Methyl transfers

Caste]on H and Wiberg K B 1999 Solvent effects on methyl transfer reactions. 1. The Menshutkin reaction J. Am. Ohem. Soc. 121 2139-46... 

Mechanistic aspects of the action of folate-requiring enzymes involve one-carbon unit transfer at the oxidation level of formaldehyde, formate and methyl (78ACR314, 8OMI2I6OO) and are exemplified in pyrimidine and purine biosynthesis. A more complex mechanism has to be suggested for the methyl transfer from 5-methyl-THF (322) to homocysteine, since this transmethylation reaction is cobalamine-dependent to form methionine in E. coli. 

It was reported only recently that A-methyl transfer from an oxaziridine to an amine occurs with formation of an N—N bond (79JA6671). N—N bond forming reactions with A-unsubstituted oxaziridines had been found immediately after discovery of this class of compound (64CB2521) and have led to simple hydrazine syntheses (79AHC(24)63). Secondary amines like diethylamine or morpholine are A-aminated by (52) in the course of some minutes at room temperature with yields exceeding 90% (77JPR195). Further examples are the amination of aniline to phenylhydrazine, and of the Schiff base (96) to the diaziridine (97). 

The first two of these are mediated by 5 -deoxyadenosylcobalamin, whereas methyl transfers are effected by methylcobalamin. The mechanism of ribonucleotide reductase is discussed in Chapter 27. Methyl group transfers that employ tetrahydrofolate as a coenzyme are described later in this chapter. 

Equation (3.34) without the H X ) and the H 2la terms is identical to the Marcus equation for methyl transfer reactions (Ref. 13). This equation predicts, at the range ( AG0 < a), a linear relationship between AAG0 and AAg by... 

When R is CH3 the process is called methyl transfer. For such reactions, the work terms and are assumed to be very small compared to AG° and can be neglected, so that the Marcus equation simplifies to... 

Demonstration that the enzymatic methyl transfer from methyl-Co to Ni uses Em Sn2, not a radicEd, mechanism. "... 

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. 

Methyl Transfer Reactions Catalysed by Corrinoid-Containing Enzymes... 

Stupperich E, R Konle (1993) Corrinoid-dependent methyl transfer reactions are involved in methanol and 3,4-dimethoxybenmzoate metabolism by Sporomusa ovata. Appl Environ Microbiol 59 3110-3116. 

With the characterized mechanism, the next key question is the origin of its catalytic power. A prerequisite for this investigation is to reliably compute free energy barriers for both enzyme and solution reactions. By employing on-the-fly Born-Oppenheimer molecular dynamics simulations with the ab initio QM/MM approach and the umbrella sampling method, we have determined free energy profiles for the methyl-transfer reaction catalyzed by the histone lysine methyltransferase SET7/9... 

Kwon T, Chang JH, Kwak E, Lee CW, Joachimiak A, Kim YC, Lee JW, Cho Y (2003) Mechanism of histone lysine methyl transfer revealed by the structure of set7/9-adomet. EMBO J., 22 292-303... 

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. 

Studies have been carried out on the methylated complex [H3C-Niin(17)(H20)]2+, which is obtained from the reaction of methyl radicals (generated by pulse radiolysis) with [Ni(17)]2+. The volumes of activation are consistent with the coherent formation of Ni—C and Ni—OH2 bonds, as expected for the generation of a Ni111 complex from a square planar Ni11 precursor.152 The kinetics of reactions of [H3C-Niin(17)(H20)] + involving homolysis, 02 insertion and methyl transfer to Crn(aq) have been determined, and intermediates have been considered relevant as models for biological systems.153 Comparing different alkyl radicals, rate constants for the... 

In this review we shall not deal with the synthesis of this coordination complex, but we shall deal with the chemical properties of B 12-coenzymes with special emphasis on how these properties relate to Bi2-enzyme mechanisms. Also, we shall show how B -catalyzed methyl-transfer reactions have special significance in the biosynthesis of methylated heavy metals in the aqueous environment, and how the synthesis of these organometallic compounds has special relevance to problems concerned with continuing global environmental health hazards. 

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. 

Methylcobalamin acts as the functional molecule for methyl-transfer in a second group of enzyme reactions. Theoretically methyl-transfer... 

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