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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Kirby, Stephen D. Norris, Joseph R. Richard Smith, J. Bahnson, Brian J. Cerasoli, Douglas M. |
| Description | Country affiliation: United States Author Affiliation: Kirby SD ( US Army Medical Research Institute of Chemical Defense, Research Division, Physiology and Immunology Branch, 3100 Ricketts Point Road, Aberdeen Proving Grounds, MD 21010-5400, USA. stephen.drew.kirby@us.army.mil) |
| Abstract | Variants of human paraoxonase 1 (PON1) are being developed as catalytic bioscavengers for the organophosphorus chemical warfare agents (OP). It is preferable that the new PON1 variants have broad spectrum hydrolase activities to hydrolyze both G- and V-class OPs. H115W PON1 has shown improvements over wild type PON1 in its capacity to hydrolyze some OP compounds. We improved upon these activities either by substituting a tryptophan (F347W) near the putative active site residues for enhanced substrate binding or by reducing a bulky group (Y71A) at the periphery of the putative enzyme active site. When compared to H115W alone, we found that H115W/Y71A and H115W/F347W maintained VX catalytic efficiency but showed mixed results for the capacity to hydrolyze paraoxon. Testing our double mutants against racemic sarin, we observed reduced values of K(M) for H115W/F347W that modestly improved catalytic efficiency over wild type and H115W. Contrary to previous reports, we show that H115W can hydrolyze soman, and the double mutant H115W/Y71A is nearly 4-fold more efficient than H115W for paraoxon hydrolysis. We also observed modest stereoselectivity for hydrolysis of the P(-) stereoisomer of tabun by H115W/F347W. These data demonstrate enhancements made in PON1 for the purpose of developing an improved catalytic bioscavenger to protect cholinesterase against chemical warfare agents. |
| File Format | HTM / HTML |
| ISSN | 00092797 |
| Issue Number | 1 |
| Volume Number | 203 |
| e-ISSN | 18727786 |
| Journal | Chemico-Biological Interactions |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2013-03-25 |
| Publisher Place | Ireland |
| Access Restriction | One Nation One Subscription (ONOS) |
| Subject Keyword | Discipline Biochemistry Discipline Pharmacology Aryldialkylphosphatase Genetics Metabolism Chemical Warfare Agents Organophosphorus Compounds Amino Acid Substitution Antidotes Chemistry Catalytic Domain Classification Toxicity Humans Hydrolysis Kinetics Models, Molecular Mutagenesis, Site-directed Mutant Proteins Organophosphates Organothiophosphorus Compounds Paraoxon Protein Engineering Recombinant Proteins Sarin Soman Substrate Specificity Journal Article Research Support, U.s. Gov't, Non-p.h.s. |
| Content Type | Text |
| Resource Type | Article |
| Subject | Medicine Toxicology |
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