Efficient formation of nitric oxide from selective oxidation of N-aryl N'-hydroxyguanidines by inducible nitric oxide synthase.
Inducible nitric oxide synthase (NOS II) efficiently catalyzes the oxidation of N-(4-chlorophenyl)N'-hydroxyguanidine 1 by NADPH and O2, with concomitant formation of the corresponding urea and NO. The characteristics of this reaction are very similar to those of the NOS-dependent oxidation of endogenous Nomega-hydroxy-L-arginine (NOHA), i.e., (i) the formation of products resulting from an oxidation of the substrate C=N(OH) bond, the corresponding urea and NO, in a 1:1 molar ratio, (ii) the absolute requirement of the tetrahydrobiopterin (BH4) cofactor for NO formation, and (iii) the strong inhibitory effects of L-arginine (L-arg) and classical inhibitors of NOSs. N-Hydroxyguanidine 1 is not as good a substrate for NOS II as is NOHA (Km = 500 microM versus 15 microM for NOHA). However, it leads to relatively high rates of NO formation which are only 4-fold lower than those obtained with NOHA (Vm = 390 +/- 50 nmol NO min-1 mg protein-1, corresponding roughly to 100 turnovers min-1). Preliminary results indicate that some other N-aryl N'-hydroxyguanidines exhibit a similar behavior. These results show for the first time that simple exogenous compounds may act as NO donors after oxidative activation by NOSs. They also suggest a possible implication of NOSs in the oxidative metabolism of certain classes of xenobiotics.
Renodon-Cornière
A
A
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, URA 400 CNRS, Université Paris V, 45 Rue des Saints-Pères, 75270 Paris Cedex 06, France.
Boucher
J L
JL
Dijols
S
S
Stuehr
D J
DJ
Mansuy
D
D
D001708:Biopterins / Q000031:analogs & derivatives / Q000737:chemistry; D002384:Catalysis; D006146:Guanidines / Q000737:chemistry*; D006898:Hydroxylamines; D007700:Kinetics; D009249:NADP / Q000737:chemistry; D009569:Nitric Oxide / Q000138:chemical synthesis*; D019001:Nitric Oxide Synthase / Q000737:chemistry*; D052247:Nitric Oxide Synthase Type II; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry; D014508:Urea / Q000737:chemistry
D006146:Guanidines; D006898:Hydroxylamines; D001708:Biopterins; D009569:Nitric Oxide; D009249:NADP; C029604:hydroxyguanidine; D014508:Urea; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C003402:sapropterin; D010100:Oxygen