General structures of sphingolipids
Sphingolipids, or glycosylceramides, are a class of lipids containing a backbone of sphingoid bases, a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named for the mythological Sphinx because of their enigmatic nature.[1] These compounds play important roles in signal transmission and cell recognition. Sphingolipidoses, or disorders of sphingolipid metabolism, have particular impact on neural tissue. A sphingolipid with an R group consisting of a hydrogen atom only is a ceramide. Other common R groups include phosphocholine, yielding a sphingomyelin, and various sugar monomers or dimers, yielding cerebrosides and globosides, respectively. Cerebrosides and globosides are collectively known as glycosphingolipids.
Contents
- 1 Structure
- 2 Types
- 3 Mammalian sphingolipid metabolism
- 4 Functions of mammalian sphingolipids
- 5 Yeast sphingolipids
- 6 Plant sphingolipids
- 7 Disorders
- 8 Additional images
- 9 References
- 10 External links
Structure
The long-chain bases, sometimes simply known as sphingoid bases, are the first non-transient products of de novo sphingolipid synthesis in both yeast and mammals. These compounds, specifically known as phytosphingosine and dihydrosphingosine (also known as sphinganine,[2] although this term is less common), are mainly C18 compounds, with somewhat lower levels of C20 bases.[3] Ceramides and glycosphingolipids are N-acyl derivatives of these compounds.[4]
The sphingosine backbone is O-linked to a (usually) charged head group such as ethanolamine, serine, or choline.
The backbone is also amide-linked to an acyl group, such as a fatty acid.
Types
Simple sphingolipids, which include the sphingoid bases and ceramides, make up the early products of the sphingolipid synthetic pathways.
- Sphingoid bases are the fundamental building blocks of all sphingolipids. The main mammalian sphingoid bases are dihydrosphingosine and sphingosine, while dihydrosphingosine and phytosphingosine are the principle sphingoid bases in yeast.[5][6] Sphingosine, dihydrosphingosine, and phytosphingosine may be phosphorylated.
- Ceramides, as a general class, are N-acylated sphingoid bases lacking additional head groups.
- Dihydroceramide is produced by N-acylation of dihydrosphingosine. Dihydroceramide is found in both yeast and mammalian systems.
- Ceramide is produced in mammalian systems by desaturation of dihydroceramide by dihydroceramide desaturase 1 (DES1). This highly bioactive molecule may also be phosphorylated to form ceramide-1-phosphate.
- Phytoceramide is produced in yeast by hydroxylation of dihydroceramide at C-4.
Complex sphingolipids may be formed by addition of head groups to ceramide or phytoceramide:
- Sphingomyelins have a phosphocholine or phosphoethanolamine molecule with an ester linkage to the 1-hydroxy group of a ceramide.
- Glycosphingolipids are ceramides with one or more sugar residues joined in a β-glycosidic linkage at the 1-hydroxyl position (see image).
- Cerebrosides have a single glucose or galactose at the 1-hydroxy position.
- Sulfatides are sulfated cerebrosides.
- Gangliosides have at least three sugars, one of which must be sialic acid.
- Inositol-containing ceramides, which are derived from phytoceramide, are produced in yeast. These include inositol phosphorylceramide, mannose inositol phosphorylceramide, and mannose diinositol phosphorylceramide.
Mammalian sphingolipid metabolism
De novo sphingolipid synthesis begins with formation of 3-keto-dihydrosphingosine by serine palmitoyltransferase.[7] The preferred substrates for this reaction are palmitoyl-CoA and serine. However, studies have demonstrated that serine palmitoyltransferase has some activity toward other species of fatty acyl-CoA[8] and alternative amino acids,[9] and the diversity of sphingoid bases has recently been reviewed.[10] Next, 3-keto-dihydrosphingosine is reduced to form dihydrosphingosine. Dihydrosphingosine is acylated by a (dihydro)-ceramide synthase, such as Lass1p or Lass2p (also termed as CerS), to form dihydroceramide.[11] This is desaturated to form ceramide.[12]
Metabolic pathways of various forms of sphingolipids. Sphingolipidoses are labeled at corresponding stages that are deficient.
Ceramide may subsequently have several fates. It may be phosphorylated by ceramide kinase to form ceramide-1-phosphate. Alternatively, it may be glycosylated by glucosylceramide synthase or galactosylceramide synthase. Additionally, it can be converted to sphingomyelin by the addition of a phosphorylcholine headgroup by sphingomyelin synthase. Diacylglycerol is generated by this process. Finally, ceramide may be broken down by a ceramidase to form sphingosine. Sphingosine may be phosphorylated to form sphingosine-1-phosphate. This may be dephosphorylated to reform sphingosine.[13]
Breakdown pathways allow the reversion of these metabolites to ceramide. The complex glycosphingolipids are hydrolyzed to glucosylceramide and galactosylceramide. These lipids are then hydrolyzed by beta-glucosidases and beta-galactosidases to regenerate ceramide. Similarly, sphingomyelin may be broken down by sphingomyelinase to form ceramide.
The only route by which sphingolipids are converted to non-sphingolipids is through sphingosine-1-phosphate lyase. This forms ethanolamine phosphate and hexadecenal.[14]
Functions of mammalian sphingolipids
Sphingolipids are commonly believed to protect the cell surface against harmful environmental factors by forming a mechanically stable and chemically resistant outer leaflet of the plasma membrane lipid bilayer. Certain complex glycosphingolipids were found to be involved in specific functions, such as cell recognition and signaling. Cell recognition depends mainly on the physical properties of the sphingolipids, whereas signaling involves specific interactions of the glycan structures of glycosphingolipids with similar lipids present on neighboring cells or with proteins.
Recently, simple sphingolipid metabolites, such as ceramide and sphingosine-1-phosphate, have been shown to be important mediators in the signaling cascades involved in apoptosis, proliferation, stress responses, necrosis, inflammation, autophagy, senescence, and differentiation.[15][16][17][18][19][20] Ceramide-based lipids self-aggregate in cell membranes and form separate phases less fluid than the bulk phospholipids. These sphingolipid-based microdomains, or "lipid rafts" were originally proposed to sort membrane proteins along the cellular pathways of membrane transport. At present, most research focuses on the organizing function during signal transduction.[21]
Sphingolipids are synthesized in a pathway that begins in the ER and is completed in the Golgi apparatus, but these lipids are enriched in the plasma membrane and in endosomes, where they perform many of their functions.[22] Transport occurs via vesicles and monomeric transport in the cytosol. Sphingolipids are virtually absent from mitochondria and the ER, but constitute a 20-35 molar fraction of plasma membrane lipids.[23]
In experimental animals, feeding sphingolipids inhibits colon carcinogenesis, reduces (bad) LDL cholesterol and elevates (good) HDL cholesterol.[24]
Yeast sphingolipids
Because of the incredible complexity of mammalian systems, yeast are often used as a model organism for working out new pathways. These single-celled organisms are often more genetically tractable than mammalian cells, and strain libraries are available to supply strains harboring almost any non-lethal open reading frame single deletion. The two most commonly used yeasts are Saccharomyces cerevisiae and Schizosaccharomyces pombe, although research is also done in the pathological yeast Candida albicans.
In addition to the important structural functions of complex sphingolipids (inositol phosphorylceramide and its mannosylated derivatives), the sphingoid bases phytosphingosine and dihydrosphingosine (sphinganine) play vital signaling roles in S. cerevisiae. These effects include regulation of endocytosis, ubiquitin-dependent proteolysis (and, thus, regulation of nutrient uptake [25]), cytoskeletal dynamics, the cell cycle, translation, posttranslational protein modification, and the heat stress response.[26] Additionally, modulation of sphingolipid metabolism by phosphatidylinositol (4,5)-bisphosphate signaling via Slm1p and Slm2p and calcineurin has recently been described.[27] Additionally, a substrate-level interaction has been shown between complex sphingolipid synthesis and cycling of phosphatidylinositol 4-phosphate by the phosphatidylinositol kinase Stt4p and the lipid phosphatase Sac1p.[28]
Plant sphingolipids
Higher plants contain a wider variety of sphingolipids than animals and fungi.
Disorders
Main article: Sphingolipidoses
There are several disorders of sphingolipid metabolism, known as sphingolipidoses. The main members of this group are Niemann-Pick disease, Fabry disease, Krabbe disease, Gaucher disease, Tay-Sachs disease and Metachromatic leukodystrophy. They are generally inherited in an autosomal recessive fashion, but notably Fabry disease is X-linked. Taken together, sphingolipidoses have an incidence of approximately 1 in 10.000, but substantially more in certain populations such as Ashkenazi Jews. Enzyme replacement therapy is available to treat mainly Fabry disease and Gaucher disease, and people with these types of sphingolipidoses may live well into adulthood. The other types are generally fatal by age 1 to 5 years for infantile forms, but progression may be mild for juvenile- or adult-onset forms.
Additional images
References
- ^ Chun, J.; Hartung, H.P. Mechanism of Action of Oral Fingolimod (FTY720) in Multiple Sclerosis. Clin. Neuropharmacol. 2010, 33(2), 91-101.
- ^ Product page at Sigma Aldrich
- ^ Reviewed in Dickson, R.C. (1998)Annual Review of Biochemistry. 67, 27-48.
- ^ A brief, very comprehensible review is given in Gunstone, F. (1996) Fatty Acid and Lipid Chemistry, pp 43-44. Blackie Academic and Professional. ISBN 0-7514-0253-2
- ^ Dickson, Robert C. "New insights into sphingolipid metabolism and function in budding yeast." J Lipid Res. (2008) 49, 909-921. doi:10.1194/jlr.R800003-JLR200
- ^ Bartke N and Y. Hannun. "Bioactive sphingolipids: metabolism and function." J Lipid Res. (2009) 50 Suppl:S91-6. doi:10.1194/jlr.R800080-JLR200
- ^ Merrill. "Characterization of serine palmitoyltransferase activity in Chinese hamster ovary cells." Biochim Biophys Acta (1983) 754(3):284-91.
- ^ Merrill and Williams. "Utilization of different fatty acyl-CoA thioesters by serine palmitoyltransferase from rat brain". Journal of Lipid Research (1984) 25 (2): 185-188.
- ^ Zitomer NC, Mitchell T, Voss KA, Bondy GS, Pruett ST, Garnier-Amblard EC, Liebeskind LS, Park H, Wang E, Sullards MC, Merrill AH Jr, Riley RT. "Ceramide Synthase Inhibition by Fumonisin B1 Causes Accumulation of 1-Deoxysphinganine: A Novel Category of Bioactive 1-Deoxysphingoid Bases And 1-Deoxydihydroceramides Biosynthesized By Mammalian Cell Lines And Animals". Journal of Biological Chemistry (2009) 284 (8): 4786-4795.
- ^ Pruett et al. "Biodiversity of sphingoid bases ("sphingosines") and related amino alcohols". Journal of Lipid Research. (2008) 49:1621-1639.
- ^ Pewzner-Jung et al. "When do Lasses (longevity assurrance genes) become CerS (ceramide synthases)?: insights into the regulation of ceramide synthesis". Journal of Biological Chemistry. (2006) 281, 25001-25005.
- ^ Causeret et al. "Further characterization of rat dihydroceramide desaturase: tissue distribution, subcellular localization, and substrate specificity". Lipids. (2005) 35:1117-1125.
- ^ Reviewed in Hannun and Obeid. "Principles of bioactive lipid signalling: lessons from sphingolipids". Nature Reviews Molecular Cell Biology. (2008) 9, 139-150.
- ^ Bandhuvulua & Saba. "Sphingosine-1-phosphate lyase in immunity and cancer: silencing the siren". Trends in Molecular Medicine. (2007) 13:210-217.
- ^ Hannun YA, Obeid LM (July 2002). "The Ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind". J. Biol. Chem. 277 (29): 25847–50. doi:10.1074/jbc.R200008200. PMID 12011103.
- ^ Spiegel S, Milstien S (July 2002). "Sphingosine 1-phosphate, a key cell signaling molecule". J. Biol. Chem. 277 (29): 25851–4. doi:10.1074/jbc.R200007200. PMID 12011102.
- ^ Lavieu G, Scarlatti F, Sala G, Carpentier S, Levade T, Ghidoni R, Botti J, Codogno P. "Regulation of autophagy by sphingosine kinase 1 and its role in cell survival during nutrient starvation." J Biol Chem. (2006) 281(13):8518-27. doi:10.1074/jbc.M506182200
- ^ Venable, M. E., J. Y. Lee, M. J. Smyth, A. Bielawska, and L. M. Obeid. 1995. Role of ceramide in cellular senescence. J. Biol. Chem. 270: 30701–30708.
- ^ Hetz, C. A., M. Hunn, P. Rojas, V. Torres, L. Leyton, and A. F. Quest. 2002. Caspase-dependent initiation of apoptosis and necrosis by the Fas receptor in lymphoid cells: onset of necrosis is associated with delayed ceramide increase. J. Cell Sci. 115: 4671–4683.
- ^ Snider AJ, Orr Gandy KA, Obeid LM. "Sphingosine kinase: Role in regulation of bioactive sphingolipid mediators in inflammation." Biochimie. (2010) 92(6):707-15.
- ^ Brown DA, London E (June 2000). "Structure and function of sphingolipid- and cholesterol-rich membrane rafts". J. Biol. Chem. 275 (23): 17221–4. doi:10.1074/jbc.R000005200. PMID 10770957.
- ^ Futerman AH (December 2006). "Intracellular trafficking of sphingolipids: relationship to biosynthesis". Biochim. Biophys. Acta 1758 (12): 1885–92. doi:10.1016/j.bbamem.2006.08.004. PMID 16996025.
- ^ van Meer G, Lisman Q (July 2002). "Sphingolipid transport: rafts and translocators". J. Biol. Chem. 277 (29): 25855–8. doi:10.1074/jbc.R200010200. PMID 12011105.
- ^ "Sphingolipids in Food and the Emerging Importance of Sphingolipids to Nutrition". July 15, 2013.
- ^ Chung N. (2001) "Phytosphingosine as a specific inhibitor of growth and nutrient import in Saccharomyces cerevisiae." J Biol Chem. Sep 21; 276(38):35614-21.
- ^ Cowart and Obeid. (2007) "Yeast sphingolipids: recent developments in understanding biosynthesis, regulation, and function." Biochim Biophys Acta. Mar;1771(3):421-31.
- ^ Dickson, RC. (2008) J Lipid Res. May;49(5):909-21.
- ^ Brice and Cowart. (2009) J Biol Chem. Jan 12. Epub ahead of print
External links
- Sphingolipids at the US National Library of Medicine Medical Subject Headings (MeSH)
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Structures of the cell membrane
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| Membrane lipids |
- Lipid bilayer
- Phospholipids
- Proteolipids
- Sphingolipids
- Sterols
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| Membrane proteins |
- Membrane glycoproteins
- Integral membrane proteins/transmembrane protein
- Peripheral membrane protein/Lipid-anchored protein
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| Other |
- Caveolae/Coated pits
- Cell junctions
- Glycocalyx
- Lipid raft/microdomains
- Membrane contact sites
- Membrane nanotubes
- Myelin sheath
- Nodes of Ranvier
- Nuclear envelope
- Phycobilisomes
- Porosomes
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B memb: cead, trns (1A, 1C, 1F, 2A, 3A1, 3A2-3, 3D), other
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Glycoconjugates, lipids and glycolipids: sphingolipids and glycosphingolipids, and metabolic intermediates
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| Ceramide |
- Cerebroside
- Galactocerebroside
- Glucocerebroside
- Lactosylceramide
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Ganglioside
pathway |
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From ganglioside
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From globoside
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From sphingomyelin
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From sulfatide
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To sphingosine
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| Other |
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mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m
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k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon
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m (A16/C10), i (k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)
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- Biochemical families
- carbohydrates
- alcohols
- glycoproteins
- glycosides
- lipids
- eicosanoids
- fatty acids / intermediates
- glycerides
- phospholipids
- sphingolipids
- steroids
- nucleic acids
- constituents / intermediates
- proteins
- amino acids / intermediates
- tetrapyrroles / intermediates
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- Metabolism
- lipid metabolism
- glycolipid enzymes
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| Sphingolipid |
| To glycosphingolipid |
- Glycosyltransferase
- Sulfotransferase
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| To ceramide |
- From ganglioside
- Beta-galactosidase
- Hexosaminidase A
- Neuraminidase
- Glucocerebrosidase
- From globoside
- Hexosaminidase B
- Alpha-galactosidase
- Beta-galactosidase
- Glucocerebrosidase
- From sphingomyelin
- Sphingomyelin phosphodiesterase
- Sphingomyelin phosphodiesterase 1
- From sulfatide
- Arylsulfatase A
- Galactosylceramidase
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| To sphingosine |
- Ceramidase
- ACER1
- ACER2
- ACER3
- ASAH1
- ASAH2
- ASAH2B
- ASAH2C
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| Other |
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| NCL |
- Palmitoyl protein thioesterase
- Tripeptidyl peptidase I
- CLN3
- CLN5
- CLN6
- CLN8
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| Ceramide synthesis |
- Serine C-palmitoyltransferase (SPTLC1)
- Ceramide glucosyltransferase (UGCG)
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mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m
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k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon
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m (A16/C10), i (k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)
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