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J. Biol. Chem., Vol. 283, Issue 36, 24628-24640, September 5, 2008

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15-Deoxy-^12,14-prostaglandin J₂ Impairs Phosphatidylcholine Synthesis and Induces Nuclear Accumulation of Thiol-modified Cytidylyltransferase^*

Alan J. Ryan, Bill B. Chen, Prashanth R. Vennalaganti^¶, Florita C. Henderson, Linda A. Tephly, A. Brent Carter^¶, and Rama K. Mallampalli^¶1

From the ^¶Veterans Affairs Medical Center and the Departments of Internal Medicine and Biochemistry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242

Synthesis of phosphatidylcholine, the major phospholipid of animal cell membranes, requires the key enzyme cytidylyltransferase (CCT). Cysteine sulfhydryls within CCT are needed for full catalytic activity. Here we show that prostaglandin 15-deoxy-^12,14-PGJ₂ (15d-PGJ₂) inactivates CCT by inducing generation of reactive oxidant species and the appearance of a cross-linked CCT dimer in cells. N-Acetyl-L-cysteine reduced oxidative stress, prevented CCT cross-linking, and restored CCT function in 15d-PGJ₂-treated cells. 15d-PGJ₂ modified critical cysteine residues within CCT as determined by mutagenesis studies and by incorporation of biotin-15d-PGJ₂ into CCT. These effects of 15d-PGJ₂ were associated with CCT accumulation within the nucleus. The data indicate that bioactive prostanoids significantly impair membrane phospholipid production by promoting cysteine cross-bridging within CCT.

Received for publication, February 12, 2008 , and in revised form, July 8, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants RO1 HL068135, HL080229, HL071040, and HL081784 (to R. K. M.) and ES015981 (to A. B. C.). This work was also supported by merit review awards from the Department of Veterans Affairs (to R. K. M. and A. B. C.) and by an American Lung Association career investigator award (to A. B. C.). 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.

¹ To whom correspondence should be addressed: Dept. of Internal Medicine, Division of Pulmonary Diseases, Critical Care, and Occupational Medicine, C-33K, GH, University of Iowa College of Medicine, IA City, IA 52242. Tel.: 319-356-1265; Fax: 319-353-6406; E-mail: rama-mallampalli{at}uiowa.edu.

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