Folate antagonists as antimicrobial drugs

In humans, vitamin Bi2 participates in two reactions only, but they are essential to life. Humans who cannot absorb vitamin Bi2 die of pernicious anemia if untreated (now by injection of the vitamin formerly by eating large amounts of raw liver). Vitamin B]2 contains a cobalt metal ion bound to a porphyrin ring. Cobalt normally forms six coordinate bonds. Besides the four bonds to the nitrogens of the porphyrin, one bond is to a ring nitrogen of dimethylbenzamidine. The final bond is to a cyanide ion in the vitamin, or to the 5 carbon of adenosine in the active coenzyme. 

Vitamin B12 is essential for the methylmalonyl-CoAmutase reaction. Methylmalonyl-CoA mutase is required during the degradation of odd-chain fatty acids and of branched-chain amino acids. Odd-chained fatty acids lead to propionyl-CoA as the last step of P-oxida-tion. Methylmalonyl-CoA can be derived from propionyl-CoA by a carboxylase reaction similar to that of fatty acid biosynthesis. The cofactor for this carboxylation reaction is biotin, just as for acetyl-CoA carboxylase. The reaction of methylmalonyl-CoA mutase uses a free radical intermediate to insert the methyl group into the dicar-boxylic acid chain. The product is succinyl-CoA, a Krebs cycle intermediate. The catabolisms of branched-chain lipids and of the branched-chain amino acids also require the methylmalonyl-CoA mutase, because these pathways also generate propionyl-CoA. 

Vitamin B12 activates methyl groups for methionine biosynthesis by binding them to the Co ion at the sixth position. The methyl group donor to Bi2 is 5-methyl tetrahydrofolate. The methyl-Bi2 donates its methyl group to homocysteine, forming methionine. 

Besides being incorporated into proteins, methionine is the source of methyl groups for several important reactions, including the modification of cellular RNAs and the biosynthesis of lipids. 

Homocysteine isn t harmless. Evidence from population studies indicates that high levels of homocysteine in the blood are correlated with heart disease. Folic acid supplements may prevent this problem by ensuring that the homocysteine is rapidly converted to methionine. Similarly, pregnant women generally take folic acid supplements to prevent their babies from being bom with neural tube defects. The mechanism for its action isn t known, but the folic acid may help decrease the level of homocysteine in this case as well. 

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