Computational Design of Phosphotriesterase Improves V-Agent Degradation Efficiency

Jacob Kronenberg; Stanley Chu; Andrew Olsen; Dustin Britton; Leif Halvorsen; Shengbo Guo; Ashwitha Lakshmi; Jason Chen; Maria Jinu Kulapurathazhe; Cetara A. Baker; Benjamin C. Wadsworth; Cynthia J. Van Acker; John G. Lehman; Tamara C. Otto; P. Douglas Renfrew; Richard Bonneau; Jin Kim Montclare

doi:10.1002/open.202300263

Computational Design of Phosphotriesterase Improves V-Agent Degradation Efficiency

Jacob Kronenberg, Stanley Chu, Andrew Olsen, Dustin Britton, Leif Halvorsen, Shengbo Guo, Ashwitha Lakshmi, Jason Chen, Maria Jinu Kulapurathazhe, Cetara A. Baker, Benjamin C. Wadsworth, Cynthia J. Van Acker, John G. Lehman, Tamara C. Otto, P. Douglas Renfrew, Richard Bonneau, Jin Kim Montclare

Research output: Contribution to journal › Article › peer-review

Abstract

Organophosphates (OPs) are a class of neurotoxic acetylcholinesterase inhibitors including widely used pesticides as well as nerve agents such as VX and VR. Current treatment of these toxins relies on reactivating acetylcholinesterase, which remains ineffective. Enzymatic scavengers are of interest for their ability to degrade OPs systemically before they reach their target. Here we describe a library of computationally designed variants of phosphotriesterase (PTE), an enzyme that is known to break down OPs. The mutations G208D, F104A, K77A, A80V, H254G, and I274N broadly improve catalytic efficiency of VX and VR hydrolysis without impacting the structure of the enzyme. The mutation I106 A improves catalysis of VR and L271E abolishes activity, likely due to disruptions of PTE's structure. This study elucidates the importance of these residues and contributes to the design of enzymatic OP scavengers with improved efficiency.

Original language	English (US)
Article number	e202300263
Journal	ChemistryOpen
Volume	13
Issue number	7
DOIs	https://doi.org/10.1002/open.202300263
State	Published - Jul 2024

Keywords

computational design
enzyme engineering
nanoscavengers
nerve agents
organophosphates

ASJC Scopus subject areas

General Chemistry

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10.1002/open.202300263

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Kronenberg, J., Chu, S., Olsen, A., Britton, D., Halvorsen, L., Guo, S., Lakshmi, A., Chen, J., Kulapurathazhe, M. J., Baker, C. A., Wadsworth, B. C., Van Acker, C. J., Lehman, J. G., Otto, T. C., Renfrew, P. D., Bonneau, R., & Montclare, J. K. (2024). Computational Design of Phosphotriesterase Improves V-Agent Degradation Efficiency. ChemistryOpen, 13(7), Article e202300263. https://doi.org/10.1002/open.202300263

Kronenberg, J, Chu, S, Olsen, A, Britton, D, Halvorsen, L, Guo, S, Lakshmi, A, Chen, J, Kulapurathazhe, MJ, Baker, CA, Wadsworth, BC, Van Acker, CJ, Lehman, JG, Otto, TC, Renfrew, PD, Bonneau, R & Montclare, JK 2024, 'Computational Design of Phosphotriesterase Improves V-Agent Degradation Efficiency', ChemistryOpen, vol. 13, no. 7, e202300263. https://doi.org/10.1002/open.202300263

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title = "Computational Design of Phosphotriesterase Improves V-Agent Degradation Efficiency",

abstract = "Organophosphates (OPs) are a class of neurotoxic acetylcholinesterase inhibitors including widely used pesticides as well as nerve agents such as VX and VR. Current treatment of these toxins relies on reactivating acetylcholinesterase, which remains ineffective. Enzymatic scavengers are of interest for their ability to degrade OPs systemically before they reach their target. Here we describe a library of computationally designed variants of phosphotriesterase (PTE), an enzyme that is known to break down OPs. The mutations G208D, F104A, K77A, A80V, H254G, and I274N broadly improve catalytic efficiency of VX and VR hydrolysis without impacting the structure of the enzyme. The mutation I106 A improves catalysis of VR and L271E abolishes activity, likely due to disruptions of PTE's structure. This study elucidates the importance of these residues and contributes to the design of enzymatic OP scavengers with improved efficiency.",

keywords = "computational design, enzyme engineering, nanoscavengers, nerve agents, organophosphates",

author = "Jacob Kronenberg and Stanley Chu and Andrew Olsen and Dustin Britton and Leif Halvorsen and Shengbo Guo and Ashwitha Lakshmi and Jason Chen and Kulapurathazhe, {Maria Jinu} and Baker, {Cetara A.} and Wadsworth, {Benjamin C.} and {Van Acker}, {Cynthia J.} and Lehman, {John G.} and Otto, {Tamara C.} and Renfrew, {P. Douglas} and Richard Bonneau and Montclare, {Jin Kim}",

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AU - Guo, Shengbo

AU - Lakshmi, Ashwitha

AU - Chen, Jason

AU - Kulapurathazhe, Maria Jinu

AU - Baker, Cetara A.

AU - Wadsworth, Benjamin C.

AU - Van Acker, Cynthia J.

AU - Lehman, John G.

AU - Otto, Tamara C.

AU - Renfrew, P. Douglas

AU - Bonneau, Richard

AU - Montclare, Jin Kim

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AB - Organophosphates (OPs) are a class of neurotoxic acetylcholinesterase inhibitors including widely used pesticides as well as nerve agents such as VX and VR. Current treatment of these toxins relies on reactivating acetylcholinesterase, which remains ineffective. Enzymatic scavengers are of interest for their ability to degrade OPs systemically before they reach their target. Here we describe a library of computationally designed variants of phosphotriesterase (PTE), an enzyme that is known to break down OPs. The mutations G208D, F104A, K77A, A80V, H254G, and I274N broadly improve catalytic efficiency of VX and VR hydrolysis without impacting the structure of the enzyme. The mutation I106 A improves catalysis of VR and L271E abolishes activity, likely due to disruptions of PTE's structure. This study elucidates the importance of these residues and contributes to the design of enzymatic OP scavengers with improved efficiency.

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Computational Design of Phosphotriesterase Improves V-Agent Degradation Efficiency

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Keywords

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