title: Energetic and stereochemical effects of the protein environment on substrate: a theoretical study of methylmalonyl-CoA mutase.
abstract: QM/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.
authors.affiliation: Institute of General, Inorganic, and Theoretical Chemistry, University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Loferer
authors.forename: Ben M
authors.initials: BM
authors.lastname: Webb
authors.forename: Guy H
authors.initials: GH
authors.lastname: Grant
authors.forename: Klaus R
authors.initials: KR
authors.lastname: Liedl
mesh_terms: D000214:Acyl Coenzyme A / Q000737:chemistry / Q000378:metabolism; D008765:Methylmalonyl-CoA Mutase / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D013237:Stereoisomerism; D013816:Thermodynamics
chemical_list: D000214:Acyl Coenzyme A; C015357:methylmalonyl-coenzyme A; C012046:succinyl-coenzyme A; D008765:Methylmalonyl-CoA Mutase