Biosynthesis and Metabolism of Endothelium-Derived Nitric Oxide

BIOSYNTHESIS AND METABOLISM OF ENDOTHELIUM-DERIVED NITRIC OXIDE 

Schematic illustration of the conversion of L-arginine to NO plus L-citrulline by the enzyme NO synthase. Conversion requires the presence of NADPH, calcium (Ca), calmodulin (CM), and O2. Calcium complexes with CM and the Ca-CM complex binds to the enzyme. The asterisk signifies the basic amino nitrogen atom that undergoes oxidation and cleavage to form NO. Both of the basic amino nittogens are equivalent and either nitrogen can be incorporated into NO. 

There are cytosolic and membrane-bound isoforms of NO synthase. Certain soluble and particulate isoforms are constitutive and other soluble isoforms are inducible. The constitutive enzyme is, by definition, present in the catalytically active form and needs only to be stimulated by an appropriate chemical species, following which there is immediate formation of NO plus L-citrulline. This form of NO synthase requires calcium, and for the most part calmodulin, for stimulation of enzymatic activity. It is likely that an increase in intracellular free calcium in the presence of calmodulin is the signal for stimulation of NO synthase, and therefore, the production of NO. This view is consistent with the general understanding that, in vascular tissue, all endothelium-dependent vaso- 

UNIQUE CHEMICAL PROPERTIES FOR A UBIQUITOUS AND GENERAL PHYSIOLOGICAL MEDIATOR 

The on signal for guanylate cyclase activation by NO is represented by the binding of NO to heme and the accompanying detachment of the heme Fe axial ligand from the enzyme protein. The off signal is represented by breakdown of the unstable NO-heme complex with liberation of NO and reestablishment of the heme Fe axial ligand. 

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Ignarro, L. J., Biosynthesis and metabolism of endothelium-derived nitric oxide, Annu. Rev. Pharmacol. Toxicol. 30 (1990), p. 535-560... 

Hutchinson, P. J. A., Palmer, R. M. J., and Moncada, S. (1987). Comparative pharmacology of EDRF and nitric oxide on vascular strips. Eur. J. Pharmacol. 141, 445-451. Ignarro, L, J. (1990). Biosynthesis and metabolism of endothelium-derived nitric oxide, Annu. Rev. Pharmacol. Toxicol. 30, 535-560. 

III. BIOSYNTHESIS AND METABOLISM OF ENDOTHELIUM-DERIVED NITRIC OXIDE... 

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