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Energetic and stereochemical effects of the protein environment on substrate: A theoretical study of methylmalonyl-CoA mutase

Research Output: Contribution to journal Article Peer-review

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.

Publication Information

Output type

Research Output: Contribution to journal Article Peer-review

Original language

English

Journal (Volume, Issue Number)

Journal of the American Chemical Society

Publication milestones

  • Published - 01/01/2003

Publication status

Published - 01/01/2003

ISSN

0002-7863

External Publication IDs

  • handle.net: 10547/294687
  • Scopus: 0347264740

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