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J. Biol. Chem., Vol. 280, Issue 7, 5983-5993, February 18, 2005

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Tyrosine 192 in Apolipoprotein A-I Is the Major Site of Nitration and Chlorination by Myeloperoxidase, but Only Chlorination Markedly Impairs ABCA1-dependent Cholesterol Transport^*

Baohai Shao, Constanze Bergt, Xiaoyun Fu, Pattie Green, John C. Voss, Michael N. Oda¶, John F. Oram, and Jay W. Heinecke||

From the Department of Medicine, University of Washington, Seattle, Washington 98195, the Department of Biological Chemistry, University of California, Davis, California 95616, and ^¶Children's Hospital Research Institute, Oakland, California 94609

High density lipoprotein (HDL) isolated from human atherosclerotic lesions and the blood of patients with established coronary artery disease contains elevated levels of 3-nitrotyrosine and 3-chlorotyrosine. Myeloperoxidase (MPO) is the only known source of 3-chlorotyrosine in humans, indicating that MPO oxidizes HDL in vivo. In the current studies, we used tandem mass spectrometry to identify the major sites of tyrosine oxidation when lipid-free apolipoprotein A-I (apoA-I), the major protein of HDL, was exposed to MPO or peroxynitrite (ONOO^-). Tyrosine 192 was the predominant site of both nitration and chlorination by MPO and was also the major site of nitration by ONOO^-. Electron paramagnetic spin resonance studies of spin-labeled apoA-I revealed that residue 192 was located in an unusually hydrophilic environment. Moreover, the environment of residue 192 became much more hydrophobic when apoA-I was incorporated into discoidal HDL, and Tyr¹⁹² of HDL-associated apoA-I was a poor substrate for nitration by both myeloperoxidase and ONOO^-, suggesting that solvent accessibility accounted in part for the reactivity of Tyr¹⁹². The ability of lipid-free apoA-I to facilitate ATP-binding cassette transporter A1 cholesterol transport was greatly reduced after chlorination by MPO. Loss of activity occurred in concert with chlorination of Tyr¹⁹². Both ONOO^- and MPO nitrated Tyr¹⁹² in high yield, but unlike chlorination, nitration minimally affected the ability of apoA-I to promote cholesterol efflux from cells. Our results indicate that Tyr¹⁹² is the predominant site of nitration and chlorination when MPO or ONOO^- oxidizes lipid-free apoA-I but that only chlorination markedly reduces the cholesterol efflux activity of apoA-I. This impaired biological activity of chlorinated apoA-I suggests that MPO-mediated oxidation of HDL might contribute to the link between inflammation and cardiovascular disease.

Received for publication, October 8, 2004 , and in revised form, November 29, 2004.

^* This work was supported by National Institutes of Health Grants AG021191, HL18645, HL75381, HL55362, DK02456, HL073996, HL30086, HL030086, and HL77268 and the Donald W. Reynolds Foundation. 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.

^|| To whom correspondence should be addressed: Division of Metabolism, Endocrinology, and Nutrition, Box 356426, University of Washington, Seattle, WA 98195. E-mail: heinecke{at}u.washington.edu.

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