Autocatalytic Hydrolysis of V-Type Nerve Agents

1996 ◽  
Vol 61 (24) ◽  
pp. 8407-8413 ◽  
Author(s):  
Yu-Chu Yang ◽  
Linda L. Szafraniec ◽  
William T. Beaudry ◽  
Dennis K. Rohrbaugh ◽  
Lawrence R. Procell ◽  
...  
Keyword(s):  
Nerve Agents ◽  
Hydrolysis Of

scholarly journals Catalytic activity and stereoselectivity of engineered phosphotriesterases towards structurally different nerve agents in vitro

2021 ◽  
Author(s):  
Anja Köhler ◽  
Benjamin Escher ◽  
Laura Job ◽  
Marianne Koller ◽  
Horst Thiermann ◽  
...  
Keyword(s):  
Plasma Clearance ◽  
Nerve Agents ◽  
Inhibition Assay ◽  
Ache Inhibition ◽  
Catalytic Activities ◽  
Chiral Lc ◽  
Hydrolysis Of ◽  
Medical Countermeasures

AbstractHighly toxic organophosphorus nerve agents, especially the extremely stable and persistent V-type agents such as VX, still pose a threat to the human population and require effective medical countermeasures. Engineered mutants of the Brevundimonas diminuta phosphotriesterase (BdPTE) exhibit enhanced catalytic activities and have demonstrated detoxification in animal models, however, substrate specificity and fast plasma clearance limit their medical applicability. To allow better assessment of their substrate profiles, we have thoroughly investigated the catalytic efficacies of five BdPTE mutants with 17 different nerve agents using an AChE inhibition assay. In addition, we studied one BdPTE version that was fused with structurally disordered PAS polypeptides to enable delayed plasma clearance and one bispecific BdPTE with broadened substrate spectrum composed of two functionally distinct subunits connected by a PAS linker. Measured kcat/KM values were as high as 6.5 and 1.5 × 108 M−1 min−1 with G- and V-agents, respectively. Furthermore, the stereoselective degradation of VX enantiomers by the PASylated BdPTE-4 and the bispecific BdPTE-7 were investigated by chiral LC–MS/MS, resulting in a several fold faster hydrolysis of the more toxic P(−) VX stereoisomer compared to P(+) VX. In conclusion, the newly developed enzymes BdPTE-4 and BdPTE-7 have shown high catalytic efficacy towards structurally different nerve agents and stereoselectivity towards the toxic P(−) VX enantiomer in vitro and offer promise for use as bioscavengers in vivo.

scholarly journals Hydrolysis of nerve agents by model nucleophiles: A computational study

2008 ◽  
Vol 175 (1-3) ◽  
pp. 200-203 ◽  
Author(s):  
Jeremy M. Beck ◽  
Christopher M. Hadad
Keyword(s):  
Computational Study ◽  
Nerve Agents ◽  
Hydrolysis Of

ChemInform Abstract: Design, Synthesis and Evaluation of New α-Nucleophiles for the Hydrolysis of Organophosphorus Nerve Agents: Application to the Reactivation of Phosphorylated Acetylcholinesterase.

ChemInform ◽  
2011 ◽  
Vol 42 (52) ◽  
pp. no-no
Author(s):  
Geraldine Saint-Andre ◽  
Maria Kliachyna ◽  
Sanjeevarao Kodepelly ◽  
Ludivine Louise-Leriche ◽  
Emilie Gillon ◽  
...  
Keyword(s):  
Nerve Agents ◽  
Design Synthesis ◽  
Organophosphorus Nerve Agents ◽  
Hydrolysis Of

Zirconium-Based Metal–Organic Frameworks for the Catalytic Hydrolysis of Organophosphorus Nerve Agents

2020 ◽  
Vol 12 (13) ◽  
pp. 14702-14720 ◽  
Author(s):  
Kent O. Kirlikovali ◽  
Zhijie Chen ◽  
Timur Islamoglu ◽  
Joseph T. Hupp ◽  
Omar K. Farha
Keyword(s):  
Metal Organic Frameworks ◽  
Nerve Agents ◽  
Catalytic Hydrolysis ◽  
Organophosphorus Nerve Agents ◽  
Metal Organic ◽  
Hydrolysis Of

scholarly journals Enzymes for the Homeland Defense: Optimizing Phosphotriesterase for the Hydrolysis of Organophosphate Nerve Agents

Biochemistry ◽  
2012 ◽  
Vol 51 (32) ◽  
pp. 6463-6475 ◽  
Author(s):  
Ping-Chuan Tsai ◽  
Nicholas Fox ◽  
Andrew N. Bigley ◽  
Steven P. Harvey ◽  
David P. Barondeau ◽  
...  
Keyword(s):  
Nerve Agents ◽  
Homeland Defense ◽  
Hydrolysis Of

scholarly journals Stereoselective Hydrolysis of Organophosphate Nerve Agents by the Bacterial Phosphotriesterase

Biochemistry ◽  
2010 ◽  
Vol 49 (37) ◽  
pp. 7978-7987 ◽  
Author(s):  
Ping-Chuan Tsai ◽  
Andrew Bigley ◽  
Yingchun Li ◽  
Eman Ghanem ◽  
C. Linn Cadieux ◽  
...  
Keyword(s):  
Nerve Agents ◽  
Stereoselective Hydrolysis ◽  
Hydrolysis Of

scholarly journals Bacterial Cell Surface Display of Organophosphorus Hydrolase for Selective Screening of Improved Hydrolysis of Organophosphate Nerve Agents

2002 ◽  
Vol 68 (4) ◽  
pp. 2026-2030 ◽  
Author(s):  
Catherine Mee-Hie Cho ◽  
Ashok Mulchandani ◽  
Wilfred Chen
Keyword(s):  
Methyl Parathion ◽  
Solid Phase ◽  
Surface Display ◽  
Cell Surface Display ◽  
Nerve Agents ◽  
Organophosphorus Hydrolase ◽  
Dna Shuffling ◽  
Ice Nucleation Protein ◽  
Wide Range ◽  
Hydrolysis Of

ABSTRACT Organophosphorus hydrolase (OPH) is a bacterial enzyme that has been shown to degrade a wide range of neurotoxic organophosphate nerve agents. However, the effectiveness of degradation varies dramatically, ranging from highly efficient with paraoxon to relatively slow with methyl parathion. Sequential cycles of DNA shuffling and screening were used to fine-tune and enhance the activity of OPH towards poorly degraded substrates. Because of the inaccessibility of these pesticides across the cell membrane, OPH variants were displayed on the surface of Escherichia coli using the truncated ice nucleation protein in order to isolate novel enzymes with truly improved substrate specificities. A solid-phase top agar method based on the detection of the yellow product p-nitrophenol was developed for the rapid prescreening of potential variants with improved hydrolysis of methyl parathion. Two rounds of DNA shuffling and screening were carried out, and several improved variants were isolated. One variant in particular, 22A11, hydrolyzes methyl parathion 25-fold faster than does the wild type. Because of the success that we achieved with directed evolution of OPH for improved hydrolysis of methyl parathion, we believe that we can easily extend this method in creating other OPH variants with improved activity against poorly degraded pesticides such as diazinon and chlorpyrifos and nerve agents such as sarin and soman.

scholarly journals Structural and Functional Characterization of New SsoPox Variant Points to the Dimer Interface as a Driver for the Increase in Promiscuous Paraoxonase Activity

2020 ◽  
Vol 21 (5) ◽  
pp. 1683 ◽  
Author(s):  
Yoko Suzumoto ◽  
Orly Dym ◽  
Giovanni N. Roviello ◽  
Franz Worek ◽  
Joel L. Sussman ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Catalytic Efficiency ◽  
Hydrolytic Activity ◽  
Nerve Agents ◽  
Process Step ◽  
Homologous Genes ◽  
New Variant ◽  
Genes Encoding ◽  
Hydrolysis Of

Increasing attention is more and more directed toward the thermostable Phosphotriesterase-Like-Lactonase (PLL) family of enzymes, for the efficient and reliable decontamination of toxic nerve agents. In the present study, the DNA Staggered Extension Process (StEP) technique was utilized to obtain new variants of PLL enzymes. Divergent homologous genes encoding PLL enzymes were utilized as templates for gene recombination and yielded a new variant of SsoPox from Saccharolobus solfataricus. The new mutant, V82L/C258L/I261F/W263A (4Mut) exhibited catalytic efficiency of 1.6 × 105 M−1 s−1 against paraoxon hydrolysis at 70°C, which is more than 3.5-fold and 42-fold improved in comparison with C258L/I261F/W263A (3Mut) and wild type SsoPox, respectively. 4Mut was also tested with chemical warfare nerve agents including tabun, sarin, soman, cyclosarin and VX. In particular, 4Mut showed about 10-fold enhancement in the hydrolysis of tabun and soman with respect to 3Mut. The crystal structure of 4Mut has been solved at the resolution of 2.8 Å. We propose that, reorganization of dimer conformation that led to increased central groove volume and dimer flexibility could be the major determinant for the improvement in hydrolytic activity in the 4Mut.

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