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

Abstract

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