Charge Separation Propensity of the Coenzyme B12–Tyrosine Complex in Adenosylcobalamin-Dependent Methylmalonyl–CoA Mutase Enzyme

We report the electrophilic Fukui function analysis based on density functional reactivity theory (DFRT) to demonstrate the feasibility of the proton-coupled electron transfer (PCET) mechanism. To characterize the charge propensity of an electron-transfer site other than the proton-acceptor site of the coenzyme B12-tyrosine complex, several structural models (ranging from minimal to actual enzyme scaffolds) have been employed at DFT and QM/MM computations. It is shown, based on the methylmalonyl-CoA mutase (MCM) enzyme that substrate binding plays a significant role in displacing the phenoxyl proton of the tyrosine (Y89), which initiates the electron transfer from Y89 to coenzyme B12. PCET-based enzymatic reaction implies that one electron-reduced form of the AdoCbl cofactor induces the cleavage of the Co-C bond, as an alternative to its neutral analogue, which can assist in understanding the origin of the observed trillion-fold rate enhancement in MCM enzyme.