Structure of Nitric Oxide Synthase

E. D., Stuehr, D. J.,Tainer, J. A., The structure of nitric oxide synthase oxygenase domain and inhibitor complexes, Science 278 (1997),... 

Crane, B.R, Arvai, A.S., Ghosh, D.K., Wu, C., Getzoff, E.D., Stuehr, D.J., and Tainer, J.A. (1998) Structure of nitric oxide synthase oxygenase dimer with pterin and substrate, Science 279, 2121-2126. 

Raman, C.S., Li, H., Martasek, P., Southan, G., Masters, B. S. S., Poulos, and Thomas, L. (2001), Crystal Structure of Nitric Oxide Synthase Bound to Nitro Indazole Reveals a Novel Inactivation Mechanism, Biochemistry 40 13448-13455. 

X-ray crystallographic structures of nitric oxide synthases cocrystallized with nitroindazole - 5-nitro-, 6-nitro-, 7-nitro-, or 3-bromo-7-nitroindazole have been established [181],... 

Raman, C.S., H.Y. Li, R Martasek, G. Southan, B.S.S. Masters, and T.L. Poulos (2001). Crystal structure of nitric oxide synthase bound to nitro imdazole reveals a novel inactivation mechanism. Biochemistry 4f>, 13448-13455. 

Figure 10.15 Structures of nitric oxide synthase inhibitors (64-69)...

Fig. 5.3 Chemical structures of nitric oxide synthase inhibitors. Mj-nitro-L-arginine (L-NNA) (a) 5-[2-[(l-iminoethyl)amino]ethyl]-L-homocysteine (GW274150) (b) A-[3-(aminomethyl)benzyl] acetamidine (1,400 W) (c) AG-monomethyl-L-arginine (l-NMMA) (d) 7-nitroindazole (7-NI) (e) aminoguanidine (f) A6-iminoethyl-L-lysine (L-NIL) (g)...

S. K., Weber, P. C., Structural characterization of nitric oxide synthase isoforms reveals striking active-site conservation, Nat. Struct. Biol. 6 (1999), p. 233-242... 

Structures of arginine and analogs of arginine that are inhibitors of nitric oxide synthase. Highlighted in the box is the hydrazine moiety of aminoguanidine that appears to confer selectivity of this inhibitor for the inducible isoform of nitric oxide synthase. 

Fischmann, T. O., Hruza, A., Niu, X. D., Fossetta, J. D. Lunn, C. A., Dolphin, E., Prongay, A. J., Reichert, P., Lundell, D. J., Narula, S. K. and Weber, P. C. (1999) Structural characterization of nitric oxide synthase isoforms reveals striking active-site conservation, Nature Struct. Biol. 6, 233-242. 

Structural characterization and kinetics of nitric oxide synthase in-... 

Protein crystals of nitric oxide synthase revealed its three-dimensional structure. 

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, tetrahydrobiopterin, and Fe heme. NO is an unstable molecule and cannot be stored. Its synthesis is stimulated by interaction of nitric oxide synthase with Ca -calmodulin (see Fig. 12-21). 

Myatt, L., Brockman, D. E., Eis, A. L., and Pollock, J. S. (1993). Immunohistochemical localization of nitric oxide synthase in the human placenta. Placenta 14, 487-495. Nadaud, S., Bonnardeaux, A., Lathrop, M., and Soubrier, F. (1994). Gene structure, polymorphism and mapping of the human endothelial nitric oxide synthase gene. Biochem. Bio-phys. Res. Commun. 198, 1027-1033. 

Xanthine oxidase can reduce nitrate to nitrite (Westerfield et al. 1959, Fridovich and Handler 1962). Xanthine oxidase and dissimilatory nitrate reductase share structural similarities. Both are molybdoenzymes and contain flavin adenine dinucleotide and Fe/S clusters (McCord 1985, Mitchell 1986, Payne et al. 1997). Zhang et al. (1998) reported that both purified bovine buttermilk xanthine oxidase and xanthine oxidase-containing inflamed human synovial tissue can generate NO by reducing nitrite in the presence of NADH. This nitrite reductase activity of xanthine oxidase may act as a supplement to the activity of nitric oxide synthase (NOS) to redistribute blood flow to ischaemic tissues when NOS activity is absent. 

While the fluid mosaic model of membrane stmcture has stood up well to detailed scrutiny, additional features of membrane structure and function are constantly emerging. Two structures of particular current interest, located in surface membranes, are tipid rafts and caveolae. The former are dynamic areas of the exo-plasmic leaflet of the lipid bilayer enriched in cholesterol and sphingolipids they are involved in signal transduction and possibly other processes. Caveolae may derive from lipid rafts. Many if not all of them contain the protein caveolin-1, which may be involved in their formation from rafts. Caveolae are observable by electron microscopy as flask-shaped indentations of the cell membrane. Proteins detected in caveolae include various components of the signal-transduction system (eg, the insutin receptor and some G proteins), the folate receptor, and endothetial nitric oxide synthase (eNOS). Caveolae and lipid rafts are active areas of research, and ideas concerning them and their possible roles in various diseases are rapidly evolving. 

Because NO synthases belong to the same superfamily of enzymes as cytochrome P-450, they are able to produce not only nitric oxide (although it is undoubtedly their main function) but also other free radicals, first of all, superoxide. In 1992, Pou et al. [148] showed that brain nitric oxide synthase (NOS I) produced superoxide identified as a DMPO—OOH adduct in a calcium- or calmodulin-dependent manner. This finding was confirmed in numerous studies for all three isoforms of NO synthase. Although the structures of all the three NO oxidase... 

---