Objectif Nitric oxide (NO) has been known for many years as a component of air pollution, a cigarette smoke, and as an intermediate in the big scale manufacture of nitric acid. It is naturally produced, for example, through lightning discharge, and arises from many industrial processes involving combustion. Recently, however, NO and related compounds were recognized to play significant biological roles. NO is identified as the endothelium-derived relaxing factor involved in smooth muscle relaxation and vasodilatation. It also acts as a neuromodulator, is involved in macrophage activity, in platelet aggregation, and can be a carcinogen or antiparasitic agent. However, many chemical aspects of NO formation, for example the fate of NO and its derivatives under physiological conditions, remain unclear. In cells the amino acid L-arginine is converted to L-citrulline and NO by cytochrome P-450 type enzymes known as nitric oxide syntheses (NOS). In this process successive activation of two dioxygen molecules is required to oxidize a terminal guanidino group of L-arginine. The oxidation proceeds in two steps: the first one is a hydroxylation of N-H bond to form N-hydroxyl amine, while the second one is a three electron oxidation of hydroxyl amine to final products. The oxidation mechanism is not yet well understood. A databank on rate constants and thermodynamics for amine and hydroxyl amine oxidation reactions will be created first in order to facilitate the development of chemical models of NOS. Different heme- and non-heme metal complexes will be synthesized to check them as chemical models of NOS. The study of model systems will help to improve understanding of the mechanism of both oxidation steps of L-arginine by NOS. This would be used in designing a new generation of NO-pro drugs and inhibitors. The fate of NO after its formation in cells is crucial in understanding its physiological chemistry. NO could react with thiols and iron-sulfur clusters to form more stable compounds and to transfer NO to proper targets. The oxidative fate of S-nitroso thiols and iron-sulfur nytrosyl complexes is not well known and will be studied. Recombination of NO with a superoxide radical leads to the formation of peroxynitrite, which has been shown to play different biological roles. Peroxynitrite, for example, is believed to be responsible for the toxicity of NO. Phospholipid vesicles (liposomes) restore endothelium-dependent cholinergic relaxation in the thoratic aorta. This effect is probably connected to the repairing of the membrane functions of endothelium cells. Further studies are needed to determine the mechanism of membrane damage; NO and related compounds are believed to be involved in this mechanism. Thus physiological chemistry of NO derivatives, such as peroxynitrite, S-nitrosothiols, and iron-sulfur nytrosyl complexes, needs to be thoroughly investigated to evaluate their biological roles and possible targets. Different compounds, such as S-nitroso thiols, nytrosyl metal complexes, and inhibitors of NO could be brought into liposomes to have a synergetic effect on phospholipid vesicles. Programme(s) IC-INTAS - International Association for the promotion of cooperation with scientists from the independent states of the former Soviet Union (INTAS), 1993- Thème(s) 36 - Biochemistry and New Pharmaceutical Compounds Appel à propositions Data not available Régime de financement Data not available Coordinateur Centre National de la Recherche Scientifique Contribution de l’UE Aucune donnée Adresse Route de Narbonne 205 31077 Toulouse France Voir sur la carte Coût total Aucune donnée Participants (4) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire Institute of Pharmacology and Toxicology Ukraine Contribution de l’UE Aucune donnée Adresse 252057 Kiev Voir sur la carte Coût total Aucune donnée National Academy of Sciences of Ukraine Ukraine Contribution de l’UE Aucune donnée Adresse 340114 Donetsk Voir sur la carte Coût total Aucune donnée Russian Academy of Sciences Russie Contribution de l’UE Aucune donnée Adresse 142432 Chernogolovka, Moscow Region Voir sur la carte Coût total Aucune donnée UNIVERSITY OF DURHAM Royaume-Uni Contribution de l’UE Aucune donnée Adresse SOUTH ROAD DURHAM Voir sur la carte Coût total Aucune donnée
