Probing the mechanisms for the selectivity and promiscuity of methyl parathion hydrolase
Purg, Miha ; Pabis, Anna ; Baier, Florian ; Tokuriki, Nobuhiko ; Jackson, Colin and Kamerlin, Shina Caroline Lynn LU
(2016)
In Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Science
374(2080).
- 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... (More)
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'.
(Less)
- author
- Purg, Miha
; Pabis, Anna
; Baier, Florian
; Tokuriki, Nobuhiko
; Jackson, Colin
and Kamerlin, Shina Caroline Lynn
LU
- publishing date
- 2016-11-13
- type
- Contribution to journal
- publication status
- published
- keywords
- Binding Sites, Computer Simulation, Enzyme Activation, Enzyme Stability, Metals/chemistry, Models, Chemical, Models, Molecular, Organophosphates/chemistry, Phosphoric Monoester Hydrolases/chemistry, Protein Binding, Structure-Activity Relationship, Substrate Specificity
- in
- Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Science
- volume
- 374
- issue
- 2080
- article number
- 20160150
- pages
- 14 pages
- publisher
- Royal Society Publishing
- external identifiers
-
- pmid:27698033
- scopus:84992153854
- ISSN
- 1364-503X
- DOI
- 10.1098/rsta.2016.0150
- language
- English
- LU publication?
- no
- additional info
- © 2016 The Authors.
- id
- 6856838c-cb8a-4524-9aa3-09e6cddc2140
- date added to LUP
- 2025-01-11 21:27:42
- date last changed
- 2025-06-29 18:15:12
@article{6856838c-cb8a-4524-9aa3-09e6cddc2140,
abstract = {{<p>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'.</p>}},
author = {{Purg, Miha and Pabis, Anna and Baier, Florian and Tokuriki, Nobuhiko and Jackson, Colin and Kamerlin, Shina Caroline Lynn}},
issn = {{1364-503X}},
keywords = {{Binding Sites; Computer Simulation; Enzyme Activation; Enzyme Stability; Metals/chemistry; Models, Chemical; Models, Molecular; Organophosphates/chemistry; Phosphoric Monoester Hydrolases/chemistry; Protein Binding; Structure-Activity Relationship; Substrate Specificity}},
language = {{eng}},
month = {{11}},
number = {{2080}},
publisher = {{Royal Society Publishing}},
series = {{Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Science}},
title = {{Probing the mechanisms for the selectivity and promiscuity of methyl parathion hydrolase}},
url = {{http://dx.doi.org/10.1098/rsta.2016.0150}},
doi = {{10.1098/rsta.2016.0150}},
volume = {{374}},
year = {{2016}},
}