title: Probing the mechanisms for the selectivity and promiscuity of methyl parathion hydrolase.
abstract: 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'.
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, BMC Box 596, Uppsala 75124, Sweden.
authors.forename: Miha
authors.initials: M
authors.lastname: Purg
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, BMC Box 596, Uppsala 75124, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Pabis
authors.affiliation: Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, BC, Canada V6T 1Z4.
authors.forename: Florian
authors.initials: F
authors.lastname: Baier
authors.affiliation: Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, BC, Canada V6T 1Z4 tokuriki@msl.ubc.ca.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Tokuriki
authors.affiliation: Research School of Chemistry, Building 138, The Australian National University, Canberra, Australian Capital Territory 0200, Australia colin.jackson@anu.edu.au.
authors.forename: Colin
authors.initials: C
authors.lastname: Jackson
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, BMC Box 596, Uppsala 75124, Sweden kamerlin@icm.uu.se.
authors.forename: Shina Caroline Lynn
authors.identifier: http://orcid.org/0000-0002-3190-1173
authors.initials: SC
authors.lastname: Kamerlin
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D004789:Enzyme Activation; D004795:Enzyme Stability; D008670:Metals / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D010755:Organophosphates / Q000737:chemistry*; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000648:ultrastructure*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D008670:Metals; D010755:Organophosphates; C495424:methyl parathion hydrolase, Pseudomonas; D010744:Phosphoric Monoester Hydrolases
keywords: catalytic promiscuity; empirical valence bond; enzyme catalysis; metal selectivity; organophosphate hydrolysis; protein evolution