بسم الله الرحمن الرحيم

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

Overview Regulation of growth & development Very antigenic: CONT’D Regulation of growth & development Very antigenic: Blood group antigen Embryonic antigen Tumor antigen Cell transformation

Sphingolipids: Structure and Types Ceramide = Sphingosine + fatty acid Sphingomyelin = Ceramide + Phosphorylcholine Cerebrosides = Ceramide + Monosaccharides Globoosides = Ceramide + Oligosaccharides Gangliosides = Ceramide oligosaccharides + NANA

Neutral Glycosphingolipids Cerebrosides = Ceramide monosaccharides Galactocerbrosides = Ceramide + Galactose Glucocerbrosides = Ceramide + Glucose Globosides = Ceramide Oilgosaccharides Lactosylceramide = Cer-Glc-Gal Forssman antigen = Cer-Glc-(Gal)2-(GalNac)2

Galactocerbroside

Acidic Glycosphingolipids Negatively charged at physiological pH Gangliosides: Most complex Ganglion cells Ceramide oligosaccharides + NANA 2. Sulfatides: Nerve tissue and kidneys Cerbrosides + Sulfated Gal

Gangliosides GM2

Sulfate donor: PAPS

Sulfatides Galactocerbroside 3-sulfate

Sphingolipids’ Synthesis

Sphingolipids’ Degradation Lysosomal hydrolytic enzymes Last on, First off Defective: Total or partial Sphingolipidosis

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 Diagnosis: Treatment: CONT’D Measure enzyme activity Cultured fibroblasts or peripheral leukocytes Cultured amniocytes (prenatal) Histologic examination DNA analysis Treatment: Replacement Therapy: Recombinant human enzyme Bone marrow transplantation: Gaucher disease

CONT’D Sphingolipidosis

Niemann - Pick Disease

Gaucher 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 O2 Peroxidase (GSH) Parent Prostaglandin : PGH2

Prostaglandin’S Synthesis CONT’D

COX Isoenzymes COX-1: Constitutive Most tissues Important for: Integrity of gastric mucosa Renal homeostasis Platelet aggregation

COX Isoenzymes CONT’D COX-2 Inducible Limited No. of tissues Stimulus: Products of inflammatory & immune cells Mediates: Inflammatory response: Pain, Redness & Swelling Fever of infection

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 (-)

Prostaglandin’S Functions