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J Biol Chem, Vol. 273, Issue 15, 8882-8889, April 10, 1998

N⁵-(1-Imino-3-butenyl)-L-ornithine
A NEURONAL ISOFORM SELECTIVE MECHANISM-BASED INACTIVATOR OF NITRIC OXIDE SYNTHASE

From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

Nitric oxide synthase (NOS) catalyzes the NADPH- and O₂-dependent conversion of L-arginine to nitric oxide (NO) and citrulline; three isoforms, the neuronal (nNOS), endothelial, and inducible, have been identified. Because overproduction of NO is known to contribute to several pathophysiological conditions, NOS inhibitors are of interest as potential therapeutic agents. Inhibitors that are potent, mechanism-based, and relatively selective for the NOS isoform causing pathology are of particular interest. In the present studies we report that vinyl-L-NIO (N⁵-(1-imino-3-butenyl)-L-ornithine; L-VNIO) binds to and inhibits nNOS in competition with L-arginine (K_i = 100 nM); binding is accompanied by a type I optical difference spectrum consistent with binding near the heme cofactor without interaction as a sixth axial heme ligand. Such binding is fully reversible. However, in the presence of NADPH and O₂, L-VNIO irreversibly inactivates nNOS (k_inact = 0.078 min¹; K_I = 90 nM); inactivation is Ca²⁺/calmodulin-dependent. The cytochrome c reduction activity of the enzyme is not affected by such treatment, but the L-arginine-independent NADPH oxidase activity of nNOS is lost in parallel with the overall activity. Spectral analyses establish that the nNOS heme cofactor is lost or modified by L-VNIO-mediated mechanism-based inactivation of the enzyme. The inducible isoform of NOS is not inactivated by L-VNIO, and the endothelial isoform requires 20-fold higher concentrations to attain ~75% of the rate of inactivation seen with nNOS. Among the NOS inactivating L-arginine derivatives, L-VNIO is the most potent and nNOS-selective reported to date.

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