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J. Biol. Chem., Vol. 280, Issue 3, 1746-1753, January 21, 2005

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Myeloperoxidase Potentiates Nitric Oxide-mediated Nitrosation^*

Vijaya M. Lakshmi, William M. Nauseef¶, and Terry V. Zenser||**

From the Veterans Administration Medical Center and ^||Edward A. Doisy Department of Biochemistry and Molecular Biology and Division of Geriatric Medicine, St. Louis University School of Medicine, St. Louis, Missouri 63125 and the ^¶Inflammation Program and Department of Medicine, University of Iowa and Veterans Administration Medical Center, Iowa City, Iowa 52241

Nitrosation is an important reaction elicited by nitric oxide (NO). To better understand how nitrosation occurs in biological systems, we assessed the effect of myeloperoxidase (MPO), a mediator of inflammation, on nitrosation observed during NO autoxidation. Nitrosation of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ; 10 µM) to 2-nitrosoamino-3-methylimidazo[4,5-f]quinoline (N-NO-IQ) was monitored by HPLC. Using the NO donor spermine NONOate at pH 7.4, MPO potentiated N-NO-IQ formation. The minimum effective quantity of necessary components was 8.5 nM MPO, 0.25 µM H₂O₂/min, and 0.024 µM NO/min. Autoxidation was only detected at 1.2 µM NO/min. MPO potentiation was not affected by a 40-fold excess flux of H₂O₂ over NO or less than a 2.4-fold excess flux of NO over H₂O₂. Potentiation was due to an 8.8-fold increased affinity of MPO-derived nitrosating species for IQ. Autoxidation was inhibited by azide, suggesting involvement of the nitrosonium ion, NO⁺. MPO potentiation was inhibited by NADH, but not azide, suggesting oxidative nitrosylation with or an -like species. MPO nonnitrosative oxidation of IQ with 0.3 mM at pH 5.5 was inhibited by azide, but not NADH, demonstrating differences between MPO oxidation of IQ with NO compared with . Using phorbol ester-stimulated human neutrophils, N-NO-IQ formation was increased with superoxide dismutase and inhibited by catalase and NADH, but not NaN₃. This is consistent with nitrosation potentiation by MPO, not peroxynitrite. Increased N-NO-IQ formation was not detected with polymorphonuclear neutrophils from two unrelated MPO-deficient patients. Results suggest that the highly diffusible stable gas NO could initiate nitrosation at sites of neutrophil infiltration.

Received for publication, October 1, 2004

^* This work was supported by the Department of Veterans Affairs (to T. V. Z. and W. M. N) and NCI, National Institutes of Health (NIH), Grant CA72613 (to T. V. Z.). Mass spectrometry was performed at the Mass Spectrometry Resource Center (Washington University School of Medicine) through NIH Grants RR-00954 and AM-20579. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This manuscript is dedicated to Dr. Arnold A. White for his leadership and devotion to science.

^** To whom correspondence should be addressed: VA Medical Center (11G-JB), St. Louis, MO 63125. Tel.: 314-894-6510; Fax: 314-894-6614; E-mail: zensertv{at}slu.edu.

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