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JBC, Vol. 270, Issue 19, 11103-11110, May, 1995
K Narayanan, L Spack, K McMillan, RG Kilbourn, MA Hayward, BS Masters and OW Griffith
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 omega-monosubstituted L- arginine
analogs including N omega-alkyl-, N omega-amino-, and N omega-
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 (N delta-(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.
S-alkyl-L-thiocitrullines. Potent stereoselective inhibitors of nitric oxide synthase with strong pressor activity in vivo
Department of Biochemistry, Medical College of Wisconsin, Milwaukee 53226, USA.
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