possibly incorrect to consider biotin synthase an enzyme in the true sense of the word; it has a turnover number of 1. It only catalyzes the synthesis of a single molecule of biotin from dethiobiotin before being inactivated. This is because the iron-sulfur cluster of the protein is the source of the sulfur that is incorporated into biotin. There is some evidence that the enzyme can be reactivated by incorporation of sulfur from cysteine, but in vitro addition of the enzymes believed to catalyze this reaction has no effect on the turnover number of the enzyme (Frey, 2001; Marquet et al., 2001).

11.1.1.1 The Importance of Intestinal Bacterial Synthesis of Biotin It was noted in Section 11.1 that biotin is absorbed throughout the intestinal tract, including the colon, and synthesis by intestinal bacteria may make a significant contribution to biotin nutrition. In balance studies, the total output of biotin in urine plus feces is three to six times greater than the intake; most of this excess is in the feces, reflecting bacterial synthesis. In experimental animals maintained on biotin- and cellulose-free diets, the addition of cellulose or sorbitol as a substrate for bacterial fermentation can alleviate the vitamin deficiency.

1 1.2 THE METABOLIC FUNCTIONS OF BIOTIN

Biotin is the coenzyme in a small number of carboxylation reactions in mammalian metabolism and some decarboxylation and transcarboxylation reactions in bacteria. Although the biotin-dependent enzymes are cytosolic and mitochondrial, about 25% of tissue biotin is found in the nucleus, much of it bound as thioesters to histones. Biotin has two noncoenzyme functions: induction of enzyme synthesis and regulation of the cell cycle.

The biotin-dependent decarboxylases of anerobic microorganisms are transmembrane proteins. In addition to their roles in the metabolism of ox-aloacetate, methylmalonyl CoA, and glutaconyl CoA, they serve as energy transducers. They transport 2 mol of sodium out of the cell for each mole of substrate decarboxylated. The resultant sodium gradient is then used for active transport of substrates by sodium cotransport systems, or maybe used to drive ATP synthesis in a similar manner to the proton gradient in mammalian mitochondria (Buckel, 2001).

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  • tom
    Is biotin a methyl donor?
    11 days ago

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