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Glycolipids By Amr S. Moustafa, M.D.; Ph.D.
Outlines Overview and Functions Structure and Types Synthesis and Degradation Sphingolipidosis
Overview Essential component of membranes Abundant in nervous tissue Extra-nervous tissue: e.g., Receptors for Cholera toxins Diphtheria toxins Viruses
Regulation of growth & development Very antigenic: Blood group antigen Embryonic antigen Tumor antigen Cell transformation Overview CONT’D
Sphingolipids: Structure and Types Ceramide = Sphingosine + fatty acid Sphingomyelin = Ceramide + Phosphorylcholine Cerebrosides = Ceramide + Monosaccharides Gangliosides = Ceramide oligosaccharides + NANA Globoosides = Ceramide + Oligosaccharides
Neutral Glycosphingolipids Globosides = Ceramide Oilgosaccharides Cerebrosides = Ceramide monosaccharides Galactocerbrosides = Ceramide + Galactose Glucocerbrosides = Ceramide + Glucose Lactosylceramide = Cer-Glc-Gal Forssman antigen = Cer-Glc-(Gal) 2 -(GalNac) 2
Acidic Acidic Glycosphingolipids Negatively charged at physiological pH 1.Gangliosides: Most complex Ganglion cells Ceramide oligosaccharides + NANA 2. Sulfatides: Nerve tissue and kidneys Cerbrosides + Sulfated Gal
Gangliosides G M2
Sulfate donor: PAPS
Sulfatides Galactocerbroside 3-sulfate
Sphingolipids’ Degradation Lysosomal hydrolytic enzymes Last on, First off Defective: Total or partial Sphingolipidosis
Synthesis (Normal); Degradation (Defective) Substrate accumulates in organs Progressive, early death Phenotypic and genotypic variability Autosomal recessive, Except Fabry (X-linked) Rare, Except Ashkenazi Jewish
Sphingolipidosis Measure enzyme activity Cultured fibroblasts or peripheral leukocytes Cultured amniocytes (prenatal) Histologic examination DNA analysis Replacement Therapy: Recombinant human enzyme Bone marrow transplantation: Gaucher disease Diagnosis: Treatment: CONT’D
Niemann - Pick Disease
Prostaglandins Eicosanoids (20 C): Prostaglandins (PG) Thromboxanes (TX) Leukotrienes (LT) PG Vs Hormones: All cells Local acting & Not stored Short half-life Plasma membrane & nuclear receptors
Prostaglandin’S Synthesis Dietary precursor: Linoleic acid 18:2 (9, 12) Immediate precursor: Arachidonic acid 20:4 (5, 8,11,14) Prostaglandin endoperoxide synthase: Microsomal enzyme Two Catalytic activities: Fatty acid cyclooxygenase (COX), 2 O 2 Peroxidase (GSH) Parent Prostaglandin : PGH 2
Prostaglandin’S Synthesis CONT’D
COX Isoenzymes COX-1: Constitutive Most tissues Important for: Integrity of gastric mucosa Renal homeostasis Platelet aggregation
COX Isoenzymes COX-2 Inducible Limited No. of tissues Stimulus: Products of inflammatory & immune cells Mediates: Inflammatory response: Pain, Redness & Swelling Fever of infection CONT’D
COX Inhibitors Cortisol (Steroid): Selective COX-2 (-) Phospholipase A2 (-) NSAIDS: Both COX-1 and –2 (-) Side effects: Gastric, Renal & Clotting Low-dose Asprin therapy Celecoxib: Selective COX-2 (-)
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