A-methyltetrahydrofolate

Methylcobalamin is involved in a critically important physiological transformation, namely the methylation of homocysteine (8) to methionine (9) (eq. 2) catalyzed by A/ -methyltetrahydrofolate homocysteine methyltransferase. The reaction sequence involves transfer of a methyl group first from... 

Figure 11 Schematic illustration of the cobalamin-dependent enzymatic biosynthesis of methionine via methyl-group transfer from A -methyltetrahydrofolate to homocysteine...

Methylcobalamin is completely different from adenosylcobalamin because it is essentially a conduit for synthetic reactions catalyzed by methyltransferases, illustrated in Scheme 2 for the case of methionine. These reactions depend on the supemucle-ophilicity of cob(I)alamin. In one case, this species removes a methyl group from A -methyltetrahydrofolate with the formation of methylcobalamin, and then transfers this group to the acceptor homocysteine, which results in the synthesis of methionine (see Scheme 2). 

The key intermediate in the catalytic pathway is the supemucleophile cob(l)alamin, which attacks A -methyl-tetrahydrofolate, generating tetrahydrofolate and MeCbl. Then homocysteine (probably as its thiolate) attacks MeCbl, which yields methionine and regenerates cob(l)alamin (Scheme 2). The demethylation of A -methyltetrahydrofolate is not trivial, even for the supemucleophilic cob(l)alamin, and considerable efforts have been invested into understanding this reaction, dubbed improbable by Duilio Arigoni. The obvious mode of activation is by proton transfer to N-5 of A -methyl tetrahydrofolate, but as this is weakly basic (pAa 5.1) the nature of the proton source and mode of transfer has been difficult to pin down. Recent research from the Matthews group has shown how the reactivities of cob(I)alamin and methylcobalamin are modulated by the ligand trans to the lone pair of cob(l)alamin and methyl group of methylcobalamin (21). 

The synthesis of acetyl-CoA by the Ljungdahl-Wood pathway of autotrophic carbon fixation in diverse bacteria and archaea is catalyzed by a Co- and Fe-containing corrinoid iron-sulfur protein (CoFeSP). This protein participates in the transfer of a methyl group from A -methyltetrahydrofolate to the cob(I)amide of CoFeSP to give a methylcob(III)amide, from which the methyl group is transferred to the reduced Ni-Ni-(4Fe-4S) active site cluster A of acetyl-CoA synthase (27). 

Methylcobalamia is iavolved ia a critically important physiological transformation, namely the methylation of homocysteine (8) to methionine (9) (eq. 2) catalyzed by A/ -methyltetrahydrofolate homocysteine methjitransferase. The reaction sequence involves transfer of a methji group first from A/5 -methjltetrahydrofolate to cobalamin (yielding methjicobalamin) and thence to homocysteine. Once again, the intimate details of the reaction are not weU known (31). Demethylation of tetrahydrofolate to tetrahydrofohc acid is a step in the formation of thymidine phosphate, in turn requited for DNA synthesis. In the absence of the enzyme, excess RNA builds up in ted blood cells. 

The conversion of phosphatidylethanolamine, a component of cell membranes, into phosphatidylcholine requires three methylations by three equivalents of SAM. (Biological cell membranes will be discussed in Section 26.4 the use of A -methyltetrahydrofolate as a biological methylating agent is discussed in more detail in Section 25.8.)... 

A -protonated A -methyltetrahydrofolate to reconstitute the bound methyECo -corrinoid. The transfer of the methyl group takes place with overall retention of configuration (indicating two nucleophilic substitutions, each with stereochemical inversion), formally involving the transfer of a methyl cation. ... 

Folate trap The accumulation of A/ -methyltetrahydrofolate and the resulting deficiency in tetrahydrofolate that is caused by vitamin B,j deficiency (Figure 33-2)... 

The conversion of A -methyltetrahydrofolate to methyltetrahydrofolate requires adequate supplies of cobalamin (vitamin Bj ). In vitamin deficiency, A -methyltetrahydrofolate accumulates, whereas supplies of dihydrofolate, tetrahydrofolate, and dTMP are depleted. The answer is (D). 

Normally, homocysteine is either remethylated to methionine with A -methyltetrahydrofolate (/V -Me-THF) or converted to cysteine via cystathionine, bnt abnormally it can be excreted as homocystine. What does ininary excretion of homocystine indicate ... 

Alignment of the MetH sequence between residues 366 and -610 with a methyltetrahydrofolate corrinoid iron-sulfur protein methyltransferase (AcsE) reveals 22% identity and 43% homology between these proteins (6) the same region of MetH is more distantly related to pteroate synthase (6, 31). Structures for pteroate synthase (52, 55) and the recently determined structure of AcsE (6) predict that the folate binding module will be a (Pa)g barrel. Model-building (6)... 

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