Nitric oxide synthase reactions

Endogenous NO is produced almost exclusively by L-arginine catabolism to L-citrul-line in a reaction catalyzed by a family of nitric oxide synthases (NOSs) [3]. In the first step, Arg is hydroxylated to an enzyme-bound intermediate "-hydroxy-1.-arginine (NHA), and 1 mol of NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) and O2 are consumed. In the second step, N H A is oxidized to citrulline and NO, with consumption of 0.5 mol of NADPH and 1 mol of 02 (Scheme 1.1). Oxygen activation in both steps is carried out by the enzyme-bound heme, which derives electrons from NADPH. Mammalian NOS consists of an N-terminal oxy-... 

Bec, N., Gorren, A. C., Voelker, C., Mayer, B., Lange, R., Reaction of neuronal nitric-oxide synthase with oxygen at low temperature. Evidence for reductive activation of the oxy-ferrous complex by tetrahydrobiopterin, J. Biol. Chem. 273 (1998), p. 13502-13508... 

Rusche, K. M., Spiering, M. M., Marletta, M. A., Reactions catalyzed by tetrahydrobiopterin-free nitric oxide synthase, Biochemistry VI (1998),... 

The role of arginase in some cells is not to produce urea but to regulate the concentration of arginine. This is important since arginine is the substrate for the reaction that produces an important messenger molecule, nitric oxide, via the enzyme nitric oxide synthase. 

Nitric oxide, which is produced from arginine in the reaction catalysed by nitric oxide synthase, reacts with O2 to produce the very toxic peroxynitrite free radical (Figure 17.27). 

Fig. 1. Nitric oxide (NO) synthesis by nitric oxide synthase (NOS) (upper left), NO reaction with soluble guanylate cyclase (sGC) (middle), and formation of cyclic GMP, which causes tissue-specific signaling (right). The roles of the salivary nitrophorins from Rhodnius prolixus in storing and releasing NO and binding histamine are included (lower left).

A less common reactive species is the Fe peroxo anion expected from two-electron reduction of O2 at a hemoprotein iron atom (Fig. 14, structure A). Protonation of this intermediate would yield the Fe —OOH precursor (Fig. 14, structure B) of the ferryl species. However, it is now clear that the Fe peroxo anion can directly react as a nucleophile with highly electrophilic substrates such as aldehydes. Addition of the peroxo anion to the aldehyde, followed by homolytic scission of the dioxygen bond, is now accepted as the mechanism for the carbon-carbon bond cleavage reactions catalyzed by several cytochrome P450 enzymes, including aromatase, lanosterol 14-demethylase, and sterol 17-lyase (133). A similar nucleophilic addition of the Fe peroxo anion to a carbon-nitrogen double bond has been invoked in the mechanism of the nitric oxide synthases (133). 

Synthesis and reactions of nitric oxide (NO). l-NMMA inhibits nitric oxide synthase. NO complexes with the iron in hemoproteins (eg, guanylyl cyclase), resulting in the activation of cGMP synthesis and cGMP target proteins such as protein kinase G. Under conditions of oxidative stress, NO can react with superoxide to nitrate tyrosine. 

Nitric oxide is synthesized from arginine in an NADPH-dependent reaction catalyzed by nitric oxide synthase (Fig. 22-31), a dimeric enzyme structurally related to NADPH cytochrome P-450 reductase (see Box 21-1). The reaction is a five-electron oxidation. Each subunit of the enzyme contains one bound molecule of each of four different cofactors FMN, FAD, tetrahydro-... 

First isolated from human urine, biopterin (Fig. 15-17) is present in liver and other tissues where it functions in a reduced form as a hydroxylation coenzyme (see Chapter 18).338 It is also present in nitric oxide synthase (Chapter 18).341/342 Other functions in oxidative reactions, in regulation of electron transport, and in photosynthesis have been proposed.343 Neopterin, found in honeybee larvae, resembles biopterin but has a D-erythro configuration in the side chain. The red eye pigments of Drosophila, called drosopterins, are complex dimeric pterins containing fused 7-membered rings (Fig. 15-17).344 345... 

Nucleophilic aromatic substitution reactions of nitro-substituted thiophenes have been utilized to prepare biologically active thiophenes including reverse transcriptase <02H(57)97> and nitric oxide synthase <02JHC857> inhibitors. The addition-elimination reaction of 2-chloro-3-nitrothiophene (56) with metallated indole 57 afforded 58 which was transformed into the corresponding thiophene-fused azepino[5,4,3-cd]indoles 59 <02H(57)1831>. 

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