Cobalamin, methyl cofactor

Co within all compounds of the so-called cobalamin (or B12) family. The biological functions of cobalamin cofactors are defined by their axial substituents either a methyl or an adenosyl group. Both cofactors participate in biosynthesis the former in methyl transfer reactions while the latter is a free radical initiator, abstracting H atoms from substrates. Decades after their initial characterization, the fascination with the biological chemistry of cobalamins remains.1109... 

In mammals and in the majority of bacteria, cobalamin regulates DNA synthesis indirectly through its effect on a step in folate metabolism, catalyzing the synthesis of methionine from homocysteine and 5-methyltetrahydrofolate via two methyl transfer reactions. This cytoplasmic reaction is catalyzed by methionine synthase (5-methyltetrahydrofolate-homocysteine methyl-transferase), which requires methyl cobalamin (MeCbl) (253), one of the two known coenzyme forms of the complex, as its cofactor. 5 -Deoxyadenosyl cobalamin (AdoCbl) (254), the other coenzyme form of cobalamin, occurs within mitochondria. This compound is a cofactor for the enzyme methylmalonyl-CoA mutase, which is responsible for the conversion of T-methylmalonyl CoA to succinyl CoA. This reaction is involved in the metabolism of odd chain fatty acids via propionic acid, as well as amino acids isoleucine, methionine, threonine, and valine. 

Cobalamin (vitamin B12) Methionine cycle intermediate methyl carrier in the remethylation of homocysteine to methionine cofactor for methionine synthase... 

Vitamin B12 (cyanocobalamin) 3 is, in fact, not a natural product as the cyanide ligand to the cobalt ion is added during the isolation procedure. Coenzyme B12 (adenosylcobalamin) 4 and methylcobalamin 5 are the true final products of the biosynthetic pathway. Coenzyme 0,2 is the cofactor for a number of enzymic rearrangement reactions, such as that catalysed by methylmalonyl CoA mutase, and methylcobalamin is the cofactor for certain methyl transfer reactions, including the synthesis of methionine. A number of anaerobic bacteria produce related corrinoids in which the dimethylbenzimidazole moiety of the cobalamins (3 - 5) is replaced by other groups which may or may not act as ligands to the cobalt ion, such as adenine orp-cresol [12]. 

As illustrated in Fig. 1, methionine synthase is positioned at the intersection between transsulfuration and methylation pathways. As a consequence, its level of activity exerts control over cellular redox status, since it determines the proportion of HCY that will be diverted toward cysteine and GSH synthesis. Methionine synthase activity is exceptionally sensitive to inhibition during oxidative stress, primarily because its cobalamin cofactor is easily oxidized (Liptak and Brunold, 2006). This allows methionine synthase to serve as a redox sensor, lowering its activity whenever the level of oxidation increases, until increased GSH synthesis brings the system back into balance. Electrophilic compounds, such as oxygen-containing xenobiotic metabolites, also react with cobalamin, inactivating the enzyme and increasing diversion of HCY toward GSH synthesis (Watson et al., 2004). Thus, methionine synthase is a sensor of both redox and xenobiotic status. 

Methyl trap The sequestering of tetrahydrofolate as N -methyl THF because of decreased conversion of homocysteine to methionine as a result of a deficiency of methionine synthase or its cofactor, cobalamin (vitamin B ). 

Figure 42-3. The role of cobalamin as a cofactor in the methylation of homocysteine to methionine.

All known ACS enzymes are bifunctional in that they possess a C cluster with COdFI activity in addition to an A cluster (the ACS active site. Scheme 9). In the enzymes, a CO tunnel is described through which GO can pass directly from the C cluster, where it is generated from CO2, to the A cluster, where acetyl GoA synthesis takes place. Again, two mechanisms were proposed that differ in the order of binding events and redox states involved. In essence, however, GO binds to an Ni-GHs species, followed by insertion and generation of an Ni-acetyl species, which upon reaction with GoA liberates the acetyl GoA product. It is interesting to note that methylation of Ni occurs by reaction with methyl cobalamin (Scheme 7). In M. thermoacetica, the cobalamin is the cofactor for a rather unique protein called the corrinoid iron sulfur protein (GFeSP). The above process, even if mechanistic details still remain in question, resembles the industrial Monsanto acetic acid synthesis process (Scheme 9, bottom). In this case, however, the reaction is catalyzed by a low-valent Rh catalyst. 

Figure 1. The cobalamin cofactor in its alkyl Co(III) form. The alkyl substituent is a methyl group in MetH and other methyltransferases, and is 5 deoxyadenosine in Bj2 dependent mutases.

The primary reaction catalyzed by methionine synthase converts homocysteine (Hey) and methyltetrahydrofolate (CH3H4folate) to methionine and tetrahydrofolate (Figure 2). Occasional oxidation of the reactive cob(I)alamin intermediate produces an inactive cob(II)alamin enzyme, which is reactivated by a reductive methylation that uses S-adenosylmethionine (AdoMet) as the methyl donor and flavodoxin or a flavodoxin-like domain as an electron donor. Thus methionine synthase supports three distinct methyl transfer reactions each involving the cobalamin cofactor. 

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