A galactocerebroside is a type of cerebroside consisting of a ceramide with a galactose residue at the 1-hydroxyl moiety. The galactose is cleaved by galactosylceramidase. Galactocerebroside is a marker for oligodendrocytes in the brain. Globoid cell leukodystrophy Myelin Galactocerebrosides at the US National Library of Medicine Medical Subject Headings CHEMBL110111 image
Sulfatide known as 3-O-sulfogalactosylceramide, SM4, or sulfated galactocerebroside, is a class of sulfolipids a class of sulfoglycolipids, which are glycolipids that contain a sulfate group. Sulfatide is synthesized starting in the endoplasmic reticulum and ending in the Golgi apparatus where ceramide is converted to galactocerebroside and sulfated to make sulfatide. Of all of the galactolipids that are found in the myelin sheath, one fifth of them are sulfatide. Sulfatide is found on the extracellular leaflet of the myelin plasma membrane produced by the oligodendrocytes in the central nervous system and in the Schwann cells in the peripheral nervous system. However, sulfatide is present on the extracellular leaflet of the plasma membrane of many cells in eukaryotic organisms. Since sulfatide is a multifunctional molecule, it can be used in multiple biological areas. Aside from being a membrane component, sulfatide functions in protein trafficking, cell aggregation and adhesion, neural plasticity and glial-axon interactions.
Sulfatide plays a role in several physiological processes and systems, including the nervous system, the immune system, insulin secretion, blood clotting, viral infection, bacterial infection. As a result, sulfatide is associated with, able to bind to, and/or is present in kidney tissues, cancer cells/ tissues, the surface of red blood cells and platelets, CD1 a-d cells in the immune system, many bacteria cells, several viruses, myelin and astrocytes. An abnormal metabolism or change in the expression of sulfatide has been associated with various pathologies, including neuropathologies, such as metachromatic leukodystrophy, Alzheimer's disease, Parkinson's disease. Sulfatide is associated with diabetes mellitus, cancer metastasis, viruses, including HIV-1, Influenza A virus, Hepatitis C and Vaccinia virus. Additionally, overexpression of sulfatide has been linked to epilepsy and audiogenic seizures as well as other pathological states in the nervous system. Past and ongoing research continues to elucidate the many biological functions of sulfatide and their many implications as well as the pathology, associated with sulfatide.
Most research utilizes mice models, but heterologous expression systems are utilized as well, but not limited to, Madin-Darby canine kidney cells and COS-7 Cells. Sulfatide was the first sulfoglycolipid to be isolated in the human brain, it was named sulfatide in 1884 by Johann Ludwig Wilhelm Thudichum when he published "A Treatist of the Chemical Constitution of the Brain". In 1933, it was first reported by Blix that sulfatide contained amide bound fatty acid and 4-sphingenine and that the sulfate of sulfatide was thought to be attached to the C6 position of galactose; this was again supported in 1955 by Schmidt. Thus, in 1962, Yamakawa completed the corrected chemical structure of sulfatide. Sulfatide synthesis begins with a reaction between UDP-galactose and 2-hydroxylated or non-hydroxylated ceramide; this reaction is catalyzed by galactosyltransferase, where galactose is transferred to 2-hydroxylated, or non-hydroxylated ceramide, from UDP-galactose. This reaction occurs in the luminal leaflet of the endoplasmic reticulum, its final product is GalCer, or galactocerebroside, transported to the Golgi apparatus.
Here, GalCer reacts with 3’-phosphoadenosine-5’-phosphosulfate to make sulfatide. This reaction is catalyzed by cerebroside sulfotransferase. CST is a homodimeric protein, found in the Golgi apparatus, it has been demonstrated that mice models lacking CST, CGT, or both are incapable of producing sulfatide indicating that CST and CGT are necessary components of sulfatide synthesis. Sulfatide degradation occurs in the lysosomes. Here, arylsulfatase A hydrolyzes the sulfate group. However, in order for this reaction to be carried out, a sphingolipid activator protein such as saposin B must be present. Saposin B extracts sulfatide from the membrane, which makes it accessible to arylsulfatase A. Arylsulfatase A can hydrolyze the sulfate group. Accumulation of sulfatide can cause metachromatic leukodystrophy, a lysosomal storage disease and may be caused because of a defect in arylsulfatase A, leading to an inability to degrade sulfatide. Sulfatide participates in many biological systems and functions, including the nervous system, the immune system, in haemostasis/ thrombosis.
Sulfatide has been shown to play a minor role in the kidneys. Sulfatide is a major component in the nervous system and is found in high levels in the myelin sheath in both the peripheral nervous system and the central nervous system. Myelin is composed of about 70 -75% lipids, sulfatide comprises 4-7% of this 70-75%; when lacking sulfatide, myelin sheath is still produced around the axons. Thus, lacking sulfatide can lead to muscle weakness and ataxia. Elevated levels of sulfatide are associated with Metachromatic Leukodystrophy, which leads to the progressive loss of myelin as a result of sulfatide accumulation in the Schwann cells, astrocytes and neurons. Elevated levels of sulfatide have been linked to epilepsy and audiogenic seizures, while elevated levels of anti-sulfatide antibodies in the serum have been associated with multiple sclerosis and Parkinson's; as stated above, sulfatide is predominantly found in the oligodendrocytes and the Schwann cells in the nervous sys
A ganglioside is a molecule composed of a glycosphingolipid with one or more sialic acids linked on the sugar chain. NeuNAc, an acetylated derivative of the carbohydrate sialic acid, makes the head groups of gangliosides anionic at pH 7, which distinguishes them from globosides; the name ganglioside was first applied by the German scientist Ernst Klenk in 1942 to lipids newly isolated from ganglion cells of the brain. More than 60 gangliosides are known, which differ from each other in the position and number of NANA residues, it is a component of the cell plasma membrane that modulates cell signal transduction events, appears to concentrate in lipid rafts. Gangliosides have been found to be important molecules in immunology. Natural and semisynthetic gangliosides are considered possible therapeutics for neurodegenerative disorders. Gangliosides are present and concentrated on cell surfaces, with the two hydrocarbon chains of the ceramide moiety embedded in the plasma membrane and the oligosaccharides located on the extracellular surface, where they present points of recognition for extracellular molecules or surfaces of neighboring cells.
They are found predominantly in the nervous system. The oligosaccharide groups on gangliosides extend well beyond the surfaces of the cell membranes, act as distinguishing surface markers that can serve as specific determinants in cellular recognition and cell-to-cell communication; these carbohydrate head groups act as specific receptors for certain pituitary glycoprotein hormones and certain bacterial protein toxins such as cholera toxin. The functions of gangliosides as specific determinants suggest its important role in the growth and differentiation of tissues as well as in carcinogenesis, it has been found that tumor formation can induce the synthesis of a new complement of ganglioside, low concentrations of a specific ganglioside can induce differentiation of cultured neuronal tumor cells. One NANA GM1 GM2 GM3 Two NANAs GD1a GD1b GD2 GD3 Three NANAs GT1b GT3 Four NANAs GQ1 GM2-1 = aNeu5AcbDGalpbDGalNAcbDGalNAcbDGlcpCerGM3 = aNeu5AcbDGalpbDGlcpCerGM2,GM2a = N-Acetyl-D-galactose-beta-1,4--Galactose-beta-1,4-glucose-alpha-ceramide GM2b = aNeu5AcaNeu5AcbDGalpbDGlcpCerGM1,GM1a = bDGalpbDGalNAcbDGalpbDGlcpCerasialo-GM1,GA1 = bDGalpbDGalpNAcbDGalpbDGlcpCerasialo-GM2,GA2 = bDGalpNAcbDGalpbDGlcpCerGM1b = aNeu5AcbDGalpbDGalNAcbDGalpbDGlcpCerGD3 = aNeu5AcaNeu5AcbDGalpbDGlcpCerGD2 = bDGalpNAcbDGalpbDGlcpCerGD1a = aNeu5AcbDGalpbDGalNAcbDGalpbDGlcpCerGD1alpha = aNeu5AcbDGalpbDGalNAcbDGalpbDGlcpCerGD1b = bDGalpbDGalNAcbDGalpbDGlcpCerGT1a = aNeu5AcaNeu5AcbDGalpbDGalNAcbDGalpbDGlcpCerGT1,GT1b = aNeu5AcbDGalpbDGalNAcbDGalpbDGlcpCerOAc-GT1b = aNeu5AcbDGalpbDGalNAcaXNeu5Ac9AcaNeu5Ac]bDGalpbDGlcpCerGT1c = bDGalpbDGalNAcbDGalpbDGlcpCerGT3 = aNeu5AcaNeu5AcaNeu5AcbDGalbDGlcCerGQ1b = aNeu5AcaNeu5AcbDGalpbDGalNAcbDGalpbDGlcpCerGGal = aNeu5AcbDGalpCerwhere aNeu5Ac = N-acetyl-alpha-neuraminic acid aNeu5Ac9Ac = N-acetyl-9-O-acetylneuraminic acid bDGalp = beta-D-galactopyranose bDGalpNAc = N-acetyl-beta-D-galactopyranose bDGlcp = beta-D-glucopyranose Cer = ceramide Gangliosides are continuously synthesized and degraded in cells.
They are degraded to ceramides by sequential removal of sugar units in the oligosaccharide group, catalyzed by a set of specific lysosomal enzymes. Mutations in genes coding for these enzymes leads to the accumulation of broken down gangliosides in lysosomes, which results in a group of diseases called gangliosidosis. For example, the fatal Tay–Sachs disease arises as a genetic defect which leads to no functional hexosaminidase A produced, causing GM2 to accumulate in lysosomes; the ganglion cells in the nervous system swell enormously, disturbing the normal functions of neurons. Gangliosides are involved in several diseases: Influenza, in which haemagglutinin of influenza virus exploits certain gangliosides to enter and infect the cells expressing them. Guillain–Barré syndrome, linked to the production of anti-ganglioside antibodies. Cholera Tetanus Botulism Leprosy Obesity, where inadequate ganglioside expression in mediobasal hypothalamic neurons deregulates neuronal leptin and insulin signaling.
Gangliosides at the US National Library of Medicine Medical Subject Headings Overview of gangliosides at lipidlibrary.co.uk Overview of gangliosides at cyberlipid.org
Ceramides are a family of waxy lipid molecules. A ceramide is composed of a fatty acid. Ceramides are found in high concentrations within the cell membrane of eukaryotic cells, since they are component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer. Contrary to previous assumptions that ceramides and other sphingolipids found in cell membrane were purely supporting structural elements, ceramide can participate in a variety of cellular signaling: examples include regulating differentiation and programmed cell death of cells; the word ceramide comes from amide. Ceramide is a component of vernix caseosa, the waxy or cheese-like white substance found coating the skin of newborn human infants. There are three major pathways of ceramide generation; the sphingomyelinase pathway uses an enzyme to break down sphingomyelin in the cell membrane and release ceramide. The de novo pathway creates ceramide from less complex molecules. Ceramide generation can occur through breakdown of complex sphingolipids that are broken down into sphingosine, reused by reacylation to form ceramide.
This latter pathway is termed the Salvage pathway. Hydrolysis of sphingomyelin is catalyzed by the enzyme sphingomyelinase; because sphingomyelin is one of the four common phospholipids found in the plasma membrane of cells, the implications of this method of generating ceramide is that the cellular membrane is the target of extracellular signals leading to programmed cell death. There has been research suggesting that when ionizing radiation causes apoptosis in some cells, the radiation leads to the activation of sphingomyelinase in the cell membrane and to ceramide generation. De novo synthesis of ceramide begins with the condensation of palmitate and serine to form 3-keto-dihydrosphingosine; this reaction is catalyzed by the enzyme serine palmitoyl transferase and is the rate-limiting step of the pathway. In turn, 3-keto-dihydrosphingosine is reduced to dihydrosphingosine, followed by acylation by the enzyme ceramide synthase to produce dihydroceramide; the final reaction to produce ceramide is catalyzed by dihydroceramide desaturase.
De novo synthesis of ceramide occurs in the endoplasmic reticulum. Ceramide is subsequently transported to the Golgi apparatus by either vesicular trafficking or the ceramide transfer protein CERT. Once in the Golgi apparatus, ceramide can be further metabolized to other sphingolipids, such as sphingomyelin and the complex glycosphingolipids. Constitutive degradation of sphingolipids and glycosphingolipids takes place in the acidic subcellular compartments, the late endosomes and the lysosomes, with the end goal of producing sphingosine. In the case of glycosphingolipids, exohydrolases acting at acidic pH optima cause the stepwise release of monosaccharide units from the end of the oligosaccharide chains, leaving just the sphingosine portion of the molecule, which may contribute to the generation of ceramides. Ceramide can be further hydrolyzed by acid ceramidase to form sphingosine and a free fatty acid, both of which are able to leave the lysosome, unlike ceramide; the long-chain sphingoid bases released from the lysosome may re-enter pathways for synthesis of ceramide and/or sphingosine-1-phosphate.
The salvage pathway re-utilizes long-chain sphingoid bases to form ceramide through the action of ceramide synthase. Thus, ceramide synthase family members trap free sphingosine released from the lysosome at the surface of the endoplasmic reticulum or in endoplasmic reticulum-associated membranes, it should be noted that the salvage pathway has been estimated to contribute from 50% to 90% of sphingolipid biosynthesis. As a bioactive lipid, ceramide has been implicated in a variety of physiological functions including apoptosis, cell growth arrest, cell senescence, cell migration and adhesion. Roles for ceramide and its downstream metabolites have been suggested in a number of pathological states including cancer, neurodegeneration, microbial pathogenesis and inflammation. Ceramides induce skeletal muscle insulin resistance when synthesized as a result of saturated fat activation of TLR4 receptors. Unsaturated fat does not have this effect. Ceramides induce insulin resistance in many tissues by inhibition of Akt/PKB signaling.
Aggregation of LDL cholesterol by ceramide causes LDL retention in arterial walls, leading to atherosclerosis. Ceramides cause endothelial dysfunction by activating protein phosphatase 2. In mitochondria, ceramide suppresses the electron transport chain and induces production of reactive oxygen species. One of the most studied roles of ceramide pertains to its function as a proapoptotic molecule. Apoptosis, or Type I programmed cell death, is essential for the maintenance of normal cellular homeostasis and is an important physiological response to many forms of cellular stress. Ceramide accumulation has been found following treatment of cells with a number of apoptotic agents including ionizing radiation, UV light, TNF-alpha, chemotherapeutic agents; this suggests a role for ceramide in the biological responses of all these agents. Because of its apoptosis-inducing effects in cancer cells, ceramide has been termed the "tumor suppressor lipid". Several studies have attempted to define further the specific role of ceramide in the events of cell death and some evidence suggests ceramide functions upstream of the mitochondria in inducing apoptosis.
However, owing to the conflicting and variable nature of studies into the role of ceramide in apoptosis, the mechanism by which this lipid regulates apoptosis remains elusive. Ceramide is the main component of the stratum corneum of the epidermis layer of human skin. Together with choleste