Methylcobalamin biological functions

Researchers studying the metalloenzyme hydrogenase would like to design small compounds that mimic this enzyme s ability to reversibly reduce protons to H2 and H2 to 2H+, using an active center that contains iron and nickel. Cobalamins (vitamin and its derivatives) contain an easily activated Co-C bond that has a number of biological functions, one of which is as a methyl transferase, 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). This enzyme converts homocysteine (an amino acid that has one more CH2 group in its alkyl side chain than cysteine see Figure 2.2) to methionine as methylcobalamin is converted to cobalamin. 

Cyanocobalamin (la) is a relatively inert complex and, apart from being involved in the detoxification of small amounts of hydrogen cyanide [5], does not appear to serve any major biological function [10]. The only difference between this species and the metabolically active forms of B12 (methylcobalamin (MeCbl Ib) and 5 -deoxyadenosylcobalamin (AdoCbl Ic)) is the ligand that occupies the... 

Methylation of amines in nucleotides and proteins plays important roles in biological function. Methyl transferases accept a wide range of nucleophiles such as halides, amines, hydroxyls, and enolates [reactions (a) and (b), Scheme 8.6] [42-44], For example, in the biosynthesis of novobiocin, methylation takes place at only one phenolic carbon and not the remaining three hydroxyl groups [45, 46]. On the other hand, methyl transfer to electron-deficient substrates often occurs under radical mechanisms requiring methylcobalamin as the cofactor, as shown in the biosynthesis of fosfomycin, where only one of the two enantiotopic hydrogen was replaced by the methyl group [reaction (c), Scheme 8.6] [47]. 

The clarification of the structure of coenzyme B g stimulated attempts to synthesize the compound from vitamin B g and an activated adenosine derivative. Smith et described a chemical synthesis of the coentyme from fully reduced vitamin Big (Bi and the 5 -tosyl-2, 3 -isopropylidene derivative of adenosine. At the same time they reported the synthesis of Co-methyl-cobalamin from Bigg and methyl iodide. Soon thereafter a biological function of methylcobalamin in the methylation of homo steine was demonstrated by Guest et Only one other Co-alkyl-corrinoid compound has so far been... 

It soon became apparent that the biologically active forms of Vitamin Bj.2 contained the unique Co—C-a-bond, and the instability of these covalent compounds to visible light facilitated observations on the occurrence of functional corrinoids in a number of enzymes. Deoxyadenosyl-cobalamin was found to be the most abundant corrinoid in bacteria (24) and in mammalian liver (25). Methylcobalamin was found in Escherichia coli (26), calf liver and human blood plasma (27), and also in a number of Clostridia (28). 

Vitamin B12 is a biologically active corrinoid, a group of cobalt-containing compounds with macrocyclic pyrrol rings. Vitamin B12 functions as a cofactor for two enzymes, methionine synthase and L-methylmalonyl coenzyme A (CoA) mutase. Methionine synthase requires methylcobalamin for the methyl transfer from methyltetrahydrofolate to homocysteine to form methionine tetrahy-drofolate. L-methylmalonyl-CoA mutase requires adenosylcobalamin to convert L-methylmalonyl-CoA to succinyl-CoA in an isomerization reaction. An inadequate supply of vitamin B12 results in neuropathy, megaloblastic anemia, and gastrointestinal symptoms (Baik and Russell, 1999). 

The metabolically important functions of the Bn-derivatives are directly concerned either with enzymatically controlled organometalhc reactions involving protein-bound adenosylcobamides (such as coenzyme B12, (3)), or methyl-Co -corrinoids (such as methylcobalamin, (4)), or with enzyme-controlled redox reactions. Studies on the underlying biologically relevant organometalhc chemistry of the Bi2-coenzymes in homogeneous (protic) solution, as well as the characterization of the enzymatic processes themselves have attracted considerable interest. ... 

In 1968 we discovered that methylcobalamin was capable of transferring a methyl-carbanion to mercuric salts in aqueous solutions. This initial discovery opened the door to a study of reactions between methylcobalamin and a number of metal and metalloid ions. Methyl-transfer in biological systems naturally depends on the co-enzymes which are available to perform this function. Three co-enzymes have been found which are capable of the transfer of methyl groups (1) methylcorrinoid derivatives,... 

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