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J. Biol. Chem., Vol. 283, Issue 27, 19049-19057, July 4, 2008

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Molecular Identification of a Novel Mammalian Brain Isoform of Acyl-CoA:Lysophospholipid Acyltransferase with Prominent Ethanolamine Lysophospholipid Acylating Activity, LPEAT2^*

Jingsong Cao¹, Dandan Shan, Tracy Revett, Dongmei Li, Leeying Wu, Wei Liu, James F. Tobin, and Ruth E. Gimeno²

From the Departments of Cardiovascular and Metabolic Diseases and Bioinformatics, Wyeth Research, Cambridge, Massachusetts 02140

Acyl-CoA-dependent lysophospholipid acyltransferases play an important role in attaining the appropriate molecular species of phospholipids. A number of genes encoding these activities were recently identified. It has become clear that multiple genes can encode one enzymatic activity and that a given gene may encode multiple activities. Here we report the identification of a gene encoding a mammalian acyl-CoA-dependent lysophospholipid acyltransferase with prominent activity toward ethanolamine-containing lysophospholipids, which we termed acyl-CoA:lysophosphatidylethanolamine acyltransferase 2, LPEAT2 (previously annotated as AYTL3 or AGPAT7). LPEAT2 is predominantly expressed in brain, coinciding with an enrichment of phosphatidylethanolamine in this tissue. Ectopic expression of LPEAT2 in mammalian HEK293T cells led to a dramatic increase (up to 9-fold) in LPEAT activity when compared with cells transfected with empty vector or an unrelated acyltransferase. LPEAT2 also exhibited significant acyl-CoA-dependent acyltransferase activity toward 1-O-alkenyl-lysophosphatidylethanolamine, lysophosphatidylglycerol, 1-O-alkyl-lysophosphatidylcholine, lysophosphatidylserine, and lysophosphatidylcholine but lacked appreciable acylating activity toward glycerol 3-phosphate, lysophosphatidic acid, lysophosphatidylinositol, and diacylglycerol, demonstrating multiple but selective functions of LPEAT2 as an enzyme involved in phospholipid remodeling. LPEAT2 recognizes a broad range of medium and long chain fatty acyl-CoA, and its activity was not affected by Ca²⁺. When overexpressed in mammalian cells, LPEAT2 is localized to the endoplasmic reticulum. siRNA-mediated knockdown of LPEAT2 in HEK293T cells significantly decreased LPEAT and 1-alkenyl-LPEAT activities but did not affect other lysophospholipid acylating activities. These findings identify LPEAT2 as an important enzyme in the biosynthesis of ethanolamine-containing phospholipids, especially in brain.

Received for publication, January 15, 2008 , and in revised form, April 21, 2008.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence may be addressed: Cardiovascular and Metabolic Diseases, Wyeth Research, Cambridge, MA 02140. E-mail: jcao{at}wyeth.com.

² To whom correspondence may be addressed: Cardiovascular and Metabolic Diseases, Wyeth Research, Cambridge, MA 02140. E-mail: rgimeno{at}wyeth.com.

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