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

2.50
Hdl Handle:
http://hdl.handle.net/10547/294687
Title:
Energetic and stereochemical effects of the protein environment on substrate: a theoretical study of methylmalonyl-CoA mutase
Authors:
Loferer, Markus J.; Webb, Ben M.; Grant, Guy H.; Liedl, Klaus R.
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.
Citation:
Loferer, 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.
Publisher:
American Chemical Society
Journal:
Journal of the American Chemical Society
Issue Date:
2003
URI:
http://hdl.handle.net/10547/294687
DOI:
10.1021/ja028906n
Additional Links:
http://pubs.acs.org/doi/abs/10.1021/ja028906n
Type:
Article
Language:
en
ISSN:
0002-7863; 1520-5126
Appears in Collections:
Cell and Cryobiology Research Group

Full metadata record

DC FieldValue Language
dc.contributor.authorLoferer, Markus J.en_GB
dc.contributor.authorWebb, Ben M.en_GB
dc.contributor.authorGrant, Guy H.en_GB
dc.contributor.authorLiedl, Klaus R.en_GB
dc.date.accessioned2013-06-26T14:59:55Z-
dc.date.available2013-06-26T14:59:55Z-
dc.date.issued2003-
dc.identifier.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.en_GB
dc.identifier.issn0002-7863-
dc.identifier.issn1520-5126-
dc.identifier.doi10.1021/ja028906n-
dc.identifier.urihttp://hdl.handle.net/10547/294687-
dc.description.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.en_GB
dc.language.isoenen
dc.publisherAmerican Chemical Societyen_GB
dc.relation.urlhttp://pubs.acs.org/doi/abs/10.1021/ja028906nen_GB
dc.rightsArchived with thanks to Journal of the American Chemical Societyen_GB
dc.titleEnergetic and stereochemical effects of the protein environment on substrate: a theoretical study of methylmalonyl-CoA mutaseen
dc.typeArticleen
dc.identifier.journalJournal of the American Chemical Societyen_GB
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