Density functional theory analysis was performed to elucidate the impact of one-electron reduction upon the initial step of adenosylcobalamin-dependent enzymatic catalysis. The transition state (TS) corresponding to the Co-C bond cleavage and subsequent hydrogen abstraction from the substrate was located. The intrinsic reaction coordinate calculations predicted that the reaction consisting of Co-C5' bond cleavage in [Co III(corrin •)]-Rib (where Rib is ribosyl) and hydrogen-atom abstraction from the CH 3-CH 2-CHO substrate occurs in a concerted fashion. The computed activation energy barrier of the reaction (15.0 kcal/mol) was lowered by approximately 54.5% in comparison with the reaction involving the positively charged cofactor model (Im-[Co III(corrin)]-Rib +, where Im is imidazole; energy barrier = 33.0 kcal/mol). The Im base was detached during the TS search in the reaction involving the one-electron-reduced analogue. Thus, to compare the energetics of the two reactions, the axial Im ligand detachment energy for the Im-[Co III(corrin •)]-Rib model was computed [7.6 kcal/mol (gas phase); 4.6 kcal/mol (water)]. Consequently, the effective activation energy barrier for the reaction mediated by the Im-off [Co III (corrin •)]-Rib was estimated to be 22.6 kcal/mol, which implied an overall 31.5% reduction in the energetic demands of the reaction. Considering that the lengthened Co-N axial bond has been observed in X-ray crystal structure studies of B 12-dependent mutases, the catalytic impact induced by one-electron reduction of the cofactor is expected to be higher in the presence of the enzymatic environment.
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