title: A novel lysophosphatidic acid acyltransferase enzyme (LPAAT4) with a possible role for incorporating docosahexaenoic acid into brain glycerophospholipids.
abstract: Glycerophospholipids are important components of cellular membranes, required for constructing structural barriers, and for providing precursors of bioactive lipid mediators. Lysophosphatidic acid acyltransferases (LPAATs) are enzymes known to function in the de novo glycerophospholipid biosynthetic pathway (Kennedy pathway), using lysophosphatidic acid (LPA) and acyl-CoA to form phosphatidic acid (PA). Until now, three LPAATs (LPAAT1, 2, and 3) have been reported from the 1-acyl-glycerol-3-phosphate O-acyltransferase (AGPAT) family. In this study, we identified a fourth LPAAT enzyme, LPAAT4, previously known as an uncharacterized enzyme AGPAT4 (LPAATδ), from the AGPAT family. Although LPAAT4 was known to contain AGPAT motifs essential for acyltransferase activities, detailed biochemical properties were unknown. Here, we found that mouse LPAAT4 (mLPAAT4) possesses LPAAT activity with high acyl-CoA specificity for polyunsaturated fatty acyl-CoA, especially docosahexaenoyl-CoA (22:6-CoA, DHA-CoA). mLPAAT4 was distributed in many tissues, with relatively high expression in the brain, rich in docosahexaenoic acid (DHA, 22:6). mLPAAT4 siRNA in a neuronal cell line, Neuro 2A, caused a decrease in LPAAT activity with 22:6-CoA, suggesting that mLPAAT4 functions endogenously. siRNA in Neuro 2A cells caused a decrease in 18:0-22:6 PC, whereas mLPAAT4 overexpression in Chinese hamster ovary (CHO)-K1 cells caused an increase in this species. Although DHA is considered to have many important functions for the brain, the mechanism of its incorporation into glycerophospholipids is unknown. LPAAT4 might have a significant role for maintaining DHA in neural membranes. Identification of LPAAT4 will possibly contribute to understanding the regulation and the biological roles of DHA-containing glycerophospholipids in the brain.
authors: Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan; Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors: Miki
authors: M
authors: Eto
authors: Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan; CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan. Electronic address: hshindou-tky@umin.net.
authors: Hideo
authors: H
authors: Shindou
authors: Department of Lipid Signaling, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan; Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors: Takao
authors: T
authors: Shimizu
mesh_terms: D000217:Acyltransferases / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D020404:Glycerophospholipids / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D014018:Tissue Distribution
chemical_list: D020404:Glycerophospholipids; D004281:Docosahexaenoic Acids; D000217:Acyltransferases; C018764:2-acylglycerophosphate acyltransferase
keywords: 1-acyl-glycerol-3-phosphate O-acyltransferase; AGPAT; Brain; DHA; DHA-CoA; Docosahexaenoic acid; Glycerophospholipid; LPA; LPAAT; Lysophosphatidic acyltransferase; PA; PC; PE; PS; Phosphatidic acid; docosahexaenoic acid; docosahexaenoyl-CoA; lysophosphatidic acid; lysophosphatidic acid acyltransferase; phosphatidic acid; phosphatidylcholine; phosphatidylethanolamine; phosphatidylserine