Phosphotriesterase
IntroductionPhosphotriesterase (PTE) is an enzyme that plays a significant role in the detoxification and degradation of organophosphorus compounds, specifically phosphotriester pesticides and nerve agents. These compounds are highly toxic and can have detrimental effects on the environment and living organisms. Phosphotriesterase acts by catalyzing the hydrolysis of the phosphorus-oxygen bond in these compounds, converting them into non-toxic products. FunctionPhosphotriesterase or aryldialkylphosphatase or haloalkylphosphorus hydrolase or organophosphorus hydrolase or parathion hydrolase (PTE) catalyzes the conversion of aryl dialkyl phosphate to dialkyl phosphate and aryl alcohol[1]. For more details see SsoPox: a natural lactonase with promiscuous phosphotriesterase activities. RelevancePTE has no known natural substrate but has potential in detoxification of organophosphates poisons lethal effects. PTE can detoxify the insecticide paraoxon and the chemical warfare agent sarin[2]. Structural highlightsThe structure of phosphotriesterase typically consists of a single polypeptide chain folded into a globular shape. It contains an active site that can accommodate and bind phosphotriester substrates. The active site usually consists of a metal ion, such as zinc, that assists in the catalytic process. The catalytic mechanism of phosphotriesterase involves the nucleophilic attack of a water molecule on the phosphorus atom of the phosphotriester substrate. This attack results in the cleavage of the phosphorus-oxygen bond and the formation of a phosphorylated enzyme intermediate. Subsequently, a second water molecule hydrolyzes the phosphorylated enzyme intermediate, leading to the release of the hydrolyzed product and the regenerated enzyme. The [3].Water molecules are shown as red spheres. Phosphotriesterases have been extensively studied in order to increase their catalytic efficiency by directed evolution and structure based design[4][1][5][6][7][8][9]. 3D structures of phosphotriesterasePhosphotriesterase 3D structures
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ReferencesReferences
- ↑ 1.0 1.1 Roodveldt C, Tawfik DS. Directed evolution of phosphotriesterase from Pseudomonas diminuta for heterologous expression in Escherichia coli results in stabilization of the metal-free state. Protein Eng Des Sel. 2005 Jan;18(1):51-8. PMID:15790580 doi:http://dx.doi.org/10.1093/protein/gzi005
- ↑ Bigley AN, Mabanglo MF, Harvey SP, Raushel FM. Variants of Phosphotriesterase for the Enhanced Detoxification of the Chemical Warfare Agent VR. Biochemistry. 2015 Aug 25. PMID:26274608 doi:http://dx.doi.org/10.1021/acs.biochem.5b00629
- ↑ Kim J, Tsai PC, Chen SL, Himo F, Almo SC, Raushel FM. Structure of diethyl phosphate bound to the binuclear metal center of phosphotriesterase. Biochemistry. 2008 Sep 9;47(36):9497-504. Epub 2008 Aug 15. PMID:18702530 doi:10.1021/bi800971v
- ↑ Griffiths AD, Tawfik DS. Directed evolution of an extremely fast phosphotriesterase by in vitro compartmentalization. EMBO J. 2003 Jan 2;22(1):24-35. doi: 10.1093/emboj/cdg014. PMID:12505981 doi:http://dx.doi.org/10.1093/emboj/cdg014
- ↑ Jackson CJ, Foo JL, Tokuriki N, Afriat L, Carr PD, Kim HK, Schenk G, Tawfik DS, Ollis DL. Conformational sampling, catalysis, and evolution of the bacterial phosphotriesterase. Proc Natl Acad Sci U S A. 2009 Dec 4. PMID:19966226
- ↑ Goldsmith M, Eckstein S, Ashani Y, Greisen P Jr, Leader H, Sussman JL, Aggarwal N, Ovchinnikov S, Tawfik DS, Baker D, Thiermann H, Worek F. Catalytic efficiencies of directly evolved phosphotriesterase variants with structurally different organophosphorus compounds in vitro. Arch Toxicol. 2016 Nov;90(11):2711-2724. doi: 10.1007/s00204-015-1626-2. Epub, 2015 Nov 26. PMID:26612364 doi:http://dx.doi.org/10.1007/s00204-015-1626-2
- ↑ Goldsmith M, Aggarwal N, Ashani Y, Jubran H, Greisen PJ, Ovchinnikov S, Leader H, Baker D, Sussman JL, Goldenzweig A, Fleishman SJ, Tawfik DS. Overcoming an optimization plateau in the directed evolution of highly efficient nerve agent bioscavengers. Protein Eng Des Sel. 2017 Apr 1;30(4):333-345. doi: 10.1093/protein/gzx003. PMID:28159998 doi:http://dx.doi.org/10.1093/protein/gzx003
- ↑ Goldsmith M, Tawfik DS. Enzyme engineering: reaching the maximal catalytic efficiency peak. Curr Opin Struct Biol. 2017 Dec;47:140-150. doi: 10.1016/j.sbi.2017.09.002. Epub , 2017 Oct 16. PMID:29035814 doi:http://dx.doi.org/10.1016/j.sbi.2017.09.002
- ↑ Goldsmith M, Ashani Y. Catalytic bioscavengers as countermeasures against organophosphate nerve agents. Chem Biol Interact. 2018 Aug 25;292:50-64. doi: 10.1016/j.cbi.2018.07.006. Epub, 2018 Jul 7. PMID:29990481 doi:http://dx.doi.org/10.1016/j.cbi.2018.07.006