Methyl transfer reactions catalyzed by cobalamin-dependent enzymes: Insight from molecular docking

Methyl transfer reactions, mediated by methyltransferases (MeTrs), such as methionine synthase (MetH) or monomethylamine: CoM (MtmBC), constitute one of the most important classes of vitamin B₁₂-dependent reactions. The challenge in exploring the catalytic function of MeTrs is related to their modular structure. From the crystallographic point of view, the structure of each subunit has been determined, but there is a lack of understanding of how each subunit interacts with each other. So far, theoretical studies of methyl group transfer were carried out for the structural models of the active site of each subunit. However, those studies do not include the effect of the enzymatic environment, which is crucial for a comprehensive understanding of enzyme-mediated methyl transfer reactions. Herein, to explore how two subunits interact with each other and how the methyl transfer reaction is catalyzed by MeTrs, molecular docking of the functional units of MetH and MtmBC was carried out. Along with the interactions of the functional units, the reaction coordinates, including the Co-C bond distance for methylation of cob(I)alamin (Co^ICbl) and the C-S bond distance in demethylation reaction of cob(III)alamin (Co^IIICbl), were considered. The functional groups should be arranged so that there is an appropriate distance to transfer a methyl group and present results indicate that steric interactions can limit the number of potential arrangements. This calls into question the possibility of S_N2-type mechanism previously proposed for MeTrs. Further, it leads to the conclusion that the methyl transfer reaction involves some spatial changes of modules suggesting an alternate radical-based pathway for MeTrs-mediated methyl transfer reactions. The calculations also showed that changes in torsion angles induce a change in reaction coordinates, namely Co-C and C-S bond distances, for the methylation and demethylation reactions catalyzed both by MetH and MtmBC.