N-Hydroxyguanidines as Substrates of Nitric Oxide Synthases

Abstract

Nitric oxide (NO) has been implicated in a wide variety of disease states. Both inhibitors and substrates of nitric oxide synthase (NOS) could have great therapeutic potential in the treatment of these diseases. There is considerable pharmacological interest in developing inhibitors of NOS, and hundreds of inhibitors have been identified. In contrast, the study on NOS substrates is less active. The advances in the identification, design and development of NOS substrates are discussed in this review. The focus is the chemistry and biochemistry of N-hydroxyguanidines. The crystal structures of substrates bound to NOSs and the mechanisms of NOS catalyzed NO generation from substrates are also discussed.

Comparison of wild type neuronal nitric oxide synthase and its Tyr588Phe mutant towards various l-arginine analogues

“…Globally, similar results about the ability of iNOS and eNOS to form NO upon oxidation of a great number of NOHG, even not bearing an α-amino acid moiety, and of a limited number of alkyl-Gua, have been reported [33,36]. This is expected if one considers that the three NOS isoforms exhibit almost superimposable 3D structures of their active site [25][26][27][28][29][30].…”

“…Furthermore, simple molecular models suggest that a Fe III -O-O − (or a Fe III -O-OH) complex that can easily rotate around its Fe-O bond could adopt more flexible conformations than a [Fe IV O] +• complex and react with substrates less well-positioned in the NOS active site [36,48]. Such a strict substrate positioning and the existence of a distal H-bonds network well organized for proton transfer appear to be crucial for the first step of NOS catalysis.…”

“…NOSs not only catalyze the oxidation of L-Arg and NOHA but also the oxidation of some non α-amino acid alkylguanidines (Gua) [32,33], and N-alkyl-and N-aryl-N′-hydroxyguanidines (NOHG) with formation of NO in reactions very similar to the oxidation of L-Arg and NOHA to citrulline and NO [33][34][35][36]. Different binding modes are reported for some aryl-and alkyl-NOHG in the substrate-binding pocket of NOSs [29,37].…”

“…In the case of 4-chlorophenyl-NOHG, the aryl-group is directed towards the hemepropionate of eNOS [37]. Anyway, the NOHG moiety of these small compounds remains in close proximity of the heme and reacts with the heme-active species to form NO [33][34][35][36].…”

Modification of Rat Model of Sciatica Induced by Lumber Disc Herniation and the Anti-Inflammatory Effect of Osthole Given by Epidural Catheterization

“…NOS also has a C-terminal reductase domain consisting of flavin mononucleotide, flavin adenine dinucleotide, and NADPH-binding sites [32]. The constitutive isoforms (nNOS and endothelial NOS) require excess Ca 2+ and calmodulin for activity and produce relatively small amounts of NO, while iNOS is considered calcium insensitive due to covalently bound Ca 2+ and calmodulin, and therefore produces a relatively large amount of NO [33]. In this study, the crystal structure of nNOS heme domain in complex with an internal ligand was selected as target protein for binding with osthole.…”