Arginine, nitric oxide synthesis from

Hibbs, J. B., Jr., Westenfelder, C., Taintor, R., Vavrin, Z., Kablitx, C., Baranowski, R. L., Ward, J. H., Menlove, R. L., McMurry, M. P., Kushner, J. P., and Samlowski, W. E. (1992). Evidence for cytokine-inducible nitric oxide synthesis from L-arginine in patients receiving interleukin-2 therapy. J. Clin. Invest. 89, 867-877. 

Garthwaite, J., Garthwaite, G., Palmer, R.M.J., Moncada, S. (1989). NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices. Eur. J. Pharmacol. 172 413-16. 

N. K., Palmer, R. M., Whittle, B. J., Moncada, S., Synthesis of nitric oxide from L-arginine by neutrophils. Release and interaction with superoxide anion, Biochem. J. 261 (1989), p. 293-296... 

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). 

FIGURE I Role for calmodulin (CaM) in triggering interdomain electron transfer to the nitric oxide synthase (NOS) heme iron. Electrons derived from NADPH can transfer only into the flavin centers of CaM-free neuronal NOS (A). CaM binding to NOS occurs in response to elevated Ca concentrations, and this enables electrons to transfer from the flavins to the heme iron. Heme iron reduction is associated with increased NADPH oxidation and results in (B) superoxide (O2) production in the absence of L-arginine or (C) nitric oxide (NO) synthesis in the presence of L-arginine. FAD, Flavin-adenine dinucleotide FMN, flavin mononucleotide. 

FIGURE 2 Proposed dual mode for calmodulin (CaM) control of nitric oxide synthase (NOS) electron transfer. Neuronal NOS is composed of a reductase and an oxygenase domain, shown as two circles. CaM binding to NOS activates at two points in the electron transfer sequence (1) It increases the rate at which NADPH-derived electrons are transferred into the flavins, and (2) it enables the flavins to pass electrons to the oxygenase domain of NOS. Activation at the first point is associated with an increase in reductase domain-specific catalytic activities, such as electron transfer to cytochrome c or ferricyanide (FeCN ). Activation at the second point is associated with a reduction of NOS heme iron, an initiation of NO synthesis from L-arginine (Arg), or a reduction of Oj to form superoxide (O2) in the absence of substrate. FAD, Flavin-adenine dinucleotide FMN, flavin mononucleotide NO, nitric oxide. 

Murad, F., Ishii, K., Gorsky, F., FOrstermann, U., Kerwin, J. F., and Heller, M. (1990). Endothelium-derived relaxing factor is a ubiquitous intracellular second messenger and extracelluar paracrine substance for cyclic GMP synthesis. In Nitric Oxide from L-Arginine A Bioregulatory System (S. Moncada and E. A. Higgs, eds.), pp. 301-315. Elsevier, Amsterdam. 

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