Quantum chemical modeling of 1,1‐proton transfer reaction catalyzed by a cofactor‐independent α‐methylacyl‐CoA racemase

α‐Methylacyl‐CoA racemases (AMACR) are essential enzymes for branched‐chain lipids and drugs metabolism. AMACR catalyzes the chiral inversion of (2R) and (2S)‐methylacyl‐CoA esters in both directions. In this study, we investigated the catalytic mechanism of Mycobacterium tuberculosis (MCR) α‐methylacyl‐CoA racemase by using the density functional theory with the hybrid functional B3LYP. Our calculations elucidate and support the mechanism proposed by Prasenjit Bhaumik. His126 and Asp156 serve as the acid/base‐pair residues in the 1,1‐proton transfer catalytic reaction. From the optimized structures, it can be seen that an enolate intermediate is formed and the possibility of forming a ketene or a carbanion intermediate is excluded. By comparing the energy barriers, we could consider that the deprotonation step is the rate‐determined step in the invert direction from (S)‐ to (R)‐enantiomer. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012