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Distribution and Functions of Sterols and Sphingolipids

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Distribution and Functions of Sterols and Sphingolipids Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Distribution and Functions of Sterols and Sphingolipids J. Thomas Hannich1, Kyohei Umebayashi1, and Howard Riezman Department of Biochemistry, University of Geneva, CH-1211 Geneva 4, Switzerland Correspondence: [email protected] Sterols and sphingolipids are considered mainly eukaryotic lipids even though both are present in some prokaryotes, with sphingolipids being more widespread than sterols. Both sterols and sphingolipids differ in their structural features in vertebrates, plants, and fungi. Interestingly, some invertebrates cannot synthesize sterols de novo and seem to have a reduced dependence on sterols. Sphingolipids and sterols are found in the plasma mem- brane, but we do not have a clear picture of their precise intracellular localization. Advances in lipidomics and subcellular fractionation should help to improve this situation. Genetic approaches have provided insights into the diversity of sterol and sphingolipid func- tions in eukaryotes providing evidence that these two lipid classes function together. Intermediates in sphingolipid biosynthesis and degradation are involved in signaling path- ways, whereas sterol structures are converted to hormones. Both lipids have been implicated in regulating membrane trafficking. ypical examples of eukaryotic lipids, sterols, bacteria. Sphingolipids are more widely spread Tand sphingolipids can both be found in among prokaryotes than sterols and also show membranes from simple unicellular fungi and a greater variety of structures among the differ- protists to multicellular animals and plants. ent eukaryotes. Their versatile use as structural elements but In this short review we will first give an also as signaling molecules has probably played overview about the diversity of sterol and sphin- an important role during the evolution of this golipid structures and their distribution in large and diverse group of organisms. There nature. Then we will discuss their subcellular are also many eukaryotes that have lost the abil- distribution. A brief technical section will add ity to synthesize sterols de novo including nem- some information on the separation and detec- atodes, insects, and marine invertebrates, which tion of these lipid molecules. Subsequently, have to take up sterols with their diet. Sterol bio- we will summarize different genetic approaches synthesis has also been reported in a number of to study the functions of sterols and sphingo- lipids, and finally, we will discuss the functional and possible physical interactions of the two 1These authors contributed equally to this article. lipid classes within the cell. Far from being Editor: Kai Simons Additional Perspectives on The Biology of Lipids available at www.cshperspectives.org Copyright # 2011 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a004762 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a004762 1 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press J.T. Hannich et al. comprehensive, we will focus only on a few to phytosterol biosynthesis (Ohyama et al. interesting aspects and try to give new view 2009). Both cycloartenol synthase and lano- points, which are less frequently discussed. sterol synthase are closely related to each other and to the bacterial squalene-hopene cyclases, which produce the bacterial polycyclic hope- STRUCTURES AND DISTRIBUTION AMONG noids without a requirement for molecular oxy- SPECIES gen and which are most likely the evolutionary Sterol biosynthesis probably evolved after the ancestors of the sterol biosynthetic enzymes. emergence of oxygen about 2.5 billion years Cycloartenol and lanosterol are further metabo- ago (Galea and Brown 2009). The first dedi- lized via (de-) methylations and double-bond cated step, which is common to all sterol bio- modifications to give rise to the final sterol synthetic pathways, is the mono-oxygenation products: several C-24 alkylated phytosterols, of squalene catalyzed by Squalene Epoxidase/ C28 campesterol, C29 sitosterol, and stigma- Erg1p and uses molecular oxygen. Even at this sterol in plants (Benveniste 1986), a single early step in the pathway, the cyclization of the C-24 methylated C28 ergosterol in most fungi linear precursor, which gives rise to the polycy- (Weete et al. 2010), and the single nonmethy- clic sterol ring structure, shows a diversification lated C27 cholesterol in animals (Gaylor 2002) between kingdoms, with cycloartenol as the (Table 1). Most invertebrates including the product in most algae and plants and lanosterol important genetic model organisms Drosophila in fungi and animals (Volkman 2003). Recently, melanogaster and Caenorhabditis elegans have it was found that some plants also have the abil- lost the ability to synthesize sterols (Clayton ity to produce lanosterol, which can contribute 1964; Kurzchalia and Ward 2003). They are Table 1. Sterol and sphingolipid structures and distribution among species. Auxotrophic Organism Plants Fungi Vertebrates Bacteria invertebrates Main sterol Campesterol (R = methyl) Ergosterol, Cholesterol Modifications of Generally absent, Sitosterol (R = ethyl) some exceptions dietary sterols very few exceptions Stigmasterol (R = ethyl, Δ22) R H H H H H H HHHHH HO HO HO Main sphingoid Several bases including: Variety of structures Sphingosine D. melanogaster : Mostly absent, Δ8∗ S. cerevisiae: Δ4* C sphingosine some exceptions base d18:1 ∗ (d18:1 ), 14 Δ4Δ8∗ sphinganine (d18:0 ) C. elegans: d18:2 ∗ several others present Δ ∗ phytosphingosine (t18:0 ) C iso-sphingosine t18:1 8 17 P. pastoris: 9-methyl- sphinga-4,8,-dienine Higher -Inositolphosphoryl -Inositolphosphoryl -Sphingomyelin -Sphingomyelin (C. elegans) Mostly absent, sphingolipids glycolipids glycolipids -Glycosphingolipids -Phosphoethanolamine some exceptions with -Glycosphingolipids -Glycosphingolipids (mainly glucosyl-, some ceramide (D. melanogaster) glucosyl ceramide (mainly glucosyl-, some S. cerevisiae: only galactosylceramide series) -Glucosyl ceramide series series + + + mannosylceramide series) IPC , MIPC , M(IP)2C SREBP Not found Oxygen sensor, SREBP1a/c regulate fatty Regulates fatty acid and Not found but not found in acid & fat metabolism fat metabolism S. cerevisiae SREBP2 regulates sterol metabolism ÃShorthand nomenclature for sphingoid bases “aXX:YDZ”: a-number of hydroxylgroups (d ¼ 2, t ¼ 3); XX-number of carbon atoms; Y-double bonds, DZ-position of double bonds. þIPC-inositolphosphorylceramide, MIPC-mannosylinositolphosphorylceramide, M(IP)2C-mannosyldiinositolphosphorylceramide. 2 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a004762 Downloaded from http://cshperspectives.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Sterols and Sphingolipids dependent on external sterol sources and use C22 (Han and Jiang 2009) as well as 1-deoxy some of the remaining conserved sterol biosyn- and 1-deoxymethyl long chain bases can be thetic enzymes for sterol modifications, includ- found (Penno et al. 2010). Differences in double ing steroid hormone production (Vinci et al. bonds and base hydroxylation additionally give 2008) and regulation (Hannich et al. 2009). rise to sphinganine (d18:0), phytosphinganine Another very important feature of sterol (t18:0), and their analogues. Also in plants C18 biosynthesis in vertebrates is its regulation by sphingoid bases, especially with D8 and D4D8 the membrane bound basic helix-loop-helix double bonds, predominate (Pata et al. 2010). (bHLH) transcription factor SREBP (Osborne Many fungi additionally methylate the alkyl and Espenshade 2009). The vertebrate genome chain at C-9, giving rise to C19 bases (Ternes contains two copies encoding three isoforms et al. 2006), but the baker’s yeast S. cerevisiae with SREBP-2 regulating mainly cholesterol produces only sphinganine and phytosphinga- biosynthesis and SREBP-1a and c regulating nine (mainly d18:0 and t18:0, some d20:0, and mainly fatty acid and phospholipid metabolism t20:0). In invertebrates other chain lengths are as well as fat storage. Invertebrates have one abundant. Flies produce mainly C14 and some copy of SREBP, which has been shown to regu- C16 straight chain bases (Acharya and Acharya late fatty acid and phospholipid metabolism 2005), whereas nematodes build their sphingo- in flies and fatty acid metabolism and fat accu- lipids from C17 iso-branched sphingoid bases mulation in worms (see Ye and Debose-Boyd (Chitwood et al. 1995). Free LCBs exist only at 2011). Although no SREBP homolog has yet very low levels in the cell. Most of these can be been found in Saccharomyces cerevisiae, other phosphorylated to form sphingosine-1-phos- fungi like Schizosaccharomyces pombe also ex- phate and other phosphorylated sphingoid press a copy that serves as a sterol-dependent bases. The majority of sphinganine is trans- oxygen sensor that regulates oxygen-dependent formed into dihydroceramide (likewise for steps in ergosterol, heme, and sphingolipid other sphingoid bases) by N-acylation with fatty metabolism (Todd et al. 2006). So far no acids ranging from C14 to C26 or perhaps even SREBP homolog has been described in plants up to C36 in rare cases. The majority of incorpo- even though a number of membrane-bound rated fatty acids are saturated or monounsatu- bHLH transcription factors still await further rated and can be modified with an a and one characterization.
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