Oxidation nitric oxide, 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. 

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).

---