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Binding of a designed substrate analogue to diisopropyl fluorophosphatase: implications for the phosphotriesterase mechanism.

Blum MM, Löhr F, Richardt A, Rüterjans H, Chen JC
J Am Chem Soc 128 12750-7 (2006)
Related entries: 2gvu, 2gvw, 2gvx

Cited: 44 times
EuropePMC logo PMID: 17002369

Abstract

A wide range of organophosphorus nerve agents, including Soman, Sarin, and Tabun is efficiently hydrolyzed by the phosphotriesterase enzyme diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris. To date, the lack of available inhibitors of DFPase has limited studies on its mechanism. The de novo design, synthesis, and characterization of substrate analogues acting as competitive inhibitors of DFPase are reported. The 1.73 A crystal structure of O,O-dicyclopentylphosphoroamidate (DcPPA) bound to DFPase shows a direct coordination of the phosphoryl oxygen by the catalytic calcium ion. The binding mode of this substrate analogue suggests a crucial role for electrostatics in the orientation of the ligand in the active site. This interpretation is further supported by the crystal structures of double mutants D229N/N120D and D229N/N175D, designed to reorient the electrostatic environment around the catalytic calcium. The structures show no differences in their calcium coordinating environment, although they are enzymatically inactive. Additional double mutants E21Q/N120D and E21Q/N175D are also inactive. On the basis of these crystal structures and kinetic and mutagenesis data as well as isotope labeling we propose a new mechanism for DFPase activity. Calcium coordinating residue D229, in concert with direct substrate activation by the metal ion, renders the phosphorus atom of the substrate susceptible for attack of water, through generation of a phosphoenzyme intermediate. Our proposed mechanism may be applicable to the structurally related enzyme paraoxonase (PON), a component of high-density lipoprotein (HDL).

Reviews - 2gvv mentioned but not cited (4)

  1. Catalytic mechanisms for phosphotriesterases. Bigley AN, Raushel FM. Biochim Biophys Acta 1834 443-453 (2013)
  2. New insights about enzyme evolution from large scale studies of sequence and structure relationships. Brown SD, Babbitt PC. J Biol Chem 289 30221-30228 (2014)
  3. Promiscuity in the Enzymatic Catalysis of Phosphate and Sulfate Transfer. Pabis A, Duarte F, Kamerlin SC. Biochemistry 55 3061-3081 (2016)
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Articles - 2gvv mentioned but not cited (5)

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  2. Hydrolysis of DFP and the nerve agent (S)-sarin by DFPase proceeds along two different reaction pathways: implications for engineering bioscavengers. Wymore T, Field MJ, Langan P, Smith JC, Parks JM. J Phys Chem B 118 4479-4489 (2014)
  3. Similar Active Sites and Mechanisms Do Not Lead to Cross-Promiscuity in Organophosphate Hydrolysis: Implications for Biotherapeutic Engineering. Purg M, Elias M, Kamerlin SCL. J Am Chem Soc 139 17533-17546 (2017)
  4. Theoretical Studies Applied to the Evaluation of the DFPase Bioremediation Potential against Chemical Warfare Agents Intoxication. Soares FV, de Castro AA, Pereira AF, Leal DHS, Mancini DT, Krejcar O, Ramalho TC, da Cunha EFF, Kuca K. Int J Mol Sci 19 E1257 (2018)
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Reviews citing this publication (9)

  1. Enzyme promiscuity: a mechanistic and evolutionary perspective. Khersonsky O, Tawfik DS. Annu Rev Biochem 79 471-505 (2010)
  2. Neutron crystallography: opportunities, challenges, and limitations. Blakeley MP, Langan P, Niimura N, Podjarny A. Curr Opin Struct Biol 18 593-600 (2008)
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  5. Neutron Crystallography for the Study of Hydrogen Bonds in Macromolecules. Oksanen E, Chen JC, Fisher SZ. Molecules 22 E596 (2017)
  6. Organophosphate degrading microorganisms and enzymes as biocatalysts in environmental and personal decontamination applications. Yair S, Ofer B, Arik E, Shai S, Yossi R, Tzvika D, Amir K. Crit Rev Biotechnol 28 265-275 (2008)
  7. Use of NMR techniques for toxic organophosphorus compound profiling. Koskela H. J Chromatogr B Analyt Technol Biomed Life Sci 878 1365-1381 (2010)
  8. Challenges and advances in the computational modeling of biological phosphate hydrolysis. Petrović D, Szeler K, Kamerlin SCL. Chem Commun (Camb) 54 3077-3089 (2018)
  9. Organophosphate-Hydrolyzing Enzymes as First-Line of Defence Against Nerve Agent-Poisoning: Perspectives and the Road Ahead. Iyengar AR, Pande AH. Protein J 35 424-439 (2016)

Articles citing this publication (26)

  1. Computational redesign of a mononuclear zinc metalloenzyme for organophosphate hydrolysis. Khare SD, Kipnis Y, Greisen P, Takeuchi R, Ashani Y, Goldsmith M, Song Y, Gallaher JL, Silman I, Leader H, Sussman JL, Stoddard BL, Tawfik DS, Baker D. Nat Chem Biol 8 294-300 (2012)
  2. Catalytic versatility and backups in enzyme active sites: the case of serum paraoxonase 1. Ben-David M, Elias M, Filippi JJ, Duñach E, Silman I, Sussman JL, Tawfik DS. J Mol Biol 418 181-196 (2012)
  3. Structure and function of a "yellow" protein from saliva of the sand fly Lutzomyia longipalpis that confers protective immunity against Leishmania major infection. Xu X, Oliveira F, Chang BW, Collin N, Gomes R, Teixeira C, Reynoso D, My Pham V, Elnaiem DE, Kamhawi S, Ribeiro JM, Valenzuela JG, Andersen JF. J Biol Chem 286 32383-32393 (2011)
  4. Rapid determination of hydrogen positions and protonation states of diisopropyl fluorophosphatase by joint neutron and X-ray diffraction refinement. Blum MM, Mustyakimov M, Rüterjans H, Kehe K, Schoenborn BP, Langan P, Chen JC. Proc Natl Acad Sci U S A 106 713-718 (2009)
  5. Active Site Hydrophobicity and the Convergent Evolution of Paraoxonase Activity in Structurally Divergent Enzymes: The Case of Serum Paraoxonase 1. Blaha-Nelson D, Krüger DM, Szeler K, Ben-David M, Kamerlin SC. J Am Chem Soc 139 1155-1167 (2017)
  6. Structural characterization of the catalytic calcium-binding site in diisopropyl fluorophosphatase (DFPase)--comparison with related beta-propeller enzymes. Blum MM, Chen JC. Chem Biol Interact 187 373-379 (2010)
  7. In silico analyses of substrate interactions with human serum paraoxonase 1. Hu X, Jiang X, Lenz DE, Cerasoli DM, Wallqvist A. Proteins 75 486-498 (2009)
  8. Catalytic bioscavengers against toxic esters, an alternative approach for prophylaxis and treatments of poisonings. Masson P, Rochu D. Acta Naturae 1 68-79 (2009)
  9. Computational Modeling of Human Paraoxonase 1: Preparation of Protein Models, Binding Studies, and Mechanistic Insights. Sanan TT, Muthukrishnan S, Beck JM, Tao P, Hayes CJ, Otto TC, Cerasoli DM, Lenz DE, Hadad CM. J Phys Org Chem 23 357-369 (2010)
  10. Structural basis of the γ-lactone-ring formation in ascorbic acid biosynthesis by the senescence marker protein-30/gluconolactonase. Aizawa S, Senda M, Harada A, Maruyama N, Ishida T, Aigaki T, Ishigami A, Senda T. PLoS One 8 e53706 (2013)
  11. Hydrogen atoms in protein structures: high-resolution X-ray diffraction structure of the DFPase. Elias M, Liebschner D, Koepke J, Lecomte C, Guillot B, Jelsch C, Chabriere E. BMC Res Notes 6 308 (2013)
  12. Computational characterization of how the VX nerve agent binds human serum paraoxonase 1. Fairchild SZ, Peterson MW, Hamza A, Zhan CG, Cerasoli DM, Chang WE. J Mol Model 17 97-109 (2011)
  13. Paraoxonase activity against nerve gases measured by capillary electrophoresis and characterization of human serum paraoxonase (PON1) polymorphism in the coding region (Q192R). Kanamori-Kataoka M, Seto Y. Anal Biochem 385 94-100 (2009)
  14. In vitro and in vivo efficacy of PEGylated diisopropyl fluorophosphatase (DFPase). Melzer M, Heidenreich A, Dorandeu F, Gäb J, Kehe K, Thiermann H, Letzel T, Blum MM. Drug Test Anal 4 262-270 (2012)
  15. Mechanistic Insights into the Hydrolysis of Organophosphorus Compounds by Paraoxonase-1: Exploring the Limits of Substrate Tolerance in a Promiscuous Enzyme. Muthukrishnan S, Shete VS, Sanan TT, Vyas S, Oottikkal S, Porter LM, Magliery TJ, Hadad CM. J Phys Org Chem 25 1247-1260 (2012)
  16. Hyperthermophilic phosphotriesterases/lactonases for the environment and human health. Mandrich L, Merone L, Manco G. Environ Technol 31 1115-1127 (2010)
  17. Monitoring the hydrolysis of toxic organophosphonate nerve agents in aqueous buffer and in bicontinuous microemulsions by use of diisopropyl fluorophosphatase (DFPase) with (1)H- (31)P HSQC NMR spectroscopy. Gäb J, Melzer M, Kehe K, Wellert S, Hellweg T, Blum MM. Anal Bioanal Chem 396 1213-1221 (2010)
  18. Quantification of hydrolysis of toxic organophosphates and organophosphonates by diisopropyl fluorophosphatase from Loligo vulgaris by in situ Fourier transform infrared spectroscopy. Gäb J, Melzer M, Kehe K, Richardt A, Blum MM. Anal Biochem 385 187-193 (2009)
  19. The DFPase from Loligo vulgaris in sugar surfactant-based bicontinuous microemulsions: structure, dynamics, and enzyme activity. Wellert S, Tiersch B, Koetz J, Richardt A, Lapp A, Holderer O, Gäb J, Blum MM, Schulreich C, Stehle R, Hellweg T. Eur Biophys J 40 761-774 (2011)
  20. Seeing the chemistry in biology with neutron crystallography. Langan P, Chen JC. Phys Chem Chem Phys 15 13705-13712 (2013)
  21. Structure of biodiesel based bicontinuous microemulsions for environmentally compatible decontamination: A small angle neutron scattering and freeze fracture electron microscopy study. Wellert S, Karg M, Imhof H, Steppin A, Altmann HJ, Dolle M, Richardt A, Tiersch B, Koetz J, Lapp A, Hellweg T. J Colloid Interface Sci 325 250-258 (2008)
  22. Dynamics of the interfacial film in bicontinuous microemulsions based on a partly ionic surfactant mixture: A neutron spin-echo study. Wellert S, Altmann HJ, Richardt A, Lapp A, Falus P, Farago B, Hellweg T. Eur Phys J E Soft Matter 33 243-250 (2010)
  23. Three-dimensional structure of xylonolactonase from Caulobacter crescentus: A mononuclear iron enzyme of the 6-bladed β-propeller hydrolase family. Pääkkönen J, Hakulinen N, Andberg M, Koivula A, Rouvinen J. Protein Sci 31 371-383 (2022)
  24. Predicting Protein-Polymer Block Copolymer Self-Assembly from Protein Properties. Huang A, Paloni JM, Wang A, Obermeyer AC, Sureka HV, Yao H, Olsen BD. Biomacromolecules 20 3713-3723 (2019)
  25. Probing the Suitability of Different Ca2+ Parameters for Long Simulations of Diisopropyl Fluorophosphatase. Zlobin A, Diankin I, Pushkarev S, Golovin A. Molecules 26 5839 (2021)
  26. Theoretical Studies on Catalysis Mechanisms of Serum Paraoxonase 1 and Phosphotriesterase Diisopropyl Fluorophosphatase Suggest the Alteration of Substrate Preference from Paraoxonase to DFP. Zhang H, Yang L, Ma YY, Zhu C, Lin S, Liao RZ. Molecules 23 E1660 (2018)


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