Reductive cleavage mechanism of Co - C bond in cobalamin-dependent methionine synthase

Mercedes Alfonso-Prieto, Xevi Biarnés, Manoj Kumar, Carme Rovira, Pawel M. Kozlowski

Producció científica: Article en revista indexadaArticleAvaluat per experts

30 Cites (Scopus)


The key step in the catalytic cycle of methionine synthase (MetH) is the transfer of a methyl group from the methylcobalamin (MeCbl) cofactor to homocysteine (Hcy). This mechanism has been traditionally viewed as an S N2-type reaction, but a different mechanism based on one-electron reduction of the cofactor (reductive cleavage) has been recently proposed. In this work, we analyze whether this mechanism is plausible from a theoretical point of view. By means of a combination of gas-phase as well as hybrid QM/MM calculations, we show that cleavage of the Co - C bond in a MeCbl· ··Hcy complex (Hcy = methylthiolate substrate (Me-S-), a structural mimic of deprotonated homocysteine) proceeds via a [Co III(corriṅ-)] - Me··· ̇S-Me diradical configuration, involving electron transfer (ET) from a π*corrin-type state to a σ* Co - C one, and the methyl transfer displays an energy barrier ≤8.5 kcal/mol. This value is comparable to the one previously computed for the alternative SN2 reaction pathway (10.5 kcal/mol). However, the ET-based reductive cleavage pathway does not impose specific geometrical and distance constraints with respect to substrate and cofactor, as does the S N2 pathway. This might be advantageous from the enzymatic point of view because in that case, a methyl group can be transferred efficiently at longer distances.

Idioma originalAnglès
Pàgines (de-a)12965-12971
Nombre de pàgines7
RevistaJournal of Physical Chemistry B
Estat de la publicacióPublicada - 14 d’oct. 2010


Navegar pels temes de recerca de 'Reductive cleavage mechanism of Co - C bond in cobalamin-dependent methionine synthase'. Junts formen un fingerprint únic.

Com citar-ho