Computer Simulations of Enantioselective Ester Hydrolyses Catalyzed by Pseudomonas cepacia Lipase

On the basis of the X-ray crystal structure of the lipase from Pseudomonas cepacia (PcL)an enzyme representative for a whole family of Pseudomonas lipases (lipase PS, SAM-2, AK 10, and others with a high degree of homology with PcL)a computational study was performed to rationalize both the enanti...

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Bibliographic Details
Published in:Journal of organic chemistry 2000-06, Vol.65 (12), p.3659-3665
Main Authors: Tafi, Andrea, van Almsick, Andreas, Corelli, Federico, Crusco, Maria, Laumen, Kurt E, Schneider, Manfred P, Botta, Maurizio
Format: Article
Language:English
Subjects:
Burkholderia cepacia - enzymology
Computer Simulation
Crystallography, X-Ray
Esters - chemistry
Esters - metabolism
Hydrolysis
Lipase - chemistry
Lipase - metabolism
Models, Molecular
Protein Conformation
Stereoisomerism
Substrate Specificity
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Summary:On the basis of the X-ray crystal structure of the lipase from Pseudomonas cepacia (PcL)an enzyme representative for a whole family of Pseudomonas lipases (lipase PS, SAM-2, AK 10, and others with a high degree of homology with PcL)a computational study was performed to rationalize both the enantioselectivity and substrate specificity (tolerance) displayed by this lipase in the enantioselective hydrolysis of racemic esters 1a−12a from various secondary aromatic alcohols. The major goal of this project was the development of a binding model for PcL which is able to rationalize the experimental findings to predict “a priori” the enantioselective behavior of PcL toward a wider range of substrates. A two-step modeling procedure, namely, docking experiments followed by construction of tetrahedral intermediates, was used for the simulation of the involved enzyme−substrate recognition/hydrolysis processes. The study of the recognition process (docking experiments) led to unambiguous identification of the binding geometry for the two enantiomeric series of substrates, but did not suggest a definitive interpretation of the behavior of PcL. Taking into consideration the stereoelectronic requirements of the enzymatic hydrolysis reaction, both the enantioselectivity and tolerance of the enzyme were then explained through the study of the tetrahedral intermediates, in turn constructed from the calculated docking geometries of 1a−12a.
ISSN:0022-3263
1520-6904
DOI:10.1021/jo9919198