Thematic Review Series: Sphingolipids. Biodiversity of sphingoid bases (“sphingosines”) and related amino alcohols
2008; Elsevier BV; Volume: 49; Issue: 8 Linguagem: Inglês
10.1194/jlr.r800012-jlr200
ISSN1539-7262
AutoresSarah T. Pruett, Anatoliy Bushnev, Kerri Hagedorn, Madhura Adiga, Christopher A. Haynes, M. Cameron Sullards, Dennis C. Liotta, Alfred H. Merrill,
Tópico(s)Natural product bioactivities and synthesis
Resumo“Sphingosin” was first described by J. L. W. Thudichum in 1884 and structurally characterized as 2S,3R,4E-2-aminooctadec-4-ene-1,3-diol in 1947 by Herb Carter, who also proposed the designation of “lipides derived from sphingosine as sphingolipides.” This category of amino alcohols is now known to encompass hundreds of compounds that are referred to as sphingoid bases and sphingoid base-like compounds, which vary in chain length, number, position, and stereochemistry of double bonds, hydroxyl groups, and other functionalities. Some have especially intriguing features, such as the tail-to-tail combination of two sphingoid bases in the α,ω-sphingoids produced by sponges. Most of these compounds participate in cell structure and regulation, and some (such as the fumonisins) disrupt normal sphingolipid metabolism and cause plant and animal disease. Many of the naturally occurring and synthetic sphingoid bases are cytotoxic for cancer cells and pathogenic microorganisms or have other potentially useful bioactivities; hence, they offer promise as pharmaceutical leads. This thematic review gives an overview of the biodiversity of the backbones of sphingolipids and the broader field of naturally occurring and synthetic sphingoid base-like compounds. “Sphingosin” was first described by J. L. W. Thudichum in 1884 and structurally characterized as 2S,3R,4E-2-aminooctadec-4-ene-1,3-diol in 1947 by Herb Carter, who also proposed the designation of “lipides derived from sphingosine as sphingolipides.” This category of amino alcohols is now known to encompass hundreds of compounds that are referred to as sphingoid bases and sphingoid base-like compounds, which vary in chain length, number, position, and stereochemistry of double bonds, hydroxyl groups, and other functionalities. Some have especially intriguing features, such as the tail-to-tail combination of two sphingoid bases in the α,ω-sphingoids produced by sponges. Most of these compounds participate in cell structure and regulation, and some (such as the fumonisins) disrupt normal sphingolipid metabolism and cause plant and animal disease. Many of the naturally occurring and synthetic sphingoid bases are cytotoxic for cancer cells and pathogenic microorganisms or have other potentially useful bioactivities; hence, they offer promise as pharmaceutical leads. This thematic review gives an overview of the biodiversity of the backbones of sphingolipids and the broader field of naturally occurring and synthetic sphingoid base-like compounds. Sphingolipids are composed of a structurally related family of backbones termed sphingoid bases, which are sometimes referred to as “long-chain bases” or “sphingosines” after the original designation of the first isolated compound from brain as “sphingosin” by J. L. W. Thudichum in 1884 (1Thudichum J.L.W. A Treatise on the Chemical Constitution of Brain. Bailliere, Tindall, and Cox, London1884Google Scholar). Today, the term “sphingosine” is usually reserved for (2S,3R,4E)-2-aminooctadec-4-ene-1,3-diol (compound 6 in Fig. 1), which has important biological functions in cell signaling per se (2Zheng W. Kollmeyer J. Symolon H. Momin A. Munter E. Wang E. Kelly S. Allegood J.C. Liu Y. Peng Q. et al.Ceramides and other bioactive sphingolipid backbones in health and disease: lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy.Biochim. Biophys. Acta. 2006; 1758: 1864-1884Crossref PubMed Scopus (399) Google Scholar, 3Dickson R.C. Thematic review series: sphingolipids. New insights into sphingolipid metabolism and function in budding yeast.J. Lipid Res. 2008; 49: 909-921Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar) as well as after derivatization to the 1-phosphate (compound 9 in Fig. 1) (2Zheng W. Kollmeyer J. Symolon H. Momin A. Munter E. Wang E. Kelly S. Allegood J.C. Liu Y. Peng Q. et al.Ceramides and other bioactive sphingolipid backbones in health and disease: lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy.Biochim. Biophys. Acta. 2006; 1758: 1864-1884Crossref PubMed Scopus (399) Google Scholar, 4Spiegel S. Milstien S. Sphingosine-1-phosphate: an enigmatic signalling lipid.Nat. Rev. Mol. Cell Biol. 2003; 4: 397-407Crossref PubMed Scopus (1620) Google Scholar, 5Alvarez S.E. Milstien S. Spiegel S. Autocrine and paracrine roles of sphingosine-1-phosphate.Trends Endocrinol. Metab. 2007; 18: 300-307Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar), N-acylated metabolites (ceramides; compound 4 in Fig. 1) (2Zheng W. Kollmeyer J. Symolon H. Momin A. Munter E. Wang E. Kelly S. Allegood J.C. Liu Y. Peng Q. et al.Ceramides and other bioactive sphingolipid backbones in health and disease: lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy.Biochim. Biophys. Acta. 2006; 1758: 1864-1884Crossref PubMed Scopus (399) Google Scholar, 6Hannun Y.A. Obeid L.M. The ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind.J. Biol. Chem. 2002; 277: 25847-25850Abstract Full Text Full Text PDF PubMed Scopus (704) Google Scholar, 7Kitatani K. Idkowiak-Baldys J. Hannun Y.A. The sphingolipid salvage pathway in ceramide metabolism and signaling.Cell. Signal. 2008; 20: 1010-1018Crossref PubMed Scopus (326) Google Scholar), and more complex phosphosphingolipids and glycosphingolipids with head groups attached to the hydroxyl on carbon 1. The structural diversity of the latter compounds is widely appreciated, with hundreds of head group variants for mammals alone, as was reviewed recently (8Merrill Jr., A.H. Wang M.D. Park M. Sullards M.C. (Glyco)sphingolipidology: an amazing challenge and opportunity for systems biology.Trends Biochem. Sci. 2007; 32: 457-468Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 9Yu R.K. Yamagisawa M. Ariga T. Glycosphingolipid structures.In Comprehensive Glycoscience. J. P. Kamerling, editor. Elsevier, Oxford, UK. 2008; (in press)Google Scholar) and addressed at a number of “omics” web sites, such as SphinGOMAP (www.sphingomap.org), the Japanese Lipid Bank (http://www.lipidbank.jp) and Glycoforum (http://www.glycoforum.gr.jp/), the Lipid Maps Consortium (www.lipidmaps.org), the Consortium for Functional Glycomics (http://www.functionalglycomics.org/fg/), and the Complex Carbohydrate Research Center at the University of Georgia (http://www.ccrc.uga.edu/~moremen/glycomics/). Somewhat less well appreciated is that sphingoid bases also display considerable structural diversity, as was elegantly reviewed by K. A. Karlsson almost 40 years ago (10Karlsson K.A. On the chemistry and occurrence of sphingolipid long-chain bases.Chem. Phys. Lipids. 1970; 5: 6-43Crossref PubMed Scopus (233) Google Scholar, 11Karlsson K.A. Sphingolipid long chain bases.Lipids. 1970; 5: 878-891Crossref PubMed Scopus (187) Google Scholar). In remembrance of Herbert E. Carter, who first elucidated the structure of sphingosine 6 and dihydrosphingosine 2 (12Carter H.E. Glick F.J. Norris W.P. Phillips G.E. Biochemistry of the sphingolipids. III. Structure of sphingosine.J. Biol. Chem. 1947; 170: 285-294Abstract Full Text PDF Google Scholar) and “proposed to designate those lipides derived from sphingosine as sphingolipides” (13Carter H.E. Haines W.J. Ledyard W.E. Norris W.P. Biochemistry of the sphingolipides. I. Preparation of sphingolipides from beef brain and spinal cord.J. Biol. Chem. 1947; 169: 77-82Abstract Full Text PDF PubMed Google Scholar), this thematic review summarizes and updates points made previously regarding the structural diversity of sphingoid bases (10Karlsson K.A. On the chemistry and occurrence of sphingolipid long-chain bases.Chem. Phys. Lipids. 1970; 5: 6-43Crossref PubMed Scopus (233) Google Scholar, 11Karlsson K.A. Sphingolipid long chain bases.Lipids. 1970; 5: 878-891Crossref PubMed Scopus (187) Google Scholar) and expands the topic to include sphingoid bases and sphingoid base-like compounds that have been discovered in intervening years. In addition to being fascinating for their biodiversity, some of these naturally occurring compounds (and synthetic analogs) are promising drug leads, while others cause disease, as exemplified by the fumonisins (14E Wang P. Norred, C. W. Bacon, R. T. Riley, and A. H. Merrill, Jr W. Inhibition of sphingolipid biosynthesis by fumonisins. Implications for diseases associated with Fusarium moniliforme.J. Biol. Chem. 1991; 266: 14486-14490Abstract Full Text PDF PubMed Google Scholar). Within a few decades after the structure for sphingosine 6 had been determined (12Carter H.E. Glick F.J. Norris W.P. Phillips G.E. Biochemistry of the sphingolipids. III. Structure of sphingosine.J. Biol. Chem. 1947; 170: 285-294Abstract Full Text PDF Google Scholar) and sensitive methods for the analysis of sphingoid bases devised (15Sweeley C.C. Moscatelli E.A. Qualitative microanalysis and estimation of sphingolipid bases.J. Lipid Res. 1959; 1: 40-47Abstract Full Text PDF Google Scholar), there was evidence for >60 structural variations (10Karlsson K.A. On the chemistry and occurrence of sphingolipid long-chain bases.Chem. Phys. Lipids. 1970; 5: 6-43Crossref PubMed Scopus (233) Google Scholar, 11Karlsson K.A. Sphingolipid long chain bases.Lipids. 1970; 5: 878-891Crossref PubMed Scopus (187) Google Scholar). The 1997 International Union of Pure and Applied Chemists-International Union of Biochemists Joint Commission on Biochemical Nomenclature (16Chester M.A. IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). Nomenclature of glycolipids—recommendations 1997.Eur. J. Biochem. 1998; 257: 293-298Crossref PubMed Google Scholar) proposed that “Sphingoids are long-chain aliphatic amino alcohols...represented by the compound originally called 'dihydrosphingosine’ [(2S,3R)-2-aminooctadecane-1,3-diol]…[and]… imply a chain length of 18 carbon atoms.” Dihydrosphingosine (compound 2 in Fig. 1; also called “sphinganine”) is one of the major sphingoid bases found in many organisms as well as an early intermediate in the de novo biosynthesis of sphingosine via desaturation of dihydroceramides (3) to produce ceramides (4) (17Ternes P. Franke S. Zahringer U. Sperling P. Heinz E. Identification and characterization of a sphingolipid delta 4-desaturase family.J. Biol. Chem. 2002; 277: 25512-25518Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar) and for the formation of “phytosphingosine” 7 (2S,3S,4R-2-aminooctadecane-1,3,4-triol) and what is colloquially referred to as “phytoceramide” (compound 5 in Fig. 1) via hydroxylation of sphinganine (18Omae F. Miyazaki M. Enomoto A. Suzuki M. Suzuki Y. Suzuki A. DES2 protein is responsible for phytoceramide biosynthesis in the mouse small intestine.Biochem. J. 2004; 379: 687-695Crossref PubMed Scopus (81) Google Scholar) or dihydroceramide (17Ternes P. Franke S. Zahringer U. Sperling P. Heinz E. Identification and characterization of a sphingolipid delta 4-desaturase family.J. Biol. Chem. 2002; 277: 25512-25518Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar). The alternative names (4E)-sphing-4-enine and (4E)-sphingenine are sometimes used to designate the specific location of the double bond of sphingosine. The International Union of Pure and Applied Chemists-International Union of Biochemists Joint Commission (16Chester M.A. IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). Nomenclature of glycolipids—recommendations 1997.Eur. J. Biochem. 1998; 257: 293-298Crossref PubMed Google Scholar) and others (19Fahy E. Subramaniam S. Brown H.A. Glass C.K. Merrill Jr., A.H. Murphy R.C. Raetz C.R. Russell D.W. Seyama Y. Shaw W. et al.A comprehensive classification system for lipids.J. Lipid Res. 2005; 46: 839-861Abstract Full Text Full Text PDF PubMed Scopus (889) Google Scholar) have recommended naming chain length homologs by the root chemical name of the parent hydrocarbon (e.g., a 20 carbon sphinganine is called an icosasphinganine and one with 14 carbon atoms is called tetradecasphinganine), and the position and stereochemistry of substituents such as double bonds (with E/Z preferred over trans/cis), hydroxyl groups, methyl groups, etc., should be stated explicitly, if known. Examples of such compounds are shown in Figs. 2and 3.A useful shorthand nomenclature is to give the number of hydroxyl groups [“d” for the two (di-) hydroxyls of sphingosine and sphinganine and “t” (tri-) for the additional hydroxyl in 4-hydroxysphinganine] followed by the number of carbon atoms in the backbone and the number of double bonds, with the location and configuration given as a prefix or suffix. Therefore, sphingosine is designated 4E-d18:1 (and sometimes d18:1Δ4t), dihydrosphingosine is designated d18:0, and phytosphingosine (4-hydroxysphinganine) is designated t18:0.Fig. 3Sphingoid bases found in diverse organisms other than mammals.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The predominance of 18 carbon sphingoid bases (d18:0, d18:1, and t18:0) in most mammalian sphingolipids is consistent with the preference of mammalian serine palmitoyltransferase (SPT) for saturated fatty acyl-CoAs with 16 ± 1 carbon atoms, combined with the abundance of palmitoyl-CoA (20Merrill Jr., A.H. Williams R.D. Utilization of different fatty acyl-CoA thioesters by serine palmitoyltransferase from rat brain.J. Lipid Res. 1984; 25: 185-188Abstract Full Text PDF PubMed Google Scholar, 21Haynes C.A. Allegood J.C. Sims K. Wang E.W. Sullards M.C. Merrill Jr., A.H. Quantitation of fatty acyl-coenzyme As in mammalian cells by liquid chromatography-electrospray ionization tandem mass spectrometry.J. Lipid Res. 2008; 49: 1113-1125Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar); nonetheless, small amounts of sphingoid bases with other chain lengths of 12 to 26 carbons have been reported (22Farwanah H. Pierstorff B. Schmelzer C.E. Raith K. Neubert R.H. Kolter T. Sandhoff K. Separation and mass spectrometric characterization of covalently bound skin ceramides using LC/APCI-MS and Nano-ESI-MS/MS.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2007; 852: 562-570Crossref PubMed Scopus (48) Google Scholar, 23Stewart M.E. Downing D.T. Free sphingosines of human skin include 6-hydroxysphingosine and unusually long-chain dihydrosphingosines.J. Invest. Dermatol. 1995; 105: 613-618Abstract Full Text PDF PubMed Google Scholar). The most common chain length variant is eisosasphingosine (2S,3R,4E-d20:1), which has been found in substantial amounts in gangliosides from brain (24Sonnino S. Chigorno V. Ganglioside molecular species containing C18- and C20-sphingosine in mammalian nervous tissues and neuronal cell cultures.Biochim. Biophys. Acta. 2000; 1469: 63-77Crossref PubMed Scopus (111) Google Scholar) and human stomach and intestinal mucosa (25Keranen A Fatty acids and long-chain bases of gangliosides of human gastrointestinal mucosa.Chem. Phys. Lipids. 1976; 17: 14-21Crossref PubMed Scopus (0) Google Scholar) and in sphingomyelin from rats bearing Morris hepatoma 7777 (26Merrill Jr., A.H. Wang E. Wertz P.W. Differences in the long chain (sphingoid) base composition of sphingomyelin from rats bearing Morris hepatoma 7777.Lipids. 1986; 21: 529-530Crossref PubMed Scopus (11) Google Scholar). Sphingoid bases with 16 carbon atoms are found in substantial proportions in bovine sphingolipids (e.g., 25–30% in milk sphingomyelin), which also have small amounts of other even and odd carbon chain length homologs (27Byrdwell W.C. Perry R.H. Liquid chromatography with dual parallel mass spectrometry and 31P nuclear magnetic resonance spectroscopy for analysis of sphingomyelin and dihydrosphingomyelin. II. Bovine milk sphingolipids.J. Chromatogr. A. 2007; 1146: 164-185Crossref PubMed Scopus (46) Google Scholar, 28Karlsson A.A. Michelsen P. Odham G. Molecular species of sphingomyelin: determination by high-performance liquid chromatography/mass spectrometry with electrospray and high-performance liquid chromatography/tandem mass spectrometry with atmospheric pressure chemical ionization.J. Mass Spectrom. 1998; 33: 1192-1198Crossref PubMed Scopus (77) Google Scholar). Milk gangliosides appear to contain the unusual sphingoid bases 3-ethoxy-d15:0, 3-ethoxy-d17:0, and 9-methyl-3-ethoxy-d15:0 (29Martin M.J. Martin-Sosa S. Hueso P. Bovine milk gangliosides: changes in ceramide moiety with stage of lactation.Lipids. 2001; 36: 291-298Crossref PubMed Google Scholar). Sphingomyelin and cerebrosides in black epidermis from the Antarctic minke whale also have a high proportion (∼25%) of 16 carbon sphingoid bases (30Yunoki K. Ishikawa H. Fukui Y. Ohnishi M. Chemical properties of epidermal lipids, especially sphingolipids, of the Antarctic minke whale.Lipids. 2008; 43: 151-159Crossref PubMed Scopus (0) Google Scholar). Variation in the number and position of double bonds and hydroxyl groups also occurs. Plasma, brain, and human aorta contain a 4E,14Z-diene 15 (31Renkonen O. Hirvisalo E.L. Structure of plasma sphingadienine.J. Lipid Res. 1969; 10: 687-693Abstract Full Text PDF PubMed Google Scholar, 32Panganamala R.V. Geer J.C. Cornwell D.G. Long-chain bases in the sphingolipids of atherosclerotic human aorta.J. Lipid Res. 1969; 10: 445-455Abstract Full Text PDF PubMed Google Scholar), and 6-hydroxy-sphingosine 16 is present in skin sphingolipids (23Stewart M.E. Downing D.T. Free sphingosines of human skin include 6-hydroxysphingosine and unusually long-chain dihydrosphingosines.J. Invest. Dermatol. 1995; 105: 613-618Abstract Full Text PDF PubMed Google Scholar, 33Stewart M.E. Downing D.T. A new 6-hydroxy-4-sphingenine-containing ceramide in human skin.J. Lipid Res. 1999; 40: 1434-1439Abstract Full Text Full Text PDF PubMed Google Scholar, 34Chun J. Byun H.S. Bittman R. First asymmetric synthesis of 6-hydroxy-4-sphingenine-containing ceramides. Use of chiral propargylic alcohols to prepare a lipid found in human skin.J. Org. Chem. 2003; 68: 348-354Crossref PubMed Scopus (0) Google Scholar). An unusual sphingosine with the double bond between carbons 3 and 4 (5-hydroxy,3E-sphingosine; compound 17 in Fig. 3) has been found in acid-hydrolyzed brain extracts (35Kadowaki H. Bremer E.G. Evans J.E. Jungalwala F.B. McCluer R.H. Acetonitrile-hydrochloric acid hydrolysis of gangliosides for high performance liquid chromatographic analysis of their long chain bases.J. Lipid Res. 1983; 24: 1389-1397Abstract Full Text PDF PubMed Google Scholar). While it is possible that 17 is a by-product of the acid hydrolysis (36Carter H.E. Nalbandov O. Tavormina P.A. Biochemistry of the sphingolipides. VI. The o-methyl ethers of sphingosine.J. Biol. Chem. 1951; 192: 197-207Abstract Full Text PDF PubMed Google Scholar, 37A Kisic Tsuda, R. J. Kulmacz, W. K. Wilson, and G. J. Schroepfer, Jr M. Sphingolipid bases: a revisitation of the O-methyl derivatives of sphingosine. Isolation and characterization of diacetate derivatives, with revised 13C nuclear magnetic resonance assignments for D-erythro-sphingosine.J. Lipid Res. 1995; 36: 787-803Abstract Full Text PDF PubMed Google Scholar) (as will be discussed below for Fig. 8), it is nonetheless interesting that the N-octanoyl derivatives of both the 5R and 5S stereoisomers of 17 have been reported to be more potent than ceramide in inhibition of the proliferation of a human breast cancer cell line (MCF-7 cells) (38Chun J. Byun H.S. Arthur G. Bittman R. Synthesis and growth inhibitory activity of chiral 5-hydroxy-2-N-acyl-(3E)-sphingenines: ceramides with an unusual sphingoid backbone.J. Org. Chem. 2003; 68: 355-359Crossref PubMed Scopus (0) Google Scholar). This is surprising because the 4,5-trans-(E) double bond is usually necessary for ceramide signaling (39Bielawska A. Crane H.M. Liotta D. Obeid L.M. Hannun Y.A. Selectivity of ceramide-mediated biology. Lack of activity of erythro-dihydroceramide.J. Biol. Chem. 1993; 268: 26226-26232Abstract Full Text PDF PubMed Google Scholar). Sphingoid bases with branched side chains (such as the iso-18 and anteiso-19 configurations shown in Fig. 2) have been reported in sphingolipids from bovine milk and kidney (40Morrison W.R. Long-chain bases in the sphingolipids of bovine milk and kidney, rumen bacteria, rumen protozoa, hay and concentrate.Biochim. Biophys. Acta. 1973; 316: 98-107Crossref PubMed Scopus (0) Google Scholar), atherosclerotic human aorta (32Panganamala R.V. Geer J.C. Cornwell D.G. Long-chain bases in the sphingolipids of atherosclerotic human aorta.J. Lipid Res. 1969; 10: 445-455Abstract Full Text PDF PubMed Google Scholar), and pig harderian gland (41Yasugi E. Kasama T. Shibahara M. Seyama Y. Composition of long-chain bases in sphingomyelin of the guinea pig harderian gland.Biochem. Cell Biol. 1990; 68: 154-160Crossref PubMed Scopus (16) Google Scholar, 42Yasugi E. Kasama T. Seyama Y. Composition of long chain bases in ceramide of the guinea pig harderian gland.J Biochem. 1991; 110: 202-206Crossref PubMed Google Scholar) (which is not present in all mammals, including humans). Branched-chain sphingoid bases might become associated with mammalian tissues by microorganisms that are part of normal or pathogenic microflora, as illustrated by an iso-d15:0 sphingoid base that is found in Porphyromonas gingivalis from diseased dental tissues (43Nichols F.C. Rojanasomsith K. Porphyromonas gingivalis lipids and diseased dental tissues.Oral Microbiol. Immunol. 2006; 21: 84-92Crossref PubMed Scopus (24) Google Scholar). Interestingly, it appears that the poor absorption of “nonmammalian” sphingoid bases, such as the plant 4,8-diene, is due to the efflux of these compounds via P-glycoprotein in the apical membranes of enterocytes (44Sugawara T. Kinoshita M. Ohnishi M. Nagata J. Saito M. Digestion of maize sphingolipids in rats and uptake of sphingadienine by Caco-2 cells.J. Nutr. 2003; 133: 2777-2782Crossref PubMed Scopus (76) Google Scholar, 45Sugawara T. Kinoshita M. Ohnishi M. Tsuzuki T. Miyazawa T. Nagata J. Hirata T. Saito M. Efflux of sphingoid bases by P-glycoprotein in human intestinal Caco-2 cells.Biosci. Biotechnol. Biochem. 2004; 68: 2541-2546Crossref PubMed Scopus (35) Google Scholar), which raises the possibility that if this system is not working properly, there might be uptake of such compounds into mammalian tissues. Small amounts of N- and O-methyl-sphingoid bases are sometimes found in mammalian sphingolipids and are thought mostly to be artifacts of the extraction and handling (36Carter H.E. Nalbandov O. Tavormina P.A. Biochemistry of the sphingolipides. VI. The o-methyl ethers of sphingosine.J. Biol. Chem. 1951; 192: 197-207Abstract Full Text PDF PubMed Google Scholar, 37A Kisic Tsuda, R. J. Kulmacz, W. K. Wilson, and G. J. Schroepfer, Jr M. Sphingolipid bases: a revisitation of the O-methyl derivatives of sphingosine. Isolation and characterization of diacetate derivatives, with revised 13C nuclear magnetic resonance assignments for D-erythro-sphingosine.J. Lipid Res. 1995; 36: 787-803Abstract Full Text PDF PubMed Google Scholar) (as will be discussed below); however, a sphingosine N-methyltransferase activity has been found in mouse brain (46Igarashi Y. Hakomori S. Enzymatic synthesis of N,N-dimethyl-sphingosine: demonstration of the sphingosine:N-methyltransferase in mouse brain.Biochem. Biophys. Res. Commun. 1989; 164: 1411-1416Crossref PubMed Scopus (0) Google Scholar), and recent studies of mice treated with safingol, the l-threo stereoisomer of sphinganine, have found that it undergoes significant N-methylation (N-methyl, N,N-dimethyl, and N,N,N-trimethyl; compounds 11–13 in Fig. 1) and that under these conditions, there is also methylation of endogenous sphingosine and sphinganine (47Morales P.R. Dillehay D.L. Moody S.J. Pallas D.C. Pruett S. Allgood J.C. Symolon H. Merrill Jr., A.H. Safingol toxicology after oral administration to TRAMP mice: demonstration of safingol uptake and metabolism by N-acylation and N-methylation.Drug Chem. Toxicol. 2007; 30: 197-216Crossref PubMed Scopus (14) Google Scholar), which suggests that the methyltransferases are inducible. The endogenous formation of N,N-dimethylsphingosine is interesting because this compound inhibits protein kinase C (48Merrill Jr., A.H. Nimkar S. Menaldino D. Hannun Y.A. Loomis C. Bell R.M. Tyagi S.R. Lambeth J.D. Stevens V.L. Hunter R. et al.Structural requirements for long-chain (sphingoid) base inhibition of protein kinase C in vitro and for the cellular effects of these compounds.Biochemistry. 1989; 28: 3138-3145Crossref PubMed Google Scholar) and sphingosine kinase (49Melendez A.J. Carlos-Dias E. Gosink M. Allen J.M. Takacs L. Human sphingosine kinase: molecular cloning, functional characterization and tissue distribution.Gene. 2000; 251: 19-26Crossref PubMed Scopus (116) Google Scholar) as well as affects multiple cellular processes (50Kim H.L. Im D.S. N,N-Dimethyl-D-erythro-sphingosine increases intracellular Ca2+ concentration via Na+-Ca2+-exchanger in HCT116 human colon cancer cells.Arch. Pharm. Res. 2008; 31: 54-59Crossref PubMed Scopus (13) Google Scholar) and potently induces apoptosis in cancer cell lines (51Sweeney E.A. Sakakura C. Shirahama T. Masamune A. Ohta H. Hakomori S. Igarashi Y. Sphingosine and its methylated derivative N,N-dimethylsphingosine (DMS) induce apoptosis in a variety of human cancer cell lines.Int. J. Cancer. 1996; 66: 358-366Crossref PubMed Scopus (0) Google Scholar). Fungi, plants, insects, and aquatic organisms extend the structural and compositional variation even further, as illustrated in Fig. 3. Insects have primarily 14 and 16 carbon sphingoid bases (52Wiegandt H Insect glycolipids.Biochim. Biophys. Acta. 1992; 1123: 117-126Crossref PubMed Scopus (46) Google Scholar, 53H Fyrst R. Herr, G. L. Harris, and J. D. Saba D. Characterization of free endogenous C14 and C16 sphingoid bases from Drosophila melanogaster.J. Lipid Res. 2004; 45: 54-62Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar) such as 4E-d14:1 (20 in Fig. 3) and the conjugated diene 4E,6E-d14:2 21 found in Drosophila (54Fyrst H. Zhang X. Herr D.R. Byun H.S. Bittman R. Phan V.H. Harris G.L. Saba J.D. Identification and characterization by electrospray mass spectrometry of endogenous Drosophila sphingadienes.J. Lipid Res. 2008; 49: 597-606Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar). Nematodes have both iso-branched (4E,15-methyl-d17:1) and anteiso-branched (4E,14-methyl-d17:1) sphingoid bases (compare 18 and 19 in Fig. 3) (55S Gerdt D. Dennis, G. Borgonie, R. Schnabel, and R. Geyer R. Isolation, characterization and immunolocalization of phosphorylcholine-substituted glycolipids in developmental stages of Caenorhabditis elegans.Eur. J. Biochem. 1999; 266: 952-963Crossref PubMed Scopus (66) Google Scholar, 56Chitwood D.J. Lusby W.R. Thompson M.J. Kochansky J.P. Howarth O.W. The glycosylceramides of the nematode Caenorhabditis elegans contain an unusual, branched-chain sphingoid base.Lipids. 1995; 30: 567-573Crossref PubMed Scopus (0) Google Scholar) in several categories of novel glycosphingolipids, including phosphocholine-containing glycosphingolipids that have been found in the parasitic nematodes Onchocerca volvulus (57M Wuhrer Rickhoff, R. D. Dennis, G. Lochnit, P. T. Soboslay, S. Baumeister, and R. Geyer S. Phosphocholine-containing, zwitterionic glycosphingolipids of adult Onchocerca volvulus as highly conserved antigenic structures of parasitic nematodes.Biochem. J. 2000; 348: 417-423Crossref PubMed Google Scholar) and Ascaris suum (58G Lochnit Nispel, R. D. Dennis, and R. Geyer S. Structural analysis and immunohistochemical localization of two acidic glycosphingolipids from the porcine, parasitic nematode, Ascaris suum.Glycobiology. 1998; 8: 891-899Crossref PubMed Scopus (26) Google Scholar), with the latter also containing sulfatides (which is not common in invertebrates) (58G Lochnit Nispel, R. D. Dennis, and R. Geyer S. Structural analysis and immunohistochemical localization of two acidic glycosphingolipids from the porcine, parasitic nematode, Ascaris suum.Glycobiology. 1998; 8: 891-899Crossref PubMed Scopus (26) Google Scholar). A 15-carbon atom (unbranched) phytosphingosine (in amide linkage with a 21:0 iso-branched α-hydroxy fatty acid) has been found in urine of the female hairy crab, Erimacrus isenbeckii, and serves as a sex pheromone to elicit precopulatory behavior in males (59N Asai Fusetani, and S. Matsunaga N. Sex pheromones of the hair crab Erimacrus isenbeckii. II. Synthesis of ceramides.J. Nat. Prod. 2001; 64: 1210-1215Crossref PubMed Scopus (23) Google Scholar). Recent studies of a group of viruses (Coccolithovirus) that infect the marine calcifying microalga Emiliania huxleyi have revealed that the viral genome contains a cluster of putative sphingolipid biosynthetic genes, including a SPT (Fig. 1) that utilizes myristoyl-CoA when expressed in yeast (60Han G. Gable K. Yan L. Allen M.J. Wilson W.H. Moitra P. Harmon J.M. Dunn T.M. Expression of a novel marine viral single-chain serine palmitoyltransferase and construction of yeast and mammalian single-chain chimera.J. Biol. Chem. 2006; 281: 39935-39942Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). This might cause an infected host to produce a 16 carbon chain length sphingoid base, which is interesting because at least one virus (picornavirus) has a capsid protein with a hydrophobic pocket that has been suggested to bind sphingosine (61Zhao R. Pevear D.C. Kremer M.J. Giranda V.L. Kofron J.A. Kuhn R.J. Rossmann M.G. Human rhinovirus 3 at 3.0 A resolution.Structure. 1996; 4: 1205-1220Abstract Full Text Full Text PDF PubMed Google Scholar). Other types of structural variation include the location of the double
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