"Lethal Synthesis" of Fluorocitrate by Citrate Synthase Explained through QM/MM Modeling

A classic example of enzyme stereospecificity is the title reaction involving the enantioselective conversion of fluoroacetyl‐CoA. High‐level modeling of the enzyme reaction shows that preferential formation of an E‐enolate explains the experimentally observed specificity. The results indicate that...

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Published inAngewandte Chemie (International ed.) Vol. 50; no. 44; pp. 10349 - 10351
Main Authors van der Kamp, Marc W., McGeagh, John D., Mulholland, Adrian J.
Format Journal Article
LanguageEnglish
Published Weinheim WILEY-VCH Verlag 24.10.2011
WILEY‐VCH Verlag
Wiley Subscription Services, Inc
EditionInternational ed. in English
Subjects
ab initio calculations
Acetyl Coenzyme A - chemistry
Citrate (si)-Synthase - chemistry
citrate synthase
Citrates - biosynthesis
computational enzymology
enantioselectivity
enzyme catalysis
Quantum Theory
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Summary:A classic example of enzyme stereospecificity is the title reaction involving the enantioselective conversion of fluoroacetyl‐CoA. High‐level modeling of the enzyme reaction shows that preferential formation of an E‐enolate explains the experimentally observed specificity. The results indicate that selectivity is primarily a result of the inherent energy difference between the E‐ and Z‐enolates of fluoroacetyl‐CoA.
Bibliography:EU
Funded Access
ark:/67375/WNG-VFGLM2LM-9
BBSRC
M.W.v.d.K. was funded by the EU (through the BRISENZ Marie Curie Early Stage Training Centre) and by IBM (PhD fellowship). J.D.M. was funded by BBSRC. A.J.M. is an EPSRC Leadership Fellow. QM/MM=quantum mechanics/molecular mechanics.
ArticleID:ANIE201103260
istex:BD74591A509B7DB0F423B298488D8E1AC8C89E54
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201103260