Tetrahydrobiopterin nitric oxide synthase

FIGURE 32-7 Sources of free radical formation which may contribute to injury during ischemia-reperfusion. Nitric oxide synthase, the mitochondrial electron-transport chain and metabolism of arachidonic acid are among the likely contributors. CaM, calcium/calmodulin FAD, flavin adenine dinucleotide FMN, flavin mononucleotide HtT, tetrahydrobiopterin HETES, hydroxyeicosatetraenoic acids L, lipid alkoxyl radical LOO, lipid peroxyl radical NO, nitric oxide 0 "2, superoxide radical. 

Giovanelli, J., Campos, K. L., Kaufman, S., Tetrahydrobiopterin, a cofactor for rat cerebellar nitric oxide synthase, does not function as a reactant in the oxygenation of arginine, Proc. Natl. Acad. Sci. USA 88 (1991), p. 7091-7095... 

P. D., Loftus, M., Stuehr, D. J., Expression of human inducible nitric oxide synthase in a tetrahydrobiopterin (H4B)-deficient cell line H4B promotes assembly of enzyme subunits into an active dimmer, Proc. Natl. Acad. Sci. USA 92 (1995), p. 11771-11775... 

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... 

K., Wachter, H., Werner-Felmayer, G., Mayer, B., Identification of the 4-amino analogue of tetrahydrobiopterin as a dihydropteridine reductase inhibitor and a potent pteridine antagonist of rat neuronal nitric oxide synthase, Biochem. J. 320 (1996), p. 193-196... 

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

Reiativeiy recentiy, the gases nitric oxide (NO) and carbon monoxide (CO) have been found to act as neurotransmitters in the nervous system. Nitric oxide is synthesized from L-arginine via nitric oxide synthase, requiring NADPH as a co-enzyme and tetrahydrobiopterin as a cofactor. Unlike other neurotransmitters, NO is a smaii, very soiubie moiecuie and cannot be stored in synaptic vesicles. Rather, it is synthesized on demand and freeiy diffuses through membranes. It is not broken down enzymaticaiiy because it is unstabie and degrades rapidiy. NO may have several actions, one of which is to increase the production of cGMP by guanyiyi... 

A further review of the mechanism of action of tetrahydrobiopterin in nitric oxide synthases has appeared with emphasis on studies of the enzyme under high pressures <2006BBA578>. 

Mulsch, A., and Busse, R. (1991). Nitric oxide synthase in native and cultured endothelial cells Calcium/calmodulin and tetrahydrobiopterin are cofactors. J. Cardiovasc. Pharmacol. 17, S52-S56. 

Prosthetic groups contained within NOS. Nitric oxide synthases are isolated containing approximately one molecule each of heme, FAD, and FMN per subunit, and also contain variable quantities of tetrahydrobiopterin (0.1 to 1 molecule per subunit). 

Hevel, J. M., and Marietta, M. A. (1992). Macrophage nitric oxide synthase Relationship between enzyme-bound tetrahydrobiopterin and synthase activity. Biochemistry 31, 7160-7165. 

Mayer, B., John, M., and Bohme, E. (1990). Purification of a Ca /calmodulin-dependent nitric oxide synthase from procine cerebellum. Cofactor-role of tetrahydrobiopterin. FEES Lett. 277, 215-219. 

PTPS (6-Pyruvoyl Tetmhydropterin Synthase). 6-Pyruvoyl tetrahy-dropterin synthase catalyzes formation of tetrahydrobiopterin biosynthesis. Tetrahydrobiopterin is a cofactor for several important enzymes, such as aromatic amino acid hydroxylases and nitric oxide synthase (57). H. pylori protein HPAG1 0913 shares homology with members of the protein domain family PTPS. H. pylori protein shares poor sequence identity of 14% with the PTPS profile at an E-value of 10 10 and covers about 95% of the length of the profile. Fold recognition results also confirm the relationship between H. pylori protein and the PTPS protein domain family. A fold recognition algorithm ensures fitness of the H. pylori protein sequence on the three-dimensional structure of PTPS from... 

Weber, J. and Senior, A. E. (1997) Catalytic mechanism ofFl-ATPase, Biochim. Biophys. Acta 1319, 19-58. Wei, C-C., Wang, Z-Q., Wang., Q., Meade, A. L., Hemann, C., Hille, R., and Stuehr, D.J. (2001) Rapid kinetic stadies link tetrahydrobiopterin radical formation to heme-dioxy redyction and arginine hydroxylation in inducible nitric-oxide synthase, J. Biol Chem. 276, 315-319. 

Figure 11.4. Reaction catalyzedby Nitric oxide synthase (a), and arrangement of the coenzymes in the dimer (b). Electrons flow from NADPH and flavins of one snbnnit to the heme of the other. Arg denotes the snbstrate binding site. Tetrahydrobiopterin (BH4) also participates in electron transfer.

Tetrahydrobiopterin is not a vitamin, because it can be synthesized from GTP, as shown in Figure 10.2 (Thony et al., 2000). It is the coenzyme for mixed-function oxidases phenylalanine, tyrosine, and tryptophan hydroxylases alkyl glycerol monoxygenase, which catalyzes the cleavage of alkyl glycerol ethers and nitric oxide synthase in the formation of nitric oxide. In addition to its coenzyme role, tetrahydrobiopterin has a direct effect on neurons, acting to stimulate dopamine release via a cAMP-dependent protein kinase and a calcium channel (Koshimura et al., 2000). 

BH4 = Tetrahydrobiopterin CAM = Cytotoxic activated macrophage cNOS = Constitutive nitric oxide synthase CPR = Cytochrome P450 reductase EDRF = Endothelial-derived relaxation factor EPR = Electron paramagnetic resonance spectroscopy IL-1 = Interleukin-1 iNOS = Inducible nitric oxide synthase EPS = Lipopolysaccharide, or endotoxin NMMA = ISp-monomethyl-L-arginine NOS = Nitric oxide synthase ROS = Reactive oxygen species SOD = Superoxide dismutase TNF = Tumor necrosis factor. 

Matter, H., Kumar, H. S. A., Fedorov, R., Frey, A., Kotsonis, P., Hartmann, E., Froeh-lich, L. G., Reif, A., Pfeiderer, W., Scheu-rer, P., Ghosh, D. K., Schlichting, I., and Schmidt, H. H. (2005) Structural analysis of isoform-specific inhibitors targeting the tetrahydrobiopterin binding site of human nitric oxide synthases. J. Med. Chem. 48, 4783-4792. 

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). 

The amino acid Arginine is a precursor to a novel second messenger and neurotransmitter, which is a gas, nitric oxide. Nitric oxide is produced from arginine in an unusual five-electron oxidation that also yields citrulline (see Figure 21.3). The enzyme catalyzing the reaction, nitric oxide synthase, contains bound FMN, FAD, non-heme iron, and tetrahydrobiopterin. 

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