Oxidation tetrahydrobiopterin-induced

FIGURE 2 Proposed reaction sequence of (6R)-5,6,7,8-tetrahydrobiopterin-induced oxidation of nitric oxide (NO). SOD, Superoxide dismutase. 

Mayer, B., Klatt, P., Werner, E. R., and Schmidt, K. (1995). Kinetics and mechanism of tetrahydrobiopterin-induced oxidation of nitric oxide. J. Biol. Chem. 270, 655-659. 

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... 

Gross, S. S., and Levi, R. (1992). Tetrahydrobiopterin synthesis. An absolute requirement for cytokine-induced nitric oxide generation by vascular smooth muscle. J. Biol. Chem. 267, 25722-25729. 

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. 

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. 

Hurshman, A.R. and M.A. Marietta (2002). Reactions catalyzed by the heme domain of inducible nitric oxide synthase Evidence for the involvement of tetrahydrobiopterin in electron transfer. Biochemistry 41, 3439-3456. 

Chen W, Druhan LJ, Chen CA, Hemarm C, Chen YR, Berka V, Tsai AL, Zweier JL (2010) Peroxynitrite induces destruction of the tetrahydrobiopterin and heme in endothelial nitrie oxide synthase transition from reversible to irreversible enzyme inhibition. Biochemistry 49 3129 3137... 

Frank, S., Madlener, M., PfeUschifter, J., Werner, S., 1998. Induction of inducible nitric oxide synthase and its corresponding tetrahydrobiopterin-cofactor-synthesizing enzyme GTP-cy-clohydrolase I during cutaneous wound repair. Journal of Investigative Dermatology 111, 1058-1064. 

Figure 3.2 Beneficial effects of folic acid on vascular wall. Folic acid circulates in human body as 5-methyltetrahydrofolate (5-MTHF). 5-MTHF lowers circulating homocysteine (Hey) levels, thus reducing systemic oxidative stress and Hcy-induced activation of prothrombotic mechanisms. In addition, vascular 5-MTHF has a favourable effect on intracellular Hey metabolism, attenuating Hcy-induced activation of NADPH oxidase isoforms (NOXs) in the vascular wall. Furthermore vascular 5-MTHF scavenges per se peroxynitrite (ONOO ) radicals in the vascular wall preventing the oxidation of vascular tetrahydrobiopterin (BH4) associated with endothelial nitric oxide synthase (eNOS) uncoupling and diminished vascular nitric oxide (NO) bioavailability. In total through these effects 5-MTHF lowers vascular oxidative and nitrosative stress. Thus by modulating vascular redox, 5-MTHF inhibits activation of proinffammatory pathways which orchestrate vascular wall inflammation and perpetuate endothelial dysfunction and atherogenesis development (unpublished).

The production of NO by NO-synthase (NOS) (Figure 12) involves two domains, a reductase which binds flavin and an oxygenase which comprises a heme unit to which the substrate L-arginine binds. Three different forms of NOS are known, an inducible (iNOS), an endothelial (eNOS) and a neuronal one (nNOS). The details of the arginine oxidation mechanism have been studied in recent years, but only at the level of free-radical formation as far as EPR is concerned, so that the heme related part has not been addressed in great detail since the last review. The free-radical part involves determination of not only NO but also the superoxide anion and the tetrahydrobiopterin radical, to name the most prominent representatives. For the purpose of the present context we only mention briefly some of the relevant investigations. The production of O2 from the nNOS oxygenase domain was reported, as was its release by iNOS and by eNOS. A review on this aspect has become available. The role of NO in relation ofNO and ONOO has been reviewed with respect to consequences in postischemic myocardium. The detection of the tetrahydrobiopterin radical in the first reaction cycle of eNOS and nNOS has been reported. The interplay... 

---