Glycolipids

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Glycolipids

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

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• 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

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

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• 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.

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• 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.

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

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• 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.

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• 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 ).

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• Lipid storage diseases
• They are called as spingolipidoses.
• Gauchers disease
• most common lysosomal storage diseases
• enzyme deficiency Beta glucosidase

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

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• 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

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• Krabbes 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

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• 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

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• Fabrys 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

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• 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

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• 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

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

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• Sandhoffs disease
• enzyme deficiency Hexosaminidase A and B
• lipid accumulating Globoside
• Clinical symptoms
• neurological deficit, mental retardation

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• 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

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• 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.

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• 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.

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

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• Treatment
• Replacement of deficient enzyme has been tried in
  Gauchers disease, with limited success.
• Gaucher disease and Fabry disease are treated by
  recombinant human enzyme replacement therapy, but
  the monetary cost is extremely high.

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• 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.

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