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Glycolipids M.Prasad Naidu MSc Medical Biochemistry, Ph.D.Research Scholar
The Lipids are a heterogeneous group of compounds which are relatively insoluble in water, but freely soluble in nonpolar organic solvents like benzene, chloroform, ether, hot alcohol, acetone,etc. • Lipids are classified based on their chemical nature
Simple lipids • Compound lipids • Derived lipids • Lipids complexed to other compounds
Compound lipids are esters of fatty acids containing groups in addition to an alcohol and a fatty acid. • Compound lipids are phospholipids, glycolipids and other complex lipids.
Glycolipids • Glycolipids are widely distributed in every tissue of the body, particularly in nervous tissue such as brain. • They occur particularly in the outer leaflet of the plasma membrane, where they contribute to cell surface carbohydrates.
The major glycolipids found in animal tissues are glycosphingolipids. • They contain ceramide and one or more sugars. • Ceramide + Glucose ----- Glucocerebroside • Ceramide + Galactose ---Galactocerebroside
Globosides ( ceramide oligosaccharides ) • They contain two or more hexoses or hexosamines, attached to a ceramide molecule. • Ceramide + Galactose + Glucose -- Lactosyl ceramide • Lactosyl ceramide is a component of erythrocyte membrane.
Gangliosides • They are formed when ceramide oligo-saccharides have at least one molecule of NANA ( N-acetyl neuraminic acid ) ( Sialic acid) attached to them. • Ceramide – Glucose – galactose – NANA ; this is designated as GM3 ( ganglioside M3 ).
Gangliosides contribute to stability of paranodal junctions and ion channel clusters in myelinated nerve fibres. • Autoantibodies to GM1 disrupt lipid rafts, paranodal or nodal structures, and ion channel clusters in peripheral motor nerves.
A specific ganglioside on intestinal mucosal cell binds to the b subunit of the Cholera toxin when the a subunit enters the cell. • It keeps the level of cellular cAMP raised by inhibition of GTPase activity of the G protein. • Gangliosides also act as receptors for other toxins like tetanus toxin, and toxins of viral pathogens.
Sulpholipids or sulfatides • These are formed when sulfate groups are attached to ceramide oligosaccharides. • Sulphated Cerebrosides • Sulphated globosides • Sulphated Gangliosides • All these complex lipids are important components of membranes of nervous tissue.
Synthesis of Glycosphingolipids • synthesis of glycosphingolipids occurs primarily in the Golgi apparatus by sequential addition of glycosyl monomers transferred from UDP-sugar donors to the acceptor molecule.
Degeneration of Glycosphingolipids • Glycosphingolipids are internalized by endocytosis. • All of the enzymes required for the degrative process are present in lysosomes, which fuse with the endocytotic vesicles. • The lysosomal enzymes hydrolytically and irreversibly cleave specific bonds in the glycosphingolipid.
Failure of degradation of these compounds results in accumulation of these complex lipids in CNS. • This group of inborn errors is known as lipid storage diseases.
Lipid storage diseases • They are called as spingolipidoses. Gaucher’s disease • most common lysosomal storage diseases • enzyme deficiency – Beta glucosidase
lipid accumulating – Glucosylceramide • Clincal symptoms • 3 types – adult, infantile, juvenile • Hepatosplenomegaly, erosion of long bones, moderate anemia, mental retardation in infants
Niemann- pick disease • enzyme deficiency – sphingomyelinase • lipid accumulating – sphingomyelin • Clinical symptoms • severe CNS damage, mental retardation, hepatosplenomegaly, cherry rod spot in macula • neurodegenerative course ( type A ) • death occurs by 2 years of age
Krabbe’s disease • Globoid cell dystrophy • enzyme deficiency – Beta galactosidase • lipid accumulating – Galactosylceramide • Clinical symptoms • severe mental retardation, total absence of myelin in CNS, Globoid bodies in white matter
Metachromatic leukodystrophy • enzyme deficiency – arylsulfatase • lipid accumulating – 3-sulfogalactosylceramide • Clinical symptoms • Mental retardation and psychologic disturbances in adults, demyelination, neurological deficit, difficulty in speech and optic atrophy, progressive paralysis, dementia in adult form, nerves stain yellowish-brown with cresyl violet – metachromasia
Fabry’s disease • enzyme deficiency – alpha galactosidase • lipid accumulating – Globotriaosylceramide • Clinical symptoms • progressive renal failure, death by 5 years of age, skin rash, purplish papules appear, X – linked inheritance
Tay-Sachs disease • enzyme deficiency – Hexosaminidase A • lipid accumulating – GM2 Ganglioside • Clinical symptoms • Incidence 1 in 6000 births • mental retardation, blindness, cherry red spot in the macula, muscular weakness, progressive deterioration, death by 3-4 years
Generalized gangliosidoses • enzyme deficiency – Beta-galactosidase • lipid accumulating – Ganglioside (GM1) • Clinical symptoms • mental retardation, hepatosplenomegaly, skeletal deformities, foam cells in bone marrow, cherry-red macula in the retina
Lactosyl ceramidoses • enzyme deficiency – Beta-galactosidase • lipid accumulating – Lactosyl ceramide • Clinical symptoms • mainly CNS and reticulo-endothelial system affected
Sandhoff’s disease • enzyme deficiency – Hexosaminidase A and B • lipid accumulating – Globoside • Clinical symptoms • neurological deficit, mental retardation
Farber disease • enzyme deficiency – Ceramidase • lipid accumulating – ceramide • Clinical symptoms • hoarseness, dermatitis, subcutaneous nodules of lipid-laden cells, tissues show granulomas, skeletal deformation, painful and progressive joint deformity, mental retardation, fatal in early life
Laboratory diagnosis • A specific sphingolipidosis can be diagnosed by measuring enzyme activity in cultured fibroblasts or peripheral leukocytes, or by analysis of DNA. • Histologic examination of the affected tissue is also useful.
Shell-like inclusion bodies are seen in Tay-Sachs disease and a wrinkled tissue paper appearance of the cytosol is seen in Gaucher disease. • All these diseases can be diagnosed prenatally by amniocentesis and culture of amniotic fluid cells.
Lysosomal storage diseases are diagnosed by quantitative enzyme assay. • Carriers are best diagnosed by DNA analysis of the common mutations.
Treatment • Replacement of deficient enzyme has been tried in Gaucher’s disease, with limited success. • Gaucher disease and Fabry disease are treated by recombinant human enzyme replacement therapy, but the monetary cost is extremely high.
Gaucher disease has also been treated by bone marrow transplantation. • Other promising approaches are substrate deprivation therapy to inhibit the synthesis of sphingolipids and chemical chaperone therapy. • Gene therapy for lysosomal disorders is also currently under investigation.