Cobalt, methyl transfer

The third reason for favoring a non-radical pathway is based on studies of a mutant version of the CFeSP. This mutant was generated by changing a cysteine residue to an alanine, which converts the 4Fe-4S cluster of the CFeSP into a 3Fe-4S cluster (14). This mutation causes the redox potential of the 3Fe-4S cluster to increase by about 500 mV. The mutant is incapable of coupling the reduction of the cobalt center to the oxidation of CO by CODH. Correspondingly, it is unable to participate in acetate synthesis from CH3-H4 folate, CO, and CoA unless chemical reductants are present. If mechanism 3 (discussed earlier) is correct, then the methyl transfer from the methylated corrinoid protein to CODH should be crippled. However, this reaction occurred at equal rates with the wild-type protein and the CFeSP variant. We feel that this result rules out the possibility of a radical methyl transfer mechanics and offers strong support for mechanism 1. 

Lenhert and Hodgkin (15) revealed with X-ray diffraction techniques that 5 -deoxyadenosylcobalamin (Bi2-coenzyme) contained a cobalt-carbon o-bond (Fig. 3). The discovery of this stable Co—C-tr-bond interested coordination chemists, and the search for methods of synthesizing coen-zyme-Bi2 together with analogous alkyl-cobalt corrinoids from Vitamin B12 was started. In short order the partial chemical synthesis of 5 -de-oxyadenosylcobalamin was worked out in Smith s laboratory (22), and the chemical synthesis of methylcobalamin provided a second B 12-coenzyme which was found to be active in methyl-transfer enzymes (23). A general reaction for the synthesis of alkylcorrinoids is shown in Fig. 4. 

Methylation of arsenic is an important pollution problem because of the widespread use of arsenic compounds in insecticides and because of the presence of arsenate in the phosphate used in household detergents.421 422 After reduction to arsenite, methylation occurs in two steps (Eq. 16-45). Additional reduction steps result in the formation of dimethylarsine, one of the principal products of action of methanogenic bacteria on arsenate. The methyl transfer is shown as occurring through CH3+, with an accompanying loss of a proton from the substrate. However, a CH3 radical may be transferred with formation of a cobalt(II) corrinoid.423... 

Vitamin B]2 is a red crystalline, cobalt-containing compound that can be isolated from the liver. It has a functional role in preventing pernicious anaemia and also serves as a coenzyme in hydrogen and methyl transfer reactions (Co appears to be the only metal in vivo catalyzing C transfer reactions O and N transfers are more common). Vitamin B12 is also a growth-promoting factor for several microorganisms. 

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 cobalt center in MeCbl, one of the two important B12 coenzymes, is clearly involved in key steps in catalytic methyl transfer processes. Here, the Co center cycles between Co(I) and Co(III)CH3. In methionine synthase, the proposed mechanism involves direct nucleophilic attack on the C of the Co(III)CH3 group. In model reactions, the thiolate most frequently simply binds tram to the alkyl group to give a product recently established by an x-ray study of a model system. The protein may block access to the Co, thus preventing this reaction common in models. It is likely that the reactive form of the bound cofactor is five-coordinate in the key point in the catalytic cycle. This reactive form will lead to a four-coordinate Co(I) species. The axial coordination of the cofactor by a protein imidazole allows for a finer tuning of the Cbl chemistry and may permit control of the coordination number. Thus, recoordination of Co in the Co(I) state may facilitate attack on methyltetrahydrofolate and re-formation of Co(III)CH3. 

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]. 

The biomethylation reaction between platinum and methylcobalamin involves both platinum(II) and platinum(IV) oxidation states. An outer-sphere complex is formed between the charged platinum(II) salts and the corrin macrocycle, which catalytically labilizes the Co—C o bond to electrophilic attack. A two-electron redox switch mechanism has been proposed between platinum(II) and platinum(IV). However, a mechanism consistent with the kinetic data is direct electrophilic attack by PtClg on the Co—C a bond in MeBu. Studies on [Pt(NH3)2(OH2)2] indicate that the bases on cobalt interact in the coordination sphere of platinum(II). Since both platinum(ll) and platinum(rV) are together required to effect methyl transfer from methylcobalamin to platinuni, Pt and C NMR spectroscopy have been used to show that the methyl group is transferred to the platinum of the platinum(n) reactant. The kinetics of demethylation by mixtures of platinum(II) and platinum(IV) complexes show a lack of dependence on the axial ligand. The authors conclude therefore that it is unlikely that the reaction involves direct attack by the bound platinum on the Co—C bond, and instead favor electron transfer from an orbital on the corrin ring to the boimd platinum group in the slow step, followed by rapid methyl transfer. ... 

Progress of biological action in enzymatic methyl transfer and rearrangement reactions, medicinal aspects, structure and reactivity, and biosynthesis of vitamin B12 and B 12-coenzymes was very recently comprehensively presented at the 4 European Symposium on Vitamin Bi2 and B 12-Proteins and reviewed in an excellent monograph (70). Therefore it is intended with this contribution to address mainly results from research in the field of vitamin B12 biosynthesis. The procedure makes sense because of two reasons. First, many of the biosynthetic intermediates are closely related to hydroporphyrinoid structures discussed in previous sections and second, reactions of the biosynthetic pathway concern the chemistry of the hydroporphyrinoid and corrinoid frameworks involved, whereas the biochemical reactivity of vitamin B12 is mainly restricted to the central cobalt ion of the corrin macrocycle. 

Metallocene additives like cobalt (methyl cyclopentadienyl)2 work in polyolefins by providing a low-energy transfer of electrons between their adjacent aromatic layers, but they have not been widely used so far because of practical disadvantages, including inadequate heat stability. 

The cobalt-bound methyl group of methyl-Co -corrins can be readily abstracted by nucleophiles or by electrophiles, as well as by radicaloid metal centers and radicals (Figs. 7 and 8) (32,34). A unique radical methylation (see Fig. 7) has been implied specifically in the biosynthesis of fosfomycin in a Streptomyces strain (10,35), as well as in other biosynthetic transformations (36). A reversible methyl group transfer occurs rapidly in aqueous solution between methyl-Co -cobinamide (9+) and cob(I)alamin (6 ), and at equilibrium, methylcobalamin (3) and Co -cobinamide (10) prevail. From such methyl transfer equilibria, the nucleotide coordination in 3 was shown to stabilize 3 by ca. 4 kcal mol" against abstraction of the cobalt-bound methyl group by nucleophiles, to activate 3 for the abstraction of the cobalt-bound methyl group by electrophiles, but to hardly... 

An elegant model had been developed to describe the transfer of a methyl cation from the cobalt-corrinoid Fe-S protein to a proximal nickel center [116], Methyl transfer from a methyl-cobalt species to a Ni(I) complex yields a stable Ni(II)-Me species concomitant with oxidation of a second equivalent of the Ni(I) complex (Eq. 12.9). In this system, the methyl cobalt species is equivalent to a methyl cation source, although mechanistic studies revealed the involvement of methyl radicals formed via homolysis of an initially generated Co(II)-methyl species [117]. 

These systems are complicated by the fact diat they catalyze two methyl-transfer reactions, one from MeCbl to the substrate and the other from some reagent to cobalt to regenerate MeCbl. For methionine synthase, it is known that the reactions go with overall retention of the stereochemistry of the methyl group. This shows that both transfers occur either with retention or inversion. This observation, plus the absence of EPR signals indicative of Co(II) or organic radicals, suggest that these reactions do not proceed by homolysis of the Co—C bond. 

The reaction of methylcobalamin with mercury(n) is extremely rapid and has been studied by stopped flow kinetics. However, methyl transfer from methylcobalamin to tetrachloropalladate(n) is slower. In both methyl transfer reactions there are two kinetically distinct steps. The initial step involves a rapid association of the metal species with methylcobalamin, resulting in a base-on, base-off pre-equilibrium, the electrophilic metal system competing with the cobalt(m) for the lone pair of electrons on the benzimidazole nitrogen. There follows a slower demethylation step in which the electrophilic metal species attacks the Co—C bond in the uncomplexed methylcobalamin. The more rapid transfer with mercury(n) is a consequence of the greater electrophilicity of mercury(n) than palladium(ii), and the mercury(n) produces slightly more of the base-off species. ... 

This methyl transfer reaction differs from all others discussed by the participation of B12 bound to enzyme as a methyl carrier, with resultant foimation of a methyl-Bi2-enzyme intermediate. The overall reaction is sufficiently similar to most methyl transfers so that it can be visualized as the transfer of a methyl carbonium (in this case successively from tetra-hydrofolate to the cobalt atom of enzyme-bound B12 to homocysteine). If the donor is not an onium structure, there is no net production of a hydrogen ion, and the overall reaction may be written as follows ... 

The discovery of the role of methyl-Bia in the de novo synthesis of methionine drew attention to the possibility that such methyl-bearing cobalt compounds might be active in other special biological methyl transfer reactions. Subsequent investigations have revealed a probable fimction... 

Photolysis of [Co(CH2R)(L)(Hdmg)2] under oxygen proceeds by insertion of dioxygen into the cobalt carbon bond to provide a solution species for which nmr spectroscopic data is rq)orted. Reduction of this intermediate produces primary alcohols whereas thermolysis produces aldehydes and alcohols. Treatment of [Co oep)] with simple aldehydes and rm-butylhydroperoxide in the presence of sodium borohydride produces cobalt(III) acyls in 65-98% yields. In the absence of the borohydride the yield is reduced. The reaction is proposed to proceed by acyl radical trapping by the Co(n) centre. Methyl transfer in a protein free model of vitamin B12 dependent methyl transf enzymes has been studied. These systems convert homocysteine to methionine in nature. Trimethyl-phenylammonium icm reacts with the CoG) centre in cobalamin producing methylcobalamin. ... 

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