TAILIEUCHUNG - Báo cáo khoa học: Reactivity of the heme–dioxygen complex of the inducible nitric oxide synthase in the presence of alternative substrates

Single turnover reactions of the inducible nitric oxide synthase oxygenase domain (iNOSoxy) in the presence of several nona-amino acid N-hydroxy-guanidines and guanidines were studied by stopped-flow visible spectro-scopy, and compared with reactions using the native substrates l-arginine (l-arg) or N x -hydroxy-l-arginine (NOHA). | iFEBS Journal Reactivity of the heme-dioxygen complex of the inducible nitric oxide synthase in the presence of alternative substrates David Lefevre-Groboillot1 2 Jean-Luc Boucher2 Daniel Mansuy2 and Dennis J. Stuehr1 1 Department of Immunology The Lerner Research Institute Cleveland Clinic Foundation Cleveland Ohio USA 2 Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques UMR 8601 CNRS Paris France Keywords guanidines hydroxyguanidines heme-dioxygen complex nitric oxide synthase stopped flow visible spectroscopy Correspondence D. Stuehr Department of Immunology The Lerner Research Institute Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland OH 44195 USA Fax 33 1216 4449329 Tel 33 1216 4456950 E-mail stuehrd@ Received 25 July 2005 revised 17 October 2005 accepted 8 November 2005 doi Single turnover reactions of the inducible nitric oxide synthase oxygenase domain iNOSoxy in the presence of several non a-amino acid N-hydroxy-guanidines and guanidines were studied by stopped-flow visible spectroscopy and compared with reactions using the native substrates L-arginine L-arg or N -hydroxy-L-arginine NOHA . In experiments containing dihydrobiopterin a catalytically incompetent pterin and each of the studied substrates L-arg butylguanidine BuGua para-fluorophenylguanidine FPhGua NOHA N-butyl- and N- para-fluorophenyl -N -hydroxyguani-dines BuNOHG and FPhNOHG the formation of a iron II heme-dioxy-gen intermediate FenO2 was always observed. The FenO2 species then decayed to iron III iNOSoxy at rates that were dependent on the nature of the substrate. Identical reactions containing the catalytically competent cofactor tetrahydrobiopterin BH4 iNOSoxy and the three N-hydroxy-guanidines all exhibited an initial formation of an FeIIO2 species that was successively converted to an FeIIINO complex and eventually to high-spin iron III iNOSoxy. The formation and decay kinetics of the FeIIINO complex did not vary greatly

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