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Journal of Lipid Research, Vol. 50, 945-956, May 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

The microsomal cardiolipin remodeling enzyme acyl-CoA lysocardiolipin acyltransferase is an acyltransferase of multiple anionic lysophospholipids

Yang Zhao, Yan-Qun Chen, Shuyu Li, Robert J. Konrad and Guoqing Cao¹

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285

This work was supported by Lilly Research Laboratories.

Published, JLR Papers in Press, December 15, 2008.

¹ To whom correspondence should be addressed. e-mail: guoqing_cao{at}lilly.com

Phospholipids are subjected to remodeling through the Lands cycle to attain appropriate FA compositions. In recent years, at least two families of lysophospholipid acyltransferases have been identified. Acyl-CoA lysocardiolipin acyltransferase 1 (ALCAT1) was initially identified as a microsomal lysocardiolipin acyltransferase. However, the physiological relevance of how this enzyme is involved in cardiolipin remodeling has not been elucidated. We report in this study that ALCAT1 possesses acyltransferase activities toward lysophosphatidylinositol (LPI) and lysophosphatidylglycerol (LPG). Membrane preparations from human embryonic kidney 293 (HEK293) cells overexpressing human ALCAT1 demonstrated significant increases in LPI acyltransferase (LPIAT) and LPG acyltransferase (LPGAT) activities using a variety of fatty acyl-CoAs. The enzyme affinities toward LPI and LPG were determined through kinetic studies suggesting that the LPI binding affinity to ALCAT1 depends on fatty acyl-CoA. Reduced expression of ALCAT1 in Hela cells resulted in significant reductions of LPIAT and LPGAT activities, but not ALCAT activity. Through structural and functional studies, we have identified critical amino acids D168 and L169 within ALCAT1 that are potentially involved in lysophospholipid substrate binding. Our studies provide the molecular basis for future investigations of the physiological function of ALCAT1 and offer evidence of critical amino acids involved in substrate binding for the family of glycerolipid acyltransferases.

Supplementary key words lysophosphatidylinositol acyltransferase • lysophosphatidylglycerol acyltransferase • membrane bound O-acyltransferase

Abbreviations: AGPAT, acyl-CoA:acylglycerol-3-phosphate acyltransferase; ALCAT1, acyl-CoA lysocardiolipin acyltransferase 1; CL, cardiolipin; ER, endoplasmic reticulum; GPAT, glycerol-3-phosphate acyltransferase; LPCAT, lysophosphatidylcholine acyltransferase; LPG, lysophosphatidylglycerol; LPGAT, LPG acyltransferase; LPI, lysophosphatidylinositol; LPIAT, LPI acyltransferase; lysoPL, lysophospholipid; lysoPLAT, lysophospholipid acyltransferase; MBOAT, membrane-bound O-acyltransferase; PA, phosphatidic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PI, phosphatidylinositide; PL, phospholipid; PPAR, proxisome proliferator-activator receptor ; PS, phosphatidylserine

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