Glycoconjugate Journal

, Volume 20, Issue 1, pp 25–32

A turn in the road: How studies on the pharmacology of glucosylceramide synthase inhibitors led to the identification of a lysosomal phospholipase A2 with ceramide transacylase activity

Article

DOI: 10.1023/B:GLYC.0000016739.32089.55

Cite this article as:
Shayman, J.A., Abe, A. & Hiraoka, M. Glycoconj J (2003) 20: 25. doi:10.1023/B:GLYC.0000016739.32089.55

Abstract

A series of inhibitors of glucosylceramide synthesis, the PDMP based family of compounds, has been developed as a tool for the study of sphingolipid biochemistry and biology. During the course of developing more active glucosylceramide synthase inhibitors, we identified a second site of inhibitory activity for PDMP and its structural homologues that accounted for the ability of the inhibitors to raise cell and tissue ceramide levels. This inhibitory activity was directed against a previously unknown pathway for ceramide metabolism, viz. the formation of 1-O-acylceramide. In this pathway the addition of a fatty acyl group to the primary hydroxyl of ceramide occurs through a transacylation with either phosphatidylethanolamine or phosphatidylcholine as a substrate. However, both in the absence and presence of ceramide, water serves as an acceptor for the fatty acid. Thus the enzyme may be considered to be a phospholipase A2. The enzyme is unique in that it has an acidic pH optimum and is localized to lysosomes by cell fractionation. More recently, the 1-O-acylceramide synthase has been purified, sequenced, and cloned. This phospholipase A2 was discovered to be structurally homologous to lecithin cholesterol acyltransferase (LCAT). However, this phospholipase A2 does not recognize cholesterol and lacks the defined lipoprotein-binding domain present in LCAT. We now refer to this enzyme as lysosomal phospholipase A2 (LPLA2). Although acidic phospholipase A2 activities have been previously identified, LPLA2 appears to be the first lysosomal PLA2 to have been sequenced. This new phospholipase A2 lacks an obvious and proven biological function. Published in 2004.

ceramide1-O-acylceramidePDMPlysosomephospholipase A2

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  1. 1.Division of Nephrology, Department of Internal MedicineUniversity of Michigan Medical CenterAnn ArborUSA