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J. Biol. Chem., Vol. 276, Issue 37, 34458-34464, September 14, 2001
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From the Ornithine decarboxylase is the initial and
rate-limiting enzyme in the polyamine biosynthetic pathway.
Polyamines are found in all mammalian cells and are required for cell
growth. We previously demonstrated that N-hydroxyarginine
and nitric oxide inhibit tumor cell proliferation by inhibiting
arginase and ornithine decarboxylase, respectively, and, therefore,
polyamine synthesis. In addition, we showed that nitric oxide inhibits
purified ornithine decarboxylase by S-nitrosylation. Herein
we provide evidence for the chemical mechanism by which nitric oxide
and S-nitrosothiols react with cysteine residues in
ornithine decarboxylase to form an S-nitrosothiol(s) on the
protein. The diazeniumdiolate nitric oxide donor agent 1-diethyl-2-hydroxy-2-nitroso-hydrazine acts through an
oxygen-dependent mechanism leading to formation of the
nitrosating agents N2O3 and/or
N2O4. S-Nitrosoglutathione inhibits
ornithine decarboxylase by an oxygen-independent mechanism likely by
S-transnitrosation. In addition, we provide evidence for
the S-nitrosylation of 4 cysteine residues per ornithine
decarboxylase monomer including cysteine 360, which is critical for
enzyme activity. Finally S-nitrosylated ornithine
decarboxylase was isolated from intact cells treated with nitric oxide,
suggesting that nitric oxide may regulate ornithine decarboxylase
activity by S-nitrosylation in vivo.
Nitric Oxide Inhibits Ornithine Decarboxylase via
S-Nitrosylation of Cysteine 360 in the Active Site of the
Enzyme*
,,,¶
Department of Molecular and Medical
Pharmacology, UCLA School of Medicine, Los Angeles, California
90095-1735 and the § Department of Cellular and Molecular
Physiology, Milton S. Hershey Medical Center, Hershey, Pennsylvania
17033
*
This work was supported by National Institutes of Health
Grants HL 35014 (to L. J. I.), HL 40922 (to L. J. I.), and CA 18138 (to A. E. P.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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