De Novo Sphingolipid Biosynthesis: A Necessary, but Dangerous, Pathway

Abstract

serine palmitoyltransferase Sphingolipids form specialized structures, mediate cell-cell and cell-substratum interactions, modulate the behavior of cellular proteins and receptors, and participate in signal transduction. They are synthesized de novo via a common backbone (sphinganine) that is modified to produce ceramides and more complex phospho- and glycosphingolipids. This minireview summarizes sphingoid base metabolism, function, and perturbation, including the participation of de novo sphingolipid biosynthesis in disease; other minireviews in this series will focus on ceramides (1Hannun Y.A. Obeid L.M. J. Biol. Chem. 2002; 277: 25847-25850Abstract Full Text Full Text PDF PubMed Scopus (739) Google Scholar), sphingosine 1-phosphate (2Spiegel S. Milstien S. J. Biol. Chem. 2002; 277: 25843-25846Abstract Full Text Full Text PDF PubMed Scopus (508) Google Scholar), complex sphingolipids (3Kolter T. Proia R.L. Sandhoff K. J. Biol. Chem. 2002; 277: 25859-25862Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar), and sphingolipid trafficking (4van Meer G. Lisman Q. J. Biol. Chem. 2002; 277: 25855-25858Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar).Structural Diversity of Sphingoid BasesSphingoid bases 1Names in use for common sphingoid bases with those recommended by the IUPAC (7IUPAC-IUB Joint Commission on Biochemical Nomenclature Eur. J. Biochem. 1998; 257: 293-298Crossref PubMed Scopus (178) Google Scholar) shown in brackets are: sphingosine [(2S,3R,4E)- 2-aminooctadec-4-ene-1,3-diol and (E)-sphing-4-enine]; dihydrosphingosine [(2S,3R)-2-aminooctadecane-1,3-diol and sphinganine]; phytosphingosine and 4-hydroxysphinganine [(2S,3S,4R)-2-aminooctadecane-1,3,4-triol]. When alkyl chain length is not specified, it is assumed to be 18-carbon atoms; other lengths can be designated by a name or number prefix (such as icosasphingosine or C20-sphingosine for a sphingosine with 20 carbon atoms). are compounds with structural similarity to sphingosine from the root name (“sphingosin”) assigned to this family of alkaloidal lipids by Thudichum (5Thudichum J.L.W. A Treatise on the Chemical Constitution of Brain. Bailliere, Tindall, and Cox, London1884Google Scholar). They encompass a wide array of 2-amino-1,3-dihydroxyalkanes or -enes with (2S,3R)-erythro stereochemistry, alkyl chain lengths from 14 to 22 carbon atoms, 0 to 2 double bonds, and other modifications, such as hydroxyl group(s) at positions 4 or 6 and branching methyl groups at ω-l (iso), ω-2 (anti-iso), or elsewhere (6Karlsson K.-A. Lipids. 1970; 5: 6-43Crossref Scopus (243) Google Scholar, 7IUPAC-IUB Joint Commission on Biochemical Nomenclature Eur. J. Biochem. 1998; 257: 293-298Crossref PubMed Scopus (178) Google Scholar). Mammals produce mainly the species shown in Fig.1 plus small amounts of other chain length homologs; yeast have 18- and 20-carbon phytosphingosines and sphinganines (sphingoid bases with double bonds and hydroxyl and/or methyl groups are common in other fungi); and plants have unsaturated bases such as sphing-8-enines, sphing-4,8-dienes, and phytosphing-(8 or 9)-enines.Some organisms (such as fungi and sponges) produce compounds that are sphingoid base-like, examples of which are shown in Fig.2. As will be discussed later, at least some of these disrupt sphingolipid metabolism.Figure 2Examples of naturally occurring inhibitors for two key enzymes of sphingolipid biosynthesis as well as other sphingoid base-like compounds. More information on these inhibitors is given in the text. Calyxoside (65Zhou B.N. Mattern M.P. Johnson R.K. Kingston D.G.I. Tetrahedron. 2001; 57: 9459-9554Google Scholar) and BRS1 (66Willis R.H. De Vries D.J. Toxicon. Scopus Google Scholar) as compounds from for de novo sphingolipid biosynthesis is and the of sphingoid base of this by of serine palmitoyltransferase K. S. T. J. Biol. Chem. Full Text PDF PubMed Google Scholar, R.L. S. PubMed Scopus Google Scholar) or by or K. T. S. Biochem. PubMed Scopus Google Scholar) and De novo sphingolipid biosynthesis is for in sphingolipids are in the sphingoid bases are in the J. PubMed Scopus Google is that this compounds that behavior or via sphingolipid and that the can be and and or or of (1Hannun Y.A. Obeid L.M. J. Biol. Chem. 2002; 277: 25847-25850Abstract Full Text Full Text PDF PubMed Scopus (739) Google Scholar, S. Milstien S. J. Biol. Chem. 2002; 277: 25843-25846Abstract Full Text Full Text PDF PubMed Scopus (508) Google Scholar). of the enzymes of sphingolipid be with serine which the of the which sphingoid bases as well as sphingosine is from sphingolipid or and which to and two and or and are for this R.L. PubMed Scopus Google Scholar) and to be K. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). A in not to be a K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of to other with to be the of the base with this R.L. PubMed Scopus Google Scholar). be for this K. T. J. Biol. Chem. Full