When Do Lasses (Longevity Assurance Genes) Become CerS (Ceramide Synthases)?

Abstract

Ceramide is the key intermediate in the pathway of sphingolipid (SL) 2The abbreviations used are: SL, sphingolipid; CerS, ceramide synthase; ER, endoplasmic reticulum; TM, trans-membrane. biosynthesis (1Merrill Jr., A.H. J. Biol. Chem. 2002; 277: 25843-25846Abstract Full Text Full Text PDF PubMed Scopus (506) Google Scholar) and an important intracellular signaling molecule (2Kolesnick R. J. Clin. Invest. 2002; 110: 3-8Crossref PubMed Scopus (389) Google Scholar, 3Hannun Y.A. Obeid L.M. J. Biol. Chem. 2002; 277: 25847-25850Abstract Full Text Full Text PDF PubMed Scopus (770) Google Scholar). Ceramide consists of a sphingoid long chain base to which a fatty acid is attached via an amide bond (Fig. 1). When the chemical composition of SLs was first determined in the 1940s (4Klenk E.Z. Physiol. Chem. 1942; 273: 76-86Crossref Scopus (146) Google Scholar), stearic acid (C18:0) was identified as the major fatty acid attached to the sphingoid base. Later, with the development of more sensitive techniques (5Trams E.G. Giuffrida L.E. Karmen A. Nature. 1962; 193: 680-681Crossref PubMed Scopus (15) Google Scholar, 6O'Brien J.S. Fillerup D.L. Mead J.F. J. Lipid Res. 1964; 15: 109-116Abstract Full Text PDF Google Scholar), it became clear that mammalian SLs contain a wide variety of fatty acids, ranging in length from C14 to C32, that are predominantly saturated and can contain α- or ω-hydroxyl groups (7van Meer G. EMBO J. 2005; 24: 3159-3165Crossref PubMed Scopus (423) Google Scholar, 8Merrill Jr., A.H. Sullards M.C. Allegood J.C. Kelly S. Wang E. Methods. 2005; 36: 207-224Crossref PubMed Scopus (484) Google Scholar). Within the past few years, there has been renewed interest in the functional significance of this fatty acid variability, and this minireview will focus on current advances in our understanding of how the fatty acid composition of ceramide is regulated. In particular, we will discuss a recently discovered family of mammalian ceramide synthase (CerS) genes and emerging evidence that specific ceramides containing distinct fatty acids play important roles in cell growth and apoptosis. CerS acylates sphinganine (dihydrosphingosine) to form dihydroceramide and sphingosine to form ceramide; sphinganine is produced through the de novo biosynthetic pathway and sphingosine mainly through SL degradation (1Merrill Jr., A.H. J. Biol. Chem. 2002; 277: 25843-25846Abstract Full Text Full Text PDF PubMed Scopus (506) Google Scholar, 9Futerman A.H. Riezman H. Trends Cell Biol. 2005; 15: 312-318Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar). Early studies detected CerS activity in microsomal fractions, and the enzyme was shown to utilize a variety of fatty acyl-CoAs although some specificity toward certain CoAs was recognized (10Morell P. Radin N.S. J. Biol. Chem. 1970; 245: 342-350Abstract Full Text PDF PubMed Google Scholar). CerS activity was later localized to the cytoplasmic leaflet of the endoplasmic reticulum (ER) (11Mandon E.C. Ehses I. Rother J. Van Echten G. Sandhoff K. J. Biol. Chem. 1992; 267: 11144-11148Abstract Full Text PDF PubMed Google Scholar, 12Hirschberg K. Rodger J. Futerman A.H. Biochem. J. 1993; 290: 751-757Crossref PubMed Scopus (164) Google Scholar). The first clue to the molecular identity of CerS was obtained in yeast, when it was shown that Lag1p and Lac1p were required for the synthesis of C26-ceramide (13Guillas I. Kirchman P.A. Chuard R. Pfefferli M. Jiang J.C. Jazwinski S.M. Conzelmann A. EMBO J. 2001; 20: 2655-2665Crossref PubMed Scopus (228) Google Scholar, 14Schorling S. Vallee B. Barz W.P. Riezman H. Oesterhelt D. Mol. Biol. Cell. 2001; 12: 3417-3427Crossref PubMed Scopus (230) Google Scholar). 3In contrast to mammalian cells, yeast SLs contain mainly C26-fatty acid. Lag1 was originally isolated in a screen for longevity-related genes (15D'Mello N.P. Childress A.M. Franklin D.S. Kale S.P. Pinswasdi C. Jazwinski S.M. J. Biol. Chem. 1994; 269: 15451-15459Abstract Full Text PDF PubMed Google Scholar). A paralog, 4Paralogs are parallel genes in the same species, and an ortholog (see below) is the same gene in different species; homolog is a term encompassing both ortholog and paralog. Lac1, was found in a data base screen (16Jiang J.C. Kirchman P.A. Zagulski M. Hunt J. Jazwinski S.M. Genome Res. 1998; 8: 1259-1272Crossref PubMed Scopus (29) Google Scholar) along with homologs in human, mouse, and Caenorhabditis elegans. The Asc1 gene in tomato was subsequently isolated as a toxin-resistant gene (17Brandwagt B.F. Mesbah L.A. Takken F.L. Laurent P.L. Kneppers T.J. Hille J. Nijkamp H.J. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 4961-4966Crossref PubMed Scopus (182) Google Scholar); among the toxins tested was fumonisin B1, a CerS inhibitor (18Wang E. Norred W.P. Bacon C.W. Riley R.T. Merrill A.H. J. Biol. Chem. 1991; 266: 14486-14490Abstract Full Text PDF PubMed Google Scholar). Homologs of Lag1 and Lac1 have now been found in most species. Six paralogs are known in human