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Structural basis for the activity and substrate specificity of fluoroacetyl-CoA thioesterase FlK
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Dias, M. V. B., Huang, Fanglu, Chirgadze, D. Y., Tosin, Manuela, Spiteller, Dieter, Dry, E. F. V., Leadlay, P. F., Spencer, Jonathan B. and Blundell, T. L. (Tom Leon) (2010) Structural basis for the activity and substrate specificity of fluoroacetyl-CoA thioesterase FlK. Journal of Biological Chemistry, Vol.285 (No.29). pp. 22495-22504. doi:10.1074/jbc.M110.107177 ISSN 0021-9258.
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Official URL: http://dx.doi.org/10.1074/jbc.M110.107177
Abstract
The thioesterase FlK from the fluoroacetate-producing Streptomyces cattleya catalyzes the hydrolysis of fluoroacetyl-coenzyme A. This provides an effective self-defense mechanism, preventing any fluoroacetyl-coenzyme A formed from being further metabolized to 4-hydroxy-trans-aconitate, a lethal inhibitor of the tricarboxylic acid cycle. Remarkably, FlK does not accept acetyl-coenzyme A as a substrate. Crystal structure analysis shows that FlK forms a dimer, in which each subunit adopts a hot dog fold as observed for type II thioesterases. Unlike other type II thioesterases, which invariably utilize either an aspartate or a glutamate as catalytic base, we show by site-directed mutagenesis and crystallography that FlK employs a catalytic triad composed of Thr42, His76, and a water molecule, analogous to the Ser/Cys-His-acid triad of type I thioesterases. Structural comparison of FlK complexed with various substrate analogues suggests that the interaction between the fluorine of the substrate and the side chain of Arg120 located opposite to the catalytic triad is essential for correct coordination of the substrate at the active site and therefore accounts for the substrate specificity.
Item Type: | Journal Article | ||||
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Subjects: | Q Science > QD Chemistry | ||||
Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||
Library of Congress Subject Headings (LCSH): | Fluorides, Enzymes, Catalysis, Hydrolysis | ||||
Journal or Publication Title: | Journal of Biological Chemistry | ||||
Publisher: | American Society for Biochemistry and Molecular Biology | ||||
ISSN: | 0021-9258 | ||||
Official Date: | 2010 | ||||
Dates: |
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Volume: | Vol.285 | ||||
Number: | No.29 | ||||
Page Range: | pp. 22495-22504 | ||||
DOI: | 10.1074/jbc.M110.107177 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published |
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