title: Pressure-response analysis of anesthetic gases xenon and nitrous oxide on urate oxidase: a crystallographic study.
abstract: The remarkably safe anesthetics xenon (Xe) and, to lesser extent, nitrous oxide (N(2)O) possess neuroprotective properties in preclinical studies. To investigate the mechanisms of pharmacological action of these gases, which are still poorly known, we performed both crystallography under a large range of gas pressure and biochemical studies on urate oxidase, a prototype of globular gas-binding proteins whose activity is modulated by inert gases. We show that Xe and N(2)O bind to, compete for, and expand the volume of a hydrophobic cavity located just behind the active site of urate oxidase and further inhibit urate oxidase enzymatic activity. By demonstrating a significant relationship between the binding and biochemical effects of Xe and N(2)O, given alone or in combination, these data from structure to function highlight the mechanisms by which chemically and metabolically inert gases can alter protein function and produce their pharmacological effects. Interestingly, the effects of a Xe:N(2)O equimolar mixture were found to be equivalent to those of Xe alone, thereby suggesting that gas mixtures containing Xe and N(2)O could be an alternative and efficient neuroprotective strategy to Xe alone, whose widespread clinical use is limited due to the cost of production and availability of this gas.
authors.affiliation: Equipe de Recherche Technologique Interne (ERTi) 1083, Centre National de la Recherche Scientifique (CNRS), Centre Cyceron, Caen, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Marassio
authors.forename: Thierry
authors.initials: T
authors.lastname: Prangé
authors.forename: Hélène N
authors.initials: HN
authors.lastname: David
authors.forename: Jana Sopkova-de Oliveira
authors.initials: JS
authors.lastname: Santos
authors.forename: Laure
authors.initials: L
authors.lastname: Gabison
authors.forename: Nicolas
authors.initials: N
authors.lastname: Delcroix
authors.forename: Jacques H
authors.initials: JH
authors.lastname: Abraini
authors.forename: Nathalie
authors.initials: N
authors.lastname: Colloc'h
mesh_terms: D000465:Algorithms; D018685:Anesthetics, Inhalation / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D055162:Biocatalysis / Q000187:drug effects; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008958:Models, Molecular; D009609:Nitrous Oxide / Q000378:metabolism* / Q000494:pharmacology; D011312:Pressure; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D014503:Urate Oxidase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D014978:Xenon / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D018685:Anesthetics, Inhalation; D005656:Fungal Proteins; D014978:Xenon; D014503:Urate Oxidase; D009609:Nitrous Oxide