The Multigenic Sphingomyelin Synthase Family

Abstract

Sphingomyelin (SM) 3The abbreviations used are: SM, sphingomyelin; DAG, diacylglycerol; GlcCer, glucosylceramide; EPC, ethanolamine phosphorylceramide; ER, endoplasmic reticulum; IPC, inositol phosphorylceramide; LPP, lipid phosphate phosphatase; PC, phosphatidylcholine; PE, phosphatidylethanolamine; SMS, sphingomyelin synthase; SAM, sterile α motif. 3The abbreviations used are: SM, sphingomyelin; DAG, diacylglycerol; GlcCer, glucosylceramide; EPC, ethanolamine phosphorylceramide; ER, endoplasmic reticulum; IPC, inositol phosphorylceramide; LPP, lipid phosphate phosphatase; PC, phosphatidylcholine; PE, phosphatidylethanolamine; SMS, sphingomyelin synthase; SAM, sterile α motif. is a vital component of cellular membranes in organisms ranging from mammals to protozoa. Its production involves the enzymatic transfer of a phosphocholine head group from phosphatidylcholine to ceramide, yielding diacylglycerol in the process. The enzyme catalyzing this reaction, SM synthase, thus occupies a central position in sphingolipid and glycerophospholipid metabolism and has considerable biological potential as a regulator of pro-apoptotic factor ceramide and mitogenic factor diacylglycerol. Recent identification of the enzyme uncovered a multiplicity of SM synthase genes in each organism where SM synthesis is known to occur. This has shed new light on the pathways, reaction mechanism, regulation, phylogenetic distribution, and biological significance of SM synthesis. The first committed step in SM synthesis is the condensation of l-serine and palmitoyl-CoA. This reaction is catalyzed by serine palmitoyltransferase and yields 3-keto-dihydrosphingosine, which is reduced to dihydrosphingosine. Dihydrosphingosine undergoes N-acylation followed by desaturation to generate ceramide, a central molecule in sphingolipid metabolism (1Dickson R.C. Annu. Rev. Biochem. 1998; 67: 27-48Crossref PubMed Scopus (236) Google Scholar, 2Pewzner-Jung Y. Ben-Dor S. Futerman A.H. J. Biol. Chem. 2006; 281: 25001-25005Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar). These reactions occur on the cytosolic surface of the endoplasmic reticulum (ER) (3Mandon E.C. Ehses I. Rother J. van Echten G. Sandhoff K. J. Biol. Chem. 1992; 267: 11144-11148Abstract Full Text PDF PubMed Google Scholar). Subsequently, ceramide is delivered to the Golgi apparatus where it is converted to SM or glucosylceramide (GlcCer). GlcCer synthesis is mediated by GlcCer synthase, which catalyzes the transfer of glucose from UDP-glucose to ceramide. This enzyme resides in the cis Golgi and has its active site oriented toward the cytosol (4Jeckel D. Karrenbauer A. Burger K.N. van Meer G. Wieland F. J. Cell Biol. 1992; 117: 259-267Crossref PubMed Scopus (259) Google Scholar). After translocation to the Golgi lumen, GlcCer is converted to more complex glycosphingolipids. However, in most mammalian cell types the bulk of ceramide is converted to SM by a SM synthase in the lumen of the trans Golgi (5Futerman A.H. Stieger B. Hubbard A.L. Pagano R.E. J. Biol. Chem. 1990; 265: 8650-8657Abstract Full Text PDF PubMed Google Scholar, 6Huitema K. van den Dikkenberg J. Brouwers J.F. Holthuis J.C. EMBO J. 2004; 23: 33-44Crossref PubMed Scopus (469) Google Scholar, 7Yamaoka S. Miyaji M. Kitano T. Umehara H. Okazaki T. J. Biol. Chem. 2004; 279: 18688-18693Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar). This enzyme, named SMS1, catalyzes the transfer of phosphocholine from phosphatidylcholine (PC) to ceramide, yielding diacylglycerol (DAG) as a side product (Fig. 1) (8Ullman M.D. Radin N.S. J. Biol. Chem. 1974; 249: 1506-1512Abstract Full Text PDF PubMed Google Scholar, 9Voelker D.R. Kennedy E.P. Biochemistry. 1982; 21: 2753-2759Crossref PubMed Scopus (160) Google Scholar). A second SM synthase, SMS2, resides at the plasma membrane (6Huitema K. van den Dikkenberg J. Brouwers J.F. Holthuis J.C. EMBO J. 2004; 23: 33-44Crossref PubMed Scopus (469) Google Scholar, 10van Helvoort A. van't Hof W. Ritsema T. Sandra A. van Meer G. J. Biol. Chem. 1994; 269: 1763-1769Abstract Full Text PDF PubMed Google Scholar), but it is unclear whether this enzyme participates in the de novo synthesis of SM. An alternative pathway of SM synthesis has been postulated in which ceramide is first converted to ethanolamine phosphorylceramide (EPC) via transfer of the head group from phosphatidylethanolamine (PE) (11Muehlenberg B.A. Sribney M. Duffe M.K. Can J. Biochem. 1972; 50: 166-173Crossref PubMed Scopus (13) Google Scholar). EPC is then converted to SM by stepwise methylation in a reaction analogous to the S-adenosylmethionine-dependent conversion of PE to PC (Fig. 1). Even though this pathway has been demonstrated in isolated membrane fractions from rat brain and liver (12Malgat M. Maurice A. Baraud J. J. Lipid Res. 1986; 27: 251-260Abstract Full Text PDF PubMed Google Scholar, 13Malgat M. Maurice A. Baraud J. J. Lipid Res. 1987; 28: 138-143Abstract Full Text PDF PubMed Google