Energetic and stereochemical effects of the protein environment on substrate: a theoretical study of methylmalonyl-CoA mutase
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AbstractQM/MM methods were used to study the isomerization step from (2R)-methylmalonyl-CoA to succinyl-CoA. A pathway via a “fragmentation−recombination” mechanism is ruled out on energetic grounds. For the other radicalic pathway, involving an addition recombination step, geometries and vibrational contributions have been determined, and a barrier height of 11.70 kcal/mol was found. The effect of adjacent hydrogen-donating groups was found to reduce the energy barrier by 1−2 kcal/mol each and thus to provide a significant catalytic effect for this reaction. By means of molecular dynamics studies, the stereochemistry of the methylmalonyl-CoA mutase catalyzed reaction was examined. It is shown that TYR89 is essential for maintaining stereoselectivity of the abstraction of a hydrogen in the backreaction. The subsequent selective formation of one isomer of methylmalonyl-CoA is probably due to the presence of a bulky side chain.
CitationLoferer, M.J., Webb, B.M., Grant, G.H. and Liedl, K.R. (2003) 'Energetic and stereochemical effects of the protein environment on substrate: a theoretical study of methylmalonyl-CoA mutase', Journal of the American Chemical Society, 125(4),pp.1072-1078.
PublisherAmerican Chemical Society