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Molecules 2018, 23(7), 1660; https://doi.org/10.3390/molecules23071660

Theoretical Studies on Catalysis Mechanisms of Serum Paraoxonase 1 and Phosphotriesterase Diisopropyl Fluorophosphatase Suggest the Alteration of Substrate Preference from Paraoxonase to DFP

1
College of Life Science and Engineering, Northwest Minzu University, Lanzhou 730030, China
2
MIIT Key Laboratory of Critical Materials Technology for New Energy Conversion and Storage, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin 150001, China
3
Inner Mongolia University of Technology, Hohhot 010051, China
4
Department of Applied Chemistry, Institute of Molecular Science and Center for Interdisciplinary Molecular Science, National Chiao-Tung University, Hsinchu 30050, Taiwan
5
Key Laboratory for Large-Format Battery Materials and System, Ministry of Education School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan 430074, China
*
Author to whom correspondence should be addressed.
Received: 2 June 2018 / Revised: 4 July 2018 / Accepted: 5 July 2018 / Published: 7 July 2018
(This article belongs to the Special Issue Theoretical Investigations of Reaction Mechanisms)
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Abstract

The calcium-dependent β-propeller proteins mammalian serum paraoxonase 1 (PON1) and phosphotriesterase diisopropyl fluorophosphatase (DFPase) catalyze the hydrolysis of organophosphorus compounds and enhance hydrolysis of various nerve agents. In the present work, the phosphotriesterase activity development between PON1 and DFPase was investigated by using the hybrid density functional theory method B3LYP. Based on the active-site difference between PON1 and DFPase, both the wild type and the mutant (a water molecule replacing Asn270 in PON1) models were designed. The results indicated that the substitution of a water molecule for Asn270 in PON1 had little effect on the enzyme activity in kinetics, while being more efficient in thermodynamics, which is essential for DFP hydrolysis. Structure comparisons of evolutionarily related enzymes show that the mutation of Asn270 leads to the catalytic Ca2+ ion indirectly connecting the buried structural Ca2+ ion via hydrogen bonds in DFPase. It can reduce the plasticity of enzymatic structure, and possibly change the substrate preference from paraoxon to DFP, which implies an evolutionary transition from mono- to dinuclear catalytic centers. Our studies shed light on the investigation of enzyme catalysis mechanism from an evolutionary perspective. View Full-Text
Keywords: enzyme evolution; hydrolysis; β-propeller protein; plasticity; reaction mechanism enzyme evolution; hydrolysis; β-propeller protein; plasticity; reaction mechanism
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Zhang, H.; Yang, L.; Ma, Y.-Y.; Zhu, C.; Lin, S.; Liao, R.-Z. Theoretical Studies on Catalysis Mechanisms of Serum Paraoxonase 1 and Phosphotriesterase Diisopropyl Fluorophosphatase Suggest the Alteration of Substrate Preference from Paraoxonase to DFP. Molecules 2018, 23, 1660.

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