De Novo Sphingolipid Biosynthesis: A Necessary, but Dangerous, Pathway
2002; Elsevier BV; Volume: 277; Issue: 29 Linguagem: Inglês
10.1074/jbc.r200009200
ISSN1083-351X
Autores Tópico(s)Lysosomal Storage Disorders Research
Resumoserine 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. 1997; 7: 1125-1129Crossref Scopus (33) Google Scholar) were both isolated as bioactive compounds from sponges.View Large Image Figure ViewerDownload Hi-res image Download (PPT)De Novo Sphingolipid BiosynthesisThe capacity for de novo sphingolipid biosynthesis (Fig. 1) is widespread among cell types and tissues. In the absence of an exogenous sphingoid base source, loss of this pathway by mutation of serine palmitoyltransferase (SPT)2 (8Hanada K. Nishijima M. Kiso M. Hasegawall A. Fujita S. Ogawa T. Akamatsu Y. J. Biol. Chem. 1992; 267: 23527-23533Abstract Full Text PDF PubMed Google Scholar, 9Nagiec M.M. Baltisberger J.A. Wells G.B. Lester R.L. Dickson R.C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7899-7902Crossref PubMed Scopus (179) Google Scholar) or its inhibition by ISP1/myriocin or sphingofungin B (10Hanada K. Nishijima M. Fujita T. Kobayashi S. Biochem. Pharmacol. 2000; 59: 1211-1216Crossref PubMed Scopus (82) Google Scholar) affects growth and viability. De novo sphingolipid biosynthesis is probably required for survival in vivo because, although sphingolipids are present in most foods, the sphingoid bases are largely degraded in the mammalian intestine (11Vesper H. Schmelz E.-M. Nikolova-Karakashian M.N. Dillehay D.L. Lynch D.V. Merrill A.H., Jr. J. Nutr. 1999; 129: 1239-1250Crossref PubMed Scopus (355) Google Scholar).It is intriguing that this pathway contains so many compounds that affect cell behavior when added exogenously or formed via sphingolipid turnover and that the consequences can be growth arrest and cytotoxicity (ceramide and sphingosine) or growth stimulation or inhibition of apoptosis (sphingosine 1-phosphate) (1Hannun Y.A. Obeid L.M. J. Biol. Chem. 2002; 277: 25847-25850Abstract Full Text Full Text PDF PubMed Scopus (739) Google Scholar, 2Spiegel S. Milstien S. J. Biol. Chem. 2002; 277: 25843-25846Abstract Full Text Full Text PDF PubMed Scopus (508) Google Scholar). With so many bioactive intermediates, essentially all of the enzymes of sphingolipid metabolism must be efficiently coordinated, with three warranting particular attention: serine palmitoyltransferase, which catalyzes the initial step of the pathway; (dihydro)ceramide synthase, which removes sphingoid bases as well as produces dihydroceramide (or ceramide, if sphingosine is available from sphingolipid turnover or an exogenous source); and dihydroceramide desaturase, which converts relatively inactive dihydroceramides to ceramides.Serine PalmitoyltransferaseFor mammals and yeast, two gene products (termed SPTLC1 and SPTLC2, or sometimes SPT1 and SPT2) are necessary for this activity (12Dickson R.C. Lester R.L. Nagiec M.M. Methods Enzymol. 2000; 311: 3-9Crossref PubMed Scopus (39) Google Scholar) and appear to be physically associated (13Hanada K. Hara T. Nishijima M. J. Biol. Chem. 2000; 275: 8409-8415Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). A third has been identified in yeast, but there does not appear to be a mammalian homolog (14Gable K. Slife H. Bacikova D. Monaghan E. Dunn T.M. J. Biol. Chem. 2000; 275: 7597-7603Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar). The amino acid sequence of SPT2 has homology to other pyridoxal 5′-phosphate-dependent decarboxylases, with Lys377 predicted to be the site of the Schiff base with this cofactor (15Nagiec M.M. Lester R.L. Dickson R.C. Gene (Amst.). 1996; 177: 237-241Crossref PubMed Scopus (69) Google Scholar). SPT2 may be primarily responsible for catalytic activity because SPT1 lacks this Lys (16Hanada K. Hara T. Nishijima M. Kuge O. Dickson R.C. Nagiec M.M. J. Biol. Chem. 1997; 272: 32108-32114Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar); nonetheless, mutations in SPT1 (SPTLC1) cause hereditary sensory neuropathy type I (HSN1), the most common hereditary disorder of peripheral sensory neurons (17Dawkins J.L. Hulme D.J. Brahmbhatt S.B. Auer-Grumbach M. Nicholson G.A. Nat. Genet. 2001; 27: 309-312Crossref PubMed Scopus (336) Google Scholar, 18Bejaoui K., Wu, C. Scheffler M.D. Haan G. Ashby P., Wu, L. de Jong P. Brown R.H., Jr. Nat. Genet. 2001; 27: 261-262Crossref PubMed Scopus (239) Google Scholar). An intrinsic membrane protein, SPT is difficult to study; however, Sphingomonas has a soluble, homodimeric SPT (19Ikushiro H. Hayashi H. Kagamiyama H. J. Biol. Chem. 2001; 276: 18249-18256Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar).The regulation of SPT is only beginning to be understood. One of the more straightforward factors that affects SPT activity is the availability of both serine- and palmitoyl-CoA, and because SPT is highly selective for fatty acyl-CoA with 16 ± 1 carbon atoms, other fatty acids can be inhibitory in vivo, possibly by competing for the CoA pool (20Merrill A.H., Jr. Wang E. Mullins R.E. Biochemistry. 1988; 27: 340-345Crossref PubMed Scopus (80) Google Scholar). Serine palmitoyltransferase is inhibited by a number of synthetic and naturally occurring agents. As for many pyridoxal 5′-phosphate-dependent enzymes, it undergoes active site-dependent ("suicide") inhibition with β-haloalanines and other aldehyde reactive compounds (21Medlock K.A. Merrill A.H., Jr. Biochemistry. 1988; 27: 7079-7084Crossref PubMed Scopus (68) Google Scholar, 22Blazquez C. Geelen M.J. Velasco G. Guzman M. FEBS Lett. 2001; 489: 149-153Crossref PubMed Scopus (150) Google Scholar). More potent and selective inhibitors have been isolated from microorganisms (sphingofungins, lipoxamycins, and ISP1/myriocin) (Fig.2) (23Miyake Y. Kozutsumi Y. Nakamura S. Fujita T. Kawasaki T. Biochem. Biophys. Res. Commun. 1994; 211: 396-403Crossref Scopus (447) Google Scholar, 24Mandala S.M. Harris G.H. Methods Enzymol. 2000; 311: 335-348Crossref PubMed Scopus (47) Google Scholar). These inhibitors (and particularly ISP1, which is available commercially) have been valuable in identifying the roles ofde novo biosynthesis in sphingolipid-mediated cell death (25Schmelz E.M. Dombrink-Kurtzman M.A. Roberts P.C. Kozutsumi Y. Kawasaki T. Merrill A.H., Jr. Toxicol. Appl. Pharmacol. 1998; 148: 252-260Crossref PubMed Scopus (144) Google Scholar); however, care must be exerted in using the less specific inhibitors (10Hanada K. Nishijima M. Fujita T. Kobayashi S. Biochem. Pharmacol. 2000; 59: 1211-1216Crossref PubMed Scopus (82) Google Scholar). d-Serine inhibits SPT, which may have significance in brain tissue, where this stereoisomer is found (26Hanada K. Hara T. Nishijima M. FEBS Lett. 2000; 474: 63-65Crossref PubMed Scopus (20) Google Scholar).Sphingoid base synthesis can be suppressed by adding lipoproteins or free sphingoid bases to cells in culture (reviewed in Ref. 11Vesper H. Schmelz E.-M. Nikolova-Karakashian M.N. Dillehay D.L. Lynch D.V. Merrill A.H., Jr. J. Nutr. 1999; 129: 1239-1250Crossref PubMed Scopus (355) Google Scholar) perhaps by down-regulation of SPT by sphingoid base 1-phosphates (27van Echten-Deckert G. Zschoche A. Bär T. Schmidt R.R. Raths A. Heinemann T. Sandhoff K. J. Biol. Chem. 1997; 272: 15825-15833Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Regulation at a transcriptional level has been seen with a number of agents, including endotoxin and cytokines (28Memon R.A. Holleran W.M. Moser A.H. Seki T. Uchida Y. Fuller J. Shigenaga J.K. Grunfeld C. Feingold K.R. Arterioscler. Thromb. Vasc. Biol. 1998; 18: 1257-1265Crossref PubMed Scopus (135) Google Scholar), UVB irradiation (29Farrell A.M. Uchida Y. Nagiec M.M. Harris I.R. Dickson R.C. Elias P.M. Holleran W.M. J. Lipid Res. 1998; 39: 2031-2038Abstract Full Text Full Text PDF PubMed Google Scholar), retinoic acid (30Herget T. Esdar C. Oehrlein S.A. Heinrich M. Schutze S. Maelicke A. van Echten-Deckert G. J. Biol. Chem. 2000; 275: 30344-30354Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar), and other agents (31Linn S.C. Kim H.S. Keane E.M. Andras L.M. Wang E. Merrill A.H., Jr. Biochem. Soc. Trans. 2001; 29: 831-835Crossref PubMed Scopus (0) Google Scholar). Induction of both SPT1 and SPT2 occurs in balloon-injured rat carotid artery (32Uhlinger D.J. Carton J.M. Argentieri D.C. Damiano B.P. D'Andrea M.R. Thromb. Haemostasis. 2001; 86: 1320-1326Crossref PubMed Scopus (10) Google Scholar). Activation of SPT occurs post-translationally in response to etoposide (33Perry D.K. Carton J. Shah A.K. Meredith F. Uhlinger D.J. Hannun Y.A. J. Biol. Chem. 2000; 275: 9078-9084Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar) and heat shock in yeast (34Jenkins G.M. Hannun Y.A. J. Biol. Chem. 2001; 276: 8574-8581Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar). The heat shock response in yeast involves mainly eicosasphinganines (i.e. C20 sphingoid bases) (35Dickson R.C. Nagiec E.E. Skrzypek M. Tillman P. Wells G.B. Lester R.L. J. Biol. Chem. 1997; 272: 30196-30200Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar) and induces changes in amino acid transport (36Skrzypek M.S. Nagiec M.M. Lester R.L. Dickson R.C. J. Biol. Chem. 1998; 273: 2829-2834Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar) and activation of ubiquitin-dependent proteolysis (37Chung N. Jenkins G. Hannun Y.A. Heitman J. Obeid L.M. J. Biol. Chem. 2000; 275: 17229-17232Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar).(Dihydro)ceramide SynthaseThe reduction of 3-ketosphinganine and acylation of sphinganine to dihydroceramide (Fig. 1) both appear rapid in vivo due to lack of accumulation of the intermediates under usual conditions. (Dihydro)ceramide synthase(s) utilize a range of fatty acyl-CoAs (C16:0 to C26:0) and probably represent a family of isozymes. The recent identification of yeast genes essential for acyl-CoA-dependent ceramide synthesis (38Schorling S. Vallee B. Barz W.P. Riezman H. Oesterhelt D. Mol. Biol. Cell. 2001; 12: 3417-3427Crossref PubMed Scopus (219) Google Scholar) should lead to isolation of the counterpart(s) in other organisms. Ceramides can also be synthesized by the reverse reaction of ceramidase(s) (39El Bawab S. Birbes H. Roddy P. Szulc Z.M. Bielawska A. Hannun Y.A. J. Biol. Chem. 2001; 276: 16758-16766Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 40Mao C., Xu, R. Bielawska A. Obeid L.M. J. Biol. Chem. 2000; 275: 6876-6884Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar), and in yeast this route has allowed cloning of an alkaline ceramidase based on resistance to fumonisin B1(40Mao C., Xu, R. Bielawska A. Obeid L.M. J. Biol. Chem. 2000; 275: 6876-6884Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar).(Dihydro)ceramide synthesis is the target of a number of fungal inhibitors (11Vesper H. Schmelz E.-M. Nikolova-Karakashian M.N. Dillehay D.L. Lynch D.V. Merrill A.H., Jr. J. Nutr. 1999; 129: 1239-1250Crossref PubMed Scopus (355) Google Scholar) such as fumonisin B1 (FB1) (Fig. 2). Structure-function investigations suggest that the aminoalkyl backbone competes with the sphingoid base binding site of (dihydro)ceramide synthase, and the anionic tricarballylic side chains interfere with utilization of the co-substrate fatty acyl-CoA; thus, compounds with the aminopentol backbone alone (AP1 in Fig. 2) are both substrates and inhibitors (41Humpf H.-U. Schmelz E.-M. Meredith F.I. Vesper H. Vales T.R. Menaldino D.S. Liotta D.C. Merril A.H., Jr. J. Biol. Chem. 1998; 273: 19060-19064Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar).Dihydroceramide DesaturaseThe last step of ceramide synthesis is insertion of a 4,5-trans-double bond into dihydroceramide as shown in Fig. 1 (42Rother J. van Echten G. Schwarzmann G. Sandhoff K. Biochem. Biophys. Res. Commun. 1992; 189: 14-20Crossref PubMed Scopus (130) Google Scholar). This is an important reaction because ceramides (but much less so dihydroceramides) are active in inducing apoptosis (1Hannun Y.A. Obeid L.M. J. Biol. Chem. 2002; 277: 25847-25850Abstract Full Text Full Text PDF PubMed Scopus (739) Google Scholar). This reaction can be reproduced in vitro using either dihydroceramide or dihydrosphingomyelin (42Rother J. van Echten G. Schwarzmann G. Sandhoff K. Biochem. Biophys. Res. Commun. 1992; 189: 14-20Crossref PubMed Scopus (130) Google Scholar,43Michel C. van Echten-Deckert G. Rother J. Sandhoff K. Wang E. Merrill A.H., Jr. J. Biol. Chem. 1997; 292: 22432-22437Abstract Full Text Full Text PDF Scopus (248) Google Scholar). Sphingolipid desaturases have been cloned from plants (44Sperling P. Libisch B. Zähringer U. Napier J.A. Heinz E. Arch. Biochem. Biophys. 2001; 388: 293-298Crossref PubMed Scopus (51) Google Scholar), leading to the recent identification of the Δ4-desaturase genes ofHomo sapiens, Mus musculus, Drosophila melanogaster, and Candida albicans and a bifunctional Δ4-desaturase/C-4-hydroxylase from M. musculus (45Ternes P. Franke S. Zähringer U. Sperling P. Heinz E. J. Biol. Chem. 2002; 277: 25512-25518Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar). The deuterium isotope effect for C–H bond cleavage suggests that the desaturase initially oxidizes C-4 (46Savile C.K. Fabrias G. Buist P.H. J. Am. Chem. Soc. 2001; 123: 4382-4385Crossref PubMed Scopus (33) Google Scholar), which is consistent with the finding that one of the desaturases catalyzes both ceramide and phytoceramide synthesis (45Ternes P. Franke S. Zähringer U. Sperling P. Heinz E. J. Biol. Chem. 2002; 277: 25512-25518Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar). A cyclopropene analog of ceramide potently inhibits the desaturase (47Triola G. Fabrias G. Liebaria A. Angew. Chem. Int. Ed. Engl. 2001; 40: 1960-1962Crossref PubMed Scopus (39) Google Scholar). Genes responsible for phytosphingosine synthesis have been identified in yeast (48Haak D. Gable K. Beeler T. Dunn T. J. Biol. Chem. 1997; 272: 29704-29710Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar, 49Grilley M.M. Stock S.D. Dickson R.C. Lester R.L. Takemoto J.Y. J. Biol. Chem. 1998; 273: 11062-11068Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar), plants (50Sperling P. Ternes P. Moll H. Franke S. Zähringer U. Heinz E. FEBS Lett. 2001; 494: 90-94Crossref PubMed Scopus (43) Google Scholar), and M. musculus (45Ternes P. Franke S. Zähringer U. Sperling P. Heinz E. J. Biol. Chem. 2002; 277: 25512-25518Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar). In vitroassays suggest that hydroxylation can occur with both the free sphingoid base and dihydroceramide, at least in yeast (49Grilley M.M. Stock S.D. Dickson R.C. Lester R.L. Takemoto J.Y. J. Biol. Chem. 1998; 273: 11062-11068Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar) (dashed arrow in Fig. 1).Other ReactionsThe enzymes that remove ceramide (ceramidases and synthases for complex sphingolipids), the sphingoid base kinases (as well as the phosphatases that reverse this reaction and the lyase that cleaves sphingoid base 1-phosphates to a fatty aldehyde and ethanolamine phosphate) (Fig. 1) will be discussed in the accompanying minireviews (1Hannun Y.A. Obeid L.M. J. Biol. Chem. 2002; 277: 25847-25850Abstract Full Text Full Text PDF PubMed Scopus (739) Google Scholar, 2Spiegel S. Milstien S. J. Biol. Chem. 2002; 277: 25843-25846Abstract Full Text Full Text PDF PubMed Scopus (508) Google Scholar, 3Kolter T. Proia R.L. Sandhoff K. J. Biol. Chem. 2002; 277: 25859-25862Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, 4van Meer G. Lisman Q. J. Biol. Chem. 2002; 277: 25855-25858Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar).Implication of de Novo Sphingolipid Biosynthesis in Cell DeathAlteration of de novo sphingolipid biosynthesis can be toxic, as was first shown for the fumonisins (51Merrill A.H., Jr. Sullards M.C. Wang E. Voss K.A. Riley R.T. Environ. Health Perspect. 2001; 109: 283-289Crossref PubMed Scopus (328) Google Scholar). Fumonisins are mycotoxin contaminants of maize that cause a spectrum of disease: cancer (rats and humans), leukoencephalomalacia (equines), pulmonary edema (pigs), liver and kidney toxicity (multiple species), and other disease (52Marasas W.F.O. Environ. Health Perspect. 2001; 109: 239-243Crossref PubMed Scopus (434) Google Scholar). By inhibiting (dihydro)ceramide synthase, fumonisins cause the accumulation of sphinganine (Fig.3) in tissues, serum, and urine, which is widely used as a biomarker of fumonisin exposure (51Merrill A.H., Jr. Sullards M.C. Wang E. Voss K.A. Riley R.T. Environ. Health Perspect. 2001; 109: 283-289Crossref PubMed Scopus (328) Google Scholar). The accumulation of sphinganine appears to be responsible for most of the deleterious effects of these mycotoxins, although depletion of complex sphingolipids impairs the function of some membrane proteins, such as the folate transporter (53Stevens V.L. Tang J. J. Biol. Chem. 1997; 272: 18020-18025Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar), and may contribute to neural tube disease (67Sadler, T. W., Stevens, V. L., Merrill, A. H., Sullards, M. C., Wang, E., and Wang, P. (2002) Teratology, in pressGoogle Scholar).Figure 3A scheme that depicts the bioactive intermediates of de novo sphingolipid biosynthesis and some factors that influence their amounts and fates. Shown are some of the intermediates from Fig. 1: the incorporation of palmitoyl-CoA (Pal-CoA) into 3-ketosphinganine (KetoSa), which is converted to sphinganine (Sa), dihydro- (DH) ceramide (Cer), or sphinganine 1-phosphate (Sa-1-P). In hepatocytes, ceramide is not only incorporated into more complex sphingolipids but also into nascent very low density lipoproteins (VLDL), which are secreted. The sites of action of commonly used inhibitors (ISP1/myriocin and fumonisin) are also shown. The subcellular locations of these reactions are indicated only for a general context; there are likely to be other sites where some of these reactions occur (for example, ceramide formation is thought to occur in the endoplasmic reticulum (ER), but in unpublished studies we have recently found these activities in mitochondrial-associated membranes (MAM)). GSL, glycosphingolipid; SM, sphingomyelin.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fumonisins can significantly elevate sphinganine 1-phosphate (54Sullards, M. C., and Merrill, A. H., Jr. (2001)Science Signal Transduction Environment (STKE), stke.sciencemag.orgGoogle Scholar) and production of ethanolamine phosphate (55Smith E.R. Merrill A.H., Jr. J. Biol. Chem. 1995; 270: 18749-18758Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar) (Figs. 1 and 3). Because sphingoid base 1-phosphates are mitogenic and anti-apoptotic (2Spiegel S. Milstien S. J. Biol. Chem. 2002; 277: 25843-25846Abstract Full Text Full Text PDF PubMed Scopus (508) Google Scholar), this may account for (or at least contribute to) the seemingly paradoxical stimulation of growth by fumonisins in some cells (56Schroeder J.J. Crane H.M. Xia J. Liotta D.C. Merrill A.H., Jr. J. Biol. Chem. 1994; 269: 3475-3481Abstract Full Text PDF PubMed Google Scholar) and the oft cited "protection of cells from apoptosis because of de novo synthesized ceramide" 3As an inhibitor of the first step of this pathway, ISP1 (myriocin) can be used to block ceramide synthesis without elevating sphinganine and other intermediates (30Herget T. Esdar C. Oehrlein S.A. Heinrich M. Schutze S. Maelicke A. van Echten-Deckert G. J. Biol. Chem. 2000; 275: 30344-30354Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). in some cases where fumonisins are used. This cautionary statement notwithstanding, it is clear that de novo sphingolipid biosynthesis participates in cell death induced by a wide variety of agents. First noted by Kolesnick and collaborators (57Bose R. Verheij M. Haimovitz-Friedman A. Scotto K. Fuks Z. Kolesnick R. Cell. 1995; 82: 405-414Abstract Full Text PDF PubMed Scopus (782) Google Scholar) in studies of daunorubicin-induced apoptosis, activation of (dihydro)ceramide synthase may also be involved in some aspects of the toxicities of phorbol esters and radiation (58Garzotto M. White-Jones M. Jiang Y. Ehleiter D. Liao W.C. Haimovitz-Friedman A. Fuks Z. Kolesnick R. Cancer Res. 1998; 58: 2260-2264PubMed Google Scholar, 59Lin X. Fuks Z. Kolesnick R. Crit. Care Med. 2000; 28: 87-93Crossref PubMed Scopus (48) Google Scholar), angiotensin II and cannabinoids (60Lehtonen J.Y. Horiuchi M. Daviet L. Akishita M. Dzau V.J. J. Biol. Chem. 1999; 274: 16901-16906Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 61Guzman M. Galve-Roperh I. Sanchez C. Trends Pharmacol. Sci. 2001; 22: 19-22Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar), and elevations in palmitoyl-CoA because of excess production or impaired removal by mitochondrial oxidation or other metabolism (62Paumen M.B. Ishida Y. Muramatsu M. Yamamoto M. Honjo T. J. Biol. Chem. 1997; 272: 3324-3329Abstract Full Text Full Text PDF PubMed Scopus (310) Google Scholar) (Fig. 3). This has implications for a wide range of disorders and has been articulated as one of the mechanisms for "lipotoxic" disease (63Unger R.H. Annu. Rev. Med. 2002; 53: 319-336Crossref PubMed Scopus (835) Google Scholar).PerspectivesWhy would nature risk producing compounds with such a diverse spectrum of biological effects and toxicities unless these compounds have functions beyond just being pathway intermediates? One suspects that both de novo sphingolipid biosynthesis and turnover are used for cell regulation. Thus, pathologies arise from malfunctions in these pathways, and (as often occurs in nature) organisms exploit them for their own purposes, as in the case with fumonisins, which allow the fungus to kill its host.Some of the advantages of forming highly bioactive compounds via both complex sphingolipid turnover and de novo biosynthesis are as follows. 1) The amounts of the backbones (sphingoid bases and ceramides) can be raised to higher levels than by sphingolipid turnover alone because palmitoyl-CoA and serine are plentiful; 2) the bioactive sphingolipid backbone(s) can be formed with minimal perturbation of the cellular status/utilization of complex sphingolipids; 3) the bioactive compounds may be targeted more directly to the intracellular membranes where they are needed; 4) the formation and removal of these species could be integrated with other cell states, such as whether or not the mitochondria are active and utilizing palmitoyl-CoA (Fig. 3); and 5) the molecular subspecies (such as the type of ceramide) can be modified to activate/inhibit downstream targets more selectively.It should be evident that understanding de novo sphingolipid biosynthesis and turnover under normal and abnormal conditions necessitates examination of all of these bioactive species as well as when and where they are made and removed (64Hannun Y.A. Luberto C. Argraves K.M. Biochemistry. 2001; 40: 4893-4903Crossref PubMed Scopus (439) Google Scholar). This is literally an "-omic" field ("sphingolipidomics"), as foreshadowed by Thudichum (5Thudichum J.L.W. A Treatise on the Chemical Constitution of Brain. Bailliere, Tindall, and Cox, London1884Google Scholar) in declaring that lipids are "the center, life, and chemical soul of all bioplasm whatsoever, that of plants as well as animals." 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
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