NDLI: Nitrite as a Substrate and Inhibitor of Myeloperoxidase IMPLICATIONS FOR NITRATION AND HYPOCHLOROUS ACID PRODUCTION AT SITES OF INFLAMMATION

Content Provider	Journal of Biological Chemistry (JBC)
Author	Dalen, Christine J. Van Winterbourn, Christine C. Senthilmohan, Revathy Kettle, Anthony J.
Abstract	Myeloperoxidase is a heme enzyme of neutrophils that uses hydrogen peroxide to oxidize chloride to hypochlorous acid. Recently, it has been shown to catalyze nitration of tyrosine. In this study we have investigated the mechanism by which it oxidizes nitrite and promotes nitration of tyrosyl residues. Nitrite was found to be a poor substrate for myeloperoxidase but an excellent inhibitor of its chlorination activity. Nitrite slowed chlorination by univalently reducing the enzyme to an inactive form and as a consequence was oxidized to nitrogen dioxide. In the presence of physiological concentrations of nitrite and chloride, myeloperoxidase catalyzed little nitration of tyrosyl residues in a heptapeptide. However, the efficiency of nitration was enhanced at least 4-fold by free tyrosine. Our data are consistent with a mechanism in which myeloperoxidase oxidizes free tyrosine to tyrosyl radicals that exchange with tyrosyl residues in peptides. These peptide radicals then couple with nitrogen dioxide to form 3-nitrotyrosyl residues. With neutrophils, myeloperoxidase-dependent nitration required a high concentration of nitrite (1 mm), was doubled by tyrosine, and increased 4-fold by superoxide dismutase. Superoxide is likely to inhibit nitration by reacting with nitrogen dioxide and/or tyrosyl radicals. We propose that at sites of inflammation myeloperoxidase will nitrate proteins, even though nitrite is a poor substrate, because the co-substrate tyrosine will be available to facilitate the reaction. Also, production of 3-nitrotyrosine will be most favorable when the concentration of superoxide is low.
Related Links	http://www.jbc.org/content/275/16/11638.abstract
Ending Page	11644
Starting Page	11638
Page Count	7
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	16
Volume Number	275
DOI	10.1074/jbc.275.16.11638
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2000-04-21
Access Restriction	Open
Subject Keyword	Diethylenetriaminepentaacetic acid (DTPA) 4β-phorbol 12-myristate 13-acetate (PMA) Phosphate-buffered saline (PBS) High-performance liquid chromatography (HPLC) ENZYME CATALYSIS AND REGULATION
Alternative Title	Nitrite as a Substrate and Inhibitor of Myeloperoxidase
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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