Saturday 29 November 2003
Definition: Sphingolipids are a class of lipids derived from the aliphatic amino alcohol sphingosine.
There are three main types of sphingolipids: ceramides, phosphosphingolipids (sphingomyelins), and glycosphingolipids, which differ in the substituents on their head group.
Sphingolipids are often found in neural tissue, and play an important role in both signal transmission and cell recognition.
Sphingolipids are a complex family of lipids that share a common structural feature, a sphingoid base backbone (sphingosine) that is synthesized de novo from serine and a long-chain fatty acyl CoA, then converted into ceramides, phosphosphingolipids, glycosphingolipids and other species.
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.
There are three main types of sphingolipids: ceramides, sphingomyelins, and glycosphingolipids, which differ in the substituents on their head group.
The major sphingoid base of mammals is commonly referred to as sphingosine.
Ceramides: Ceramids are the simplest type of sphingolipid. They consist simply of a fatty acid chain attached through an amide linkage to sphingosine. Ceramides (N-acyl-sphingoid bases) are a major subclass of sphingoid base derivatives with an amide-linked fatty acid. The fatty acids are typically saturated or mono-unsaturated with chain lengths from 14 to 26 carbon atoms.
Sphingomyelins: The major phosphosphingolipids of mammals are sphingomyelins (ceramide phosphocholines), whereas insects contain mainly ceramide phosphoethanolamines and fungi have phytoceramidephosphoinositols and mannose containing headgroups. Sphingomyelins have a phosphorylcholine or phosphoroethanolamine molecule esterified to the 1-hydroxy group of a ceramide.
Glycosphingolipids: Glycosphingolipids are a diverse family of molecules composed of one or more sugar residues linked via a glycosidic bond to the sphingoid base. Examples of these are the simple and complex glycosphingolipids such as cerebrosides and gangliosides. Glycosphingolipids are ceramides with one or more sugar residues joined in a β-glycosidic linkage at the 1-hydroxyl position. Glycosphingolipids may be further subdivided into cerebrosides and gangliosides. Cerebrosides have a single glucose or galactose at the 1-hydroxy position, while gangliosides have at least three sugars, one of which must be sialic acid.
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. The first feature 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. See sphingolipid-mediated signaling
Relatively simple sphingolipid metabolites, such as ceramide and sphingosine 1-phosphate, have been shown to be important mediators in the signaling cascades invlolved in apoptosis, proliferation, and stress responses.
Ceramide-based lipids self-aggregate in cell membranes and form separate phases less fluid than the bulk phospholipids. These sphingolipid-based microdomains, or "rafts" were originally proposed to sort membrane proteins along the cellular pathways of membrane transport.
Sphingolipids are synthesized in the ER1 and Golgi, but are enriched in the plasma membrane and in endosomes, where they perform many of their functions. thus travelling and evolving between organelles. 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.
Besides the cholesterol and gangliosides described above, sphingolipids, in particular SM, are essential components of rafts.
The de novo synthesis of all sphingolipids begins at the cytoplasmic face of the endoplasmic reticulum (ER), which is where the enzymes that are required for ceramide biosynthesis are located.
The condensation of L-serine (Ser) with palmitoyl-CoA (Palm-CoA) is a reaction that is catalysed by serine palmitoyltransferase (SPT).
In two rapid reactions, the product, 3-ketosphinganine (Keto), is reduced to sphinganine (dihydrosphingosine; DHS) and subsequently acylated by ceramide synthase to form dihydroceramide (DH-Cer).
Dihydroceramide is then converted to ceramide by a desaturase.
Dihydroceramide and/or ceramide is translocated from the ER to the Golgi apparatus and then converted to sphingomyelin (SM) and dihydrosphingomyelin (DH-SM) by sphingomyelin synthase on the lumenal side of the Golgi, or to glucosylceramide (GlcCer) and dihydroglucosylceramide (DH-GlcCer) on the cytosolic surface of the Golgi.
After translocation into the Golgi lumen, glucosylceramide is further converted to lactosylceramide and more complex glycosphingolipids (GSLs).
The insertion of the trans 4,5 double bond into ceramide by the desaturase is an important step because ceramide, and not dihydroceramide, induces apoptosis.
Remarkably, although dihydro-S1P is also a substrate for SPP1 — it forms dihydrosphingosine, which is then converted to dihydroceramide by ceramide synthase — it does not cause significant ceramide accumulation or increase apoptosis in SPP1 transfectants, in contrast to S1P.
This indicates that dihydroceramide might be more efficiently used for sphingomyelin and/or glycosphingolipid biosynthesis than ceramide is.
Alternatively, the translocation of dihydroceramide to the Golgi might be more rapid than that of ceramide.
So, the biosynthetic trafficking of ceramide and dihydroceramide might be different, and vesicular and non-vesicular transport pathways of ceramide versus dihydroceramide might carry out special functions.
Sphingosine (Sph) produced from degradation of plasma membrane GSLs and SM in the endocytic (Endosome) recycling pathway might be used for formation of ceramide by sequential phosphorylation by sphingosine-1-phosphate (S1P) kinase (SphK) and dephosphorylation by S1P phosphatases (SPPs), or converted into pro-apoptotic C16-ceramide by ceramide synthase in the mitochondria.
The first rate-limiting step in sphingolipid synthesis is catalyzed by serine-palmitoyl-CoA-transferase, which allows the formation of 3-dehydrosphinganine through the condensation of palmitoyl-coenzyme A and L-serine.
3-Dehydrosphinganine is metabolized via several enzymes to ceramide (Cer). Cer is one of the most important branching points of this pathway.
Glycosylation of Cer leads to the glycosphingolipid production, resulting in the gangliosides described above. Ceramidase catalyzes the formation of sphingosine, and SM synthase metabolizes Cer to SM.
Pathology: disorders of sphingolipid metabolism
- Example: Gaucher disease
transport of ceramide
Sillence DJ, Platt FM. Storage diseases: new insights into sphingolipid functions. Trends Cell Biol. 2003 Apr;13(4):195-203. PMID: 12667757
Marks DL, Pagano RE. Endocytosis and sorting of glycosphingolipids in sphingolipid storage disease. Trends Cell Biol. 2002 Dec;12(12):605-13. PMID: 12495850