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Probing the mechanisms for the selectivity and promiscuity of methyl parathion hydrolase.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2016 (English)In: Philosophical Transactions of the Royal Society of London A, Mathematical, Physical and Engineering Sciences, Vol. 374, p. 20160150-Article in journal (Refereed) Published
Abstract [en]

Diverse organophosphate hydrolases have convergently evolved the ability to hydrolyse man-made organophosphates. Thus, these enzymes are attractive model systems for studying the factors shaping enzyme functional evolution. Methyl parathion hydrolase (MPH) is an enzyme from the metallo-β-lactamase superfamily, which hydrolyses a wide range of organophosphate, aryl ester and lactone substrates. In addition, MPH demonstrates metal-ion-dependent selectivity patterns. The origins of this remain unclear, but are linked to open questions about the more general role of metal ions in functional evolution and divergence within enzyme superfamilies. Here, we present detailed mechanistic studies of the paraoxonase and arylesterase activities of MPH complexed with five different transition metal ions, and demonstrate that the hydrolysis reactions proceed via similar pathways and transition states. However, while it is possible to discern a clear structural origin for the selectivity between different substrates, the selectivity between different metal ions appears to lie instead in the distinct electrostatic properties of the metal ions themselves, which causes subtle changes in transition state geometries and metal–metal distances at the transition state rather than significant structural changes in the active site. While subtle, these differences can be significant for shaping the metal-ion-dependent activity patterns observed for this enzyme.

This article is part of the themed issue ‘Multiscale modelling at the physics–chemistry–biology interface’.

Place, publisher, year, edition, pages
2016. Vol. 374, p. 20160150-
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:uu:diva-314104DOI: 10.1098/rsta.2016.0150ISI: 000391139300011OAI: oai:DiVA.org:uu-314104DiVA, id: diva2:1069218
Funder
Knut and Alice Wallenberg FoundationWenner-Gren FoundationsSwedish National Infrastructure for Computing (SNIC), 2014/11-2
Available from: 2017-01-27 Created: 2017-01-27 Last updated: 2017-02-08Bibliographically approved

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