Review the Metabolism and Function of Sphingolipids and Glycosphingolipids
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Cell. Mol. Life Sci. 64 (2007) 2270 – 2284 1420-682X/07/172270-15 Cellular and Molecular Life Sciences DOI 10.1007/s00018-007-7076-0 Birkhuser Verlag, Basel, 2007 Review The metabolism and function of sphingolipids and glycosphingolipids S. Lahiri and A. H. Futerman* Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100 (Israel), Fax : +9728-9344112, e-mail: [email protected] Received 13 February 2007; received after revision 19 April 2007; accepted 26 April 2007 Online First 11 June 2007 Abstract. Sphingolipids and glycosphingolipids are between them. We then discuss some roles of sphin- emerging as major players in many facets of cell golipids in cell physiology, particularly those of physiology and pathophysiology. We now present an ceramide and sphingosine-1-phosphate, and mention overview of sphingolipid biochemistry and physiol- current views about how these lipids act in signal ogy, followed by a brief presentation of recent transduction pathways. We end with a discussion of advances in translational research related to sphingo- sphingolipids and glycosphingolipids in the etiology lipids. In discussing sphingolipid biochemistry, we and pathology of a number of diseases, such as cancer, focus on the structure of sphingolipids, and their immunity, cystic fibrosis, emphysema, diabetes, and biosynthetic pathways – the recent identification of sepsis, areas in which sphingolipids are beginning to most of the enzymes in this pathway has led to take a central position, even though many of the significant advances and better characterization of a details remain to be elucidated. number of the biosynthetic steps, and the relationship Keywords. Sphingolipid, glycosphingolipid, ceramide, sphingosine-1-phosphate, apoptosis, cancer. Introduction lipid bilayers and their roles in signaling, and over the past few years in lipidomics, as well as advances in All eukaryotic cells are surrounded by a membrane understanding the biophysical properties of lipids, has composed of a lipid bilayer, whose chemical nature led to a major rethink of the structural and functional and essential role in cell permeability were first complexity of lipid bilayers and the role that specific proposed around a hundred years ago. Today it is lipids play in defined biological events. Clearly, the known that there are three major classes of lipids in classical and simplistic cartoon of a membrane, eukaryotic cell membranes, namely glycerolipids, containing a hydrophilic head group (often depicted sphingolipids (SLs), and sterols, whose biochemical as a ball) with two fatty acyl chains attached (depicted and biophysical properties vary considerably and as two sticks) does not do justice to the intricacies of impact upon their function. Progress over the past bilayer structure. Indeed, the number of possible lipid two or three decades in elucidating the components of species, as well as the number observed experimen- tally to date (see for instance Lipid Maps at http:// www.lipidmaps.org) implies previously unsuspected * Corresponding author. complexity [1]. Moreover, since many of these lipids Cell. Mol. Life Sci. Vol. 64, 2007 Review Article 2271 Figure 1. The structure of SLs and GSLs. S1P, sphingosine 1- phosphate; SM, sphingomyelin; GlcCer, glucosyl ceramide. The inset shows the numbering of the first five carbon atoms of the sphingoid long chain base. The sphingoid base is in the D-erythro (2S,3R) conformation. are bioactive and turn over in signaling pathways, SL structure combinatorial aspects of lipid structure and function are bound to play increasingly important roles in The backbone of all SLs, and the compound from models of membrane structure. which SLs derive their name, is the sphingoid long- Having briefly introduced the enormous combinato- chain base, the most common of which are sphinga- rial diversity of lipids, we will focus in this review on nine and sphingosine (Fig. 1). Sphinganine differs one particular class of lipids, the SLs, and their from sphingosine inasmuch as the latter contains a glycosylated derivatives, the glycosphingolipids trans 4–5 double bond, which is essential for some of (GSLs). Our rationale is that a reductionist approach the bioactive roles in which sphingosine-based SLs are to understanding lipid complexity is the most reason- involved. A number of other sphingoid long-chain able lead-in, and a required first step, to appreciate the bases exist, such as phytosphingosine (4-hydroxy- complexity of lipid bilayers and how this complexity sphinganine) with a hydroxyl group at C-4, and the less impacts upon their biological functions. Thus, we will common methylsphingosine, which has a methyl first describe the structure and biosynthesis of SLs, group at C-15, and sphingoid bases containing 20 and then discuss their major cellular functions, partic- carbon atoms which are found at high levels in brain ularly those of two important bioactive SLs, ceramide gangliosides. In rare cases, sphingoid bases containing and sphingosine-1-phophate (S1P). We will then 14 carbons have been described [2]. discuss some aspects of translational research con- Ceramide, the simplest SL, consists of a sphingoid cerning SLs and GSLs; this latter issue is rapidly base to which a fatty acid is attached at C-2 via N- developing and moving toward clinical manipulation acylation (Fig. 1). SLs usually contain saturated fatty of SL levels as a novel therapeutic approach in human acids of varying chain length and degree of hydrox- diseases. ylation, although monounsaturated fatty acids, partic- ularly with very long chains, can also be found in SLs [3]. Ceramide is the backbone of all complex SLs, which are formed by attachment of different head groups at C-1. Attachment of phosphorylcholine 2272 S. Lahiri and A. H. Futerman Sphingolipids and glycosphingolipids forms sphingomyelin (SM), and attachment of glucose proteins encoded by these genes are integral mem- or galactose is the first step in the formation of GSLs brane proteins that span the membrane lipid bilayer (Fig. 1). The GSLs are the most structurally diverse multiple times. Each member of the family has a class of complex SLs, and are normally classified as unique tissue distribution and uses a unique subset of acidic or neutral. More than 500 different carbohy- acyl CoAs for dihydroceramide synthesis [12]. Ce- drate structures have been described in GSLs [4, 5], ramide is subsequently formed by dihydroceramide with the main sugars being glucose, galactose, fucose, desaturase/reductase, which inserts a trans 4–5 double N-acetylglucosamine (GlcNAc), N-acetylgalactosa- bond. All of these reactions occur at the cytosolic mine (GalNAc) and sialic acid (N-acetylneuraminic leaflet of the ER [13–15]. acid). GSLs containing sialic acid are the major class Ceramide is the key hub in the SL biosynthetic of acidic GSLs, but other acidic GSLs exist, such as pathway, and is the precursor of at least five different those that contain glucuronic acid or sulfatides [6]. products (Fig. 2): The complexity of SLs is thus based on three structural a) Ceramide is glycosylated to galactosylceramide components, the sphingoid base, the fatty acid, and the (GalCer) at the lumenal leaflet of the ER by the head group. The reason for such a variety of SL transfer of galactose from a UDP-galactose donor structures is not known, but implies an as-yet un- [16]. known degree of functional complexity. It is not clear b) Ceramide can be phosphorylated by ceramide whether each particular SL or GSL structure has a kinase to produce ceramide-1-phosphate. The subcel- unique role of its own, or whether the roles of SLs and lular localization of this enzyme is unresolved, and has GSLs are defined by their combinatorial patterns at been suggested to be the PM [17, 18], Golgi apparatus any one time and their distribution (or segregation) [19], and the cytoplasm [18]. over the plasma membrane (PM) surface. In addition, c) Ceramide can be deacylated to sphingosine and although the basic pathways of SL synthesis have been free fatty acid by ceramidases, of which various forms established (see below), little is known about how are known, acting at either neutral, alkaline, or acidic these pathways are regulated at the transcriptional, pH. Neutral ceramidase is located at the PM [20, 21], translational or post-translational levels, each of acid ceramidase is lysosomal [22], and the alkaline which could determine the SL pattern of a cell or ceramidase is located at the ER/Golgi complex [23– tissue at any one time. 25]. Ceramidase activity has also been reported in mitochondria [21]. d) The synthesis of SM from ceramide occurs at the SL metabolism and intracellular transport lumenal leaflet of the Golgi apparatus [26, 27] by transfer of phosphorylcholine from phosphatidylcho- The biochemical pathways of SL metabolism are well line (PC) to ceramide, with diacylglycerol formed as a described [7, 8], and the intracellular sites of synthesis by-product [28]. Recently two SM synthases (SMs) and degradation, in the endoplasmic reticulum (ER)/ have been identified; SMS1 is located at the Golgi Golgi apparatus and lysosomes, respectively, have apparatus, and SMS2 at the PM [29, 30]. Since been characterized extensively over the past couple of ceramide is synthesized in the ER, a mechanism decades [7, 9]. As might be expected from the lipidic must exist for transferring ceramide to the Golgi nature of their substrates, the enzymes in the SL apparatus for its metabolism to SM. It was earlier biosynthetic pathway are integral membrane proteins assumed that vesicular transport would be responsible that span the membrane bilayer one or multiple times; for ceramide transfer; however, a ceramide transport in contrast, many of the lysosomal hydrolases involved protein, CERT, which transfers ceramides of relative- in SL degradation are peripheral membrane proteins ly short acyl chain length (C16–20) from the ER that require the presence of activating proteins for specifically for SM synthesis in the Golgi apparatus maximal activity in vivo [7, 10]. [31], has recently been discovered and is absolutely SL synthesis begins with the condensation of serine required for SM synthesis [32] by SMS1.