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Metabolism of the Sphingolipids
The sphingolipids, like the phospholipids, are composed of a polar head group and two nonpolar tails. The core of sphingolipids is the long-chain amino alcohol, sphingosine. Amino acylation, with a long chain fatty acid, at carbon 2 of sphingosine yields a ceramide.
"n" indicates any fatty acid may be N-acetylated at this position.
Top: Sphingosine
Bottom: Basic composition of a ceramide
The sphingolipids include the sphingomyelins and glycosphingolipids (the cerebrosides, sulfatides, globosides and gangliosides). Sphingomyelins are the only sphingolipid that are phospholipids. Sphingolipids are a component of all membranes but are particularly abundant in the myelin sheath.
Sphingomyelins are sphingolipids that are also phospholipids. Sphingomyelins are important structural lipid components of nerve cell membranes. The predominant sphingomyelins contain palmitic or stearic acid N-acylated at carbon 2 of sphingosine.
The sphingomyelins are synthesized by the transfer of phosphorylcholine from phosphatidylcholine to a ceramide in a reaction catalyzed by sphingomyelin synthase.
A Sphingomyelin
Defects in the enzyme acid sphingomyelinase result in the lysosomal storage disease known as Niemann-Pick disease. There are in fact two major forms of Niemann-Pick (NP) disease. NP disease caused by acid sphingomyelinase deficiencies comprises types A and B, referred to as NP-A and NP-B. The other form of NP disease comprises types C1 and C2, the former due to defects in the NPC1 gene and the latter due presumably to defects in a gene identified as NPC2.
Glycosphingolipids, or glycolipids, are composed of a ceramide backbone with a wide variety of carbohydrate groups (mono- or oligosaccharides) attached to carbon 1 of sphingosine. The four principal classes of glycosphingolipids are the cerebrosides, sulfatides, globosides and gangliosides.
Cerebrosides have a single sugar group linked to ceramide. The most common of these is galactose (galactocerebrosides), with a minor level of glucose (glucocerebrosides). Galactocerebrosides are found predominantly in neuronal cell membranes. By contrast glucocerebrosides are not normally found in membranes, especially neuronal membranes; instead, they represent intermediates in the synthesis or degradation of more complex glycosphingolipids.
Galactocerebrosides are synthesized from ceramide and UDP-galactose. Excess lysosomal accumulation of glucocerebrosides is observed in Gaucher disease.
A Glucocerebroside
Sulfatides: The sulfuric acid esters of galactocerebrosides are the sulfatides. Sulfatides are synthesized from galactocerebrosides and activated sulfate, 3'-phosphoadenosine 5'-phosphosulfate (PAPS). Excess accumulation of sulfatides is observed in metachromatic leukodystrophy (sulfatide lipodosis).
Globosides: Globosides represent cerebrosides that contain additional carbohydrates, predominantly galactose, glucose or GalNAc. Lactosyl ceramide is a globoside found in erythrocyte plasma membranes. Globotriaosylceramide (also called ceramide trihexoside) contains glucose and two moles of galactose and accumulates, primarily in the kidneys, of patients suffering from Fabry disease.
Gangliosides: Gangliosides are very similar to globosides except that they also contain NANA in varying amounts. The specific names for gangliosides are a key to their structure. The letter G refers to ganglioside, and the subscripts M, D, T and Q indicate that the molecule contains mono-, di-, tri and quatra(tetra)-sialic acid. The numerical subscripts 1, 2 and 3 refer to the carbohydrate sequence that is attached to ceramide; 1 stands for GalGalNAcGalGlc-ceramide, 2 for GalNAcGalGlc-ceramide and 3 for GalGlc-ceramide.
Structure of a GM2 Ganglioside
Deficiencies in lysosomal enzymes, which normally are responsible for the degradation of the carbohydrate portions of various gangliosides, underlie the symptoms observed in rare autosomally inherited diseases termed lysosomal storage diseases, (also called the sphingolipidoses or lipid storage diseases) many of which are listed below.
back to the topClinical Significances of Sphingolipids
Some of the most devastating inborn errors in metabolism are those associated with defects in the enzymes responsible for the lysosomal degradation of membrane glycosphingolipids which are particularly abundant in the membranes of neural cells. Many of these disorders lead to severe psycho-motor retardation and early lethality. Because the disorders are caused by defective lysosomal enzymes, with the result being lysosomal accumulation of pathway intermediates, these are often referred to as lysosomal storage diseases. The mucopolysaccharidoses are another class of disorders that are members of the lysosomal storage diseases.
The following figure shows several of the pathways and intermediates in glycosphingolipid metabolism. Enzymes are indicated in green and the disease(s) associated with defects in the indicated enzyme are shown in blue. SAP-A, SAP-B, SAP-C, and SAP-D are the saposins which are a family of small glycoproteins. The saposins (A, B, C, and D) are all derived from a single precursor, prosaposin. The mature saposins, as well as prosaposin, activate several lysosomal hydrolases involved in the metabolism of various sphingolipids. Prosaposin is proteolytically processed to saposins A, B, C and D, within lysosomes but also exists as an integral membrane protein not destined for lysosomal entry. Uncleaved prosaposin can be found in many biological fluids such as seminal plasma, human milk, and cerebrospinal fluid, where it appears to have a different function. Each of the disease names in the image can be clicked to go to a descriptive page of that disease. The Table below the Figure lists some additional lysosomal storage diseases caused by defective sphingolipid metabolism.
Disorders Associated with Abnormal Sphingolipid Metabolism
| Disorder | Enzyme Deficiency | Accumulating Substance | Symptoms |
| Tay-Sachs disease | HexA | GM2 ganglioside | infantile form: rapidly progressing mental retardation, blindness, early mortality |
| Sandhoff disease | HexA and HexB | globoside; GM2 ganglioside | infantile form: same symptoms as Tay-Sachs, progresses more rapidly |
| Tay-Sachs AB variant GM2 activator deficiency |
GM2 activator (GM2A) | GM2 ganglioside | infantile form: same symptoms as Tay-Sachs |
| Gaucher disease | acid β-glucosidase (glucocerebrosidase) |
glucocerebrosides | hepatosplenomegaly, mental retardation in infantile form, long bone degeneration |
| Fabry disease | α-galactosidase A | globotriaosylceramide; also called ceramide trihexoside (CTH) | kidney failure, skin rashes |
| Niemann-Pick diseases Types A and B Type C |
sphingomyelinase NPC1 protein |
sphingomyelins LDL-derived cholesterol |
type A is severe disorder with heptosplenomegaly, severe neurological involvement leading to early death, type B only visceral involvement |
| Krabbe disease; globoid cell leukodystrophy (GLD) | galactocerebrosidase | galactocerebrosides | mental retardation, myelin deficiency |
| GM1 gangliosidosis | β-galactosidase-1 | GM1 gangliosides | mental retardation, skeletal abnormalities, hepatomegaly |
| Metachromatic leukodystrophy; sulfatide lipodosis |
arylsulfatase A | sulfatides | mental retardation, metachromasia of nerves |
| Fucosidosis | α-fucosidase | pentahexosylfucoglycolipid | cerebral degeneration, thickened skin, muscle spasticity |
| Farber lipogranulomatosis | acid ceramidase | ceramides | hepatosplenomegaly, painful swollen joints |
One of the most clinically important classes of sphingolipids are those that confer antigenic determinants on the surfaces of cells, particularly the erythrocytes. The ABO blood group antigens are the carbohydrate moieties of glycolipids on the surface of cells as well as the carbohydrate portion of serum glycoproteins. When present on the surface of cells the ABO carbohydrates are linked to sphingolipid and are therefore of the glycosphingolipid class. When the ABO carbohydrates are associated with protein in the form of glycoproteins they are found in the serum and are referred to as the secreted forms. Some individuals produce the glycoprotein forms of the ABO antigens while others do not. This property distinguishes secretors from non-secretors, a property that has forensic importance such as in cases of rape.
R represents the linkage to protein in the secreted forms, sphingolipid (ceramide) in the cell-surface bound form, open square = GlcNAc, open diamond = galactose, filled square = fucose, filled diamond = GalNAc. The linkage in the glycolipid form may include a glucose in a β-1,3 or β-1,4 to the initial galactose residue.
Structure of the ABO blood group carbohydrates
A significant cause of death in premature infants and, on occasion, in full term infants is respiratory distress syndrome (RDS) or hyaline membrane disease. This condition is caused by an insufficient amount of pulmonary surfactant. Under normal conditions the surfactant is synthesized by type II endothelial cells and is secreted into the alveolar spaces to prevent atelectasis following expiration during breathing. Surfactant is comprised primarily of dipalmitoyllecithin; additional lipid components include phosphatidylglycerol and phosphatidylinositol along with proteins of 18 and 36 kDa (termed surfactant proteins). During the third trimester the fetal lung synthesizes primarily sphingomyelin, and type II endothelial cells convert the majority of their stored glycogen to fatty acids and then to dipalmitoyllecithin. Fetal lung maturity can be determined by measuring the ratio of lecithin to s phingomyelin (L/S ratio) in the amniotic fluid. An L/S ratio less than 2.0 indicates a potential risk of RDS. The risk is nearly 75-80% when the L/S ratio is 1.5.
The carbohydrate portion of the ganglioside, GM1, present on the surface of intestinal epithelial cells, is the site of attachment of cholera toxin, the protein secreted by Vibrio cholerae.
These are just a few examples of how sphingolipids and glycosphingolipids are involved in various recognition functions at the surface of cells. As with the complex glycoproteins, an understanding of all of the functions of the glycolipids is far from complete.
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Michael W. King, Ph.D / IU School of Medicine / miking at iupui.edu
