Abstract
Nitric oxide synthase catalyzes the oxidation of a guanidino nitrogen of L-arginine to nitric oxide with concomitant formation of citrulline. Enzyme activity is inhibited by a variety of N(ω)-monosubstituted L-arginine analogs including N(ω)-alkyl-, N(ω)-amino-, and N(ω)-nitro-L-arginine derivatives. We report here that both constitutive and inducible isoforms of nitric oxide synthase are strongly inhibited by S-alkyl-L-thiocitrullines (N6-(S-alkyl)isothioureido-L-ornithines) with n-alkyl groups of one to three carbons. These compounds represent a novel class of inhibitors and are the most potent nitric oxide synthase-inhibiting amino acids described to date. Inhibition is reversible, stereoselective, and competitive with L-arginine. Spectral studies show no direct interaction of inhibitor sulfur with heme iron, a result in contrast to that seen previously with the parent compound, L-thiocitrulline. The S-alkyl-L-thiocitrullines have strong pressor activity in normotensive control rats; S-methyl-L-thiocitrulline reverses hypotension in a rat model of septic peritonitis and in dogs administered endotoxin. These latter findings suggest that the inhibitors may have therapeutic utility in treating hypotension due to the overproduction of nitric oxide.
Original language | English (US) |
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Pages (from-to) | 11103-11110 |
Number of pages | 8 |
Journal | Journal of Biological Chemistry |
Volume | 270 |
Issue number | 19 |
DOIs | |
State | Published - 1995 |
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology