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Issue 24, 2005
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The effects of substrate orientation on the mechanism of a phosphotriesterase

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Abstract

While the underlying chemistry of enzyme-catalyzed reactions may be almost identical, the actual turnover rates of different substrates can vary significantly. This is seen in the turnover rates for the catalyzed hydrolysis of organophosphates by the bacterial phosphotriesterase OpdA. We investigate the variation in turnover rates by examining the hydrolysis of three classes of substrates: phosphotriesters, phosphothionates, and phosphorothiolates. Theoretical calculations were used to analyze the reactivity of these substrates and the energy barriers to their hydrolysis. This information was then compared to information derived from enzyme kinetics and crystallographic studies, providing new insights into the mechanism of this enzyme. We demonstrate that the enzyme catalyzes the hydrolysis of organophosphates through steric constraint of the reactants, and that the equilibrium between productively and unproductively bound substrates makes a significant contribution to the turnover rate of highly reactive substrates. These results highlight the importance of correct orientation of reactants within the active sites of enzymes to enable efficient catalysis.

Graphical abstract: The effects of substrate orientation on the mechanism of a phosphotriesterase

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Publication details

The article was received on 06 Sep 2005, accepted on 06 Oct 2005 and first published on 16 Nov 2005


Article type: Paper
DOI: 10.1039/B512399B
Org. Biomol. Chem., 2005,3, 4343-4350

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    The effects of substrate orientation on the mechanism of a phosphotriesterase

    C. J. Jackson, J. Liu, M. L. Coote and D. L. Ollis, Org. Biomol. Chem., 2005, 3, 4343
    DOI: 10.1039/B512399B

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