GLYCOLIPIDS

1. Glycolipids M.Prasad Naidu MSc Medical Biochemistry, Ph.D.Research Scholar

2. 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

3. Simple lipids • Compound lipids • Derived lipids • Lipids complexed to other compounds

4. 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.

5. 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.

6. The major glycolipids found in animal tissues are glycosphingolipids. • They contain ceramide and one or more sugars. • Ceramide + Glucose ----- Glucocerebroside • Ceramide + Galactose ---Galactocerebroside

7. 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.

8. 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 ).

9. 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.

10. 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.

11. 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.

12. 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.

16. 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.

17. 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.

18. Lipid storage diseases • They are called as spingolipidoses. Gaucher’s disease • most common lysosomal storage diseases • enzyme deficiency – Beta glucosidase

19. lipid accumulating – Glucosylceramide • Clincal symptoms • 3 types – adult, infantile, juvenile • Hepatosplenomegaly, erosion of long bones, moderate anemia, mental retardation in infants

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. Lactosyl ceramidoses • enzyme deficiency – Beta-galactosidase • lipid accumulating – Lactosyl ceramide • Clinical symptoms • mainly CNS and reticulo-endothelial system affected

27. Sandhoff’s disease • enzyme deficiency – Hexosaminidase A and B • lipid accumulating – Globoside • Clinical symptoms • neurological deficit, mental retardation

28. 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

30. 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.

33. 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.

34. Lysosomal storage diseases are diagnosed by quantitative enzyme assay. • Carriers are best diagnosed by DNA analysis of the common mutations.

35. 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.

36. 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.

37. thank you