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J. Biol. Chem., Vol. 269, Issue 42, 26083-26091, 10, 1994
C Frey, K Narayanan, K McMillan, L Spack, SS Gross, BS Masters and OW Griffith
Nitric-oxide synthase (NOS) catalyzes the oxidation of L-arginine to
citrulline and nitric oxide (NO). The enzyme is inhibited by a variety of N
omega-monosubstituted L-arginine analogs, and some of these compounds are
useful in reversing pathologies associated with the overproduction of NO
(e.g. the hypotension of septic shock). We report here that
L-thiocitrulline (gamma-thioureido-L-norvaline) is a potent, stereospecific
inhibitor of the constitutive brain and endothelial isoforms of NOS as well
as the isoform induced in vascular smooth muscle cells by
lipopolysaccharide and interferon-gamma. Steady state kinetic studies show
L-thiocitrulline inhibition is competitive with L- arginine (Ki
approximately 4-20% of KArgm), indicating that initial binding is as a
substrate/product analog. In contrast to L-arginine and N
omega-methyl-L-arginine, the prototypic NOS inhibitor, L- thiocitrulline
binding elicits a "Type II" difference spectrum, indicating a high spin to
low spin transition of the iron in the heme cofactor. This finding suggests
that L-thiocitrulline is contributing the sixth ligand to heme iron,
probably through the thioureido sulfur. Such interaction with heme iron
neither stimulates nor inhibits the direct flavin-mediated cytochrome c
reduction activity of the enzyme, but it does inhibit heme-dependent
superoxide formation. In vivo, L- thiocitrulline is a potent pressor agent
in both normal and endotoxemic rats, the latter finding suggesting utility
in treating the hypotension of septic shock.
L-thiocitrulline. A stereospecific, heme-binding inhibitor of nitric- oxide synthases
Department of Biochemistry, Medical College of Wisconsin, Milwaukee 53226.
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