Glycolipids By Amr S. Moustafa, M.D.; Ph.D. Outlines Overview and Functions Structure and Types Synthesis and Degradation Sphingolipidosis.

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 forCholera toxins Diphtheria toxinsViruses

Regulation of growth & development Very antigenic:

Blood group antigenEmbryonic antigenTumor antigen

Cell transformation

OverviewCONT’D

Sphingolipids: Structure and

TypesCeramide = 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-GalForssman antigen = Cer-Glc-(Gal)2-(GalNac)2

Galactocerbroside

AcidicAcidic

GlycosphingolipidsNegatively charged at physiological pH

1. Gangliosides:Most complexGanglion cellsCeramide oligosaccharides + NANA

2. Sulfatides:Nerve tissue and kidneysCerbrosides + 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

Measure enzyme activityCultured fibroblasts or peripheral leukocytesCultured amniocytes (prenatal)

Histologic examination DNA analysis

Replacement Therapy: Recombinant human enzyme

Bone marrow transplantation: Gaucher disease

Diagnosis:

Treatment:

CONT’D

Sphingolipidosis

CONT’D

Niemann - Pick Disease

Gaucher Disease

ProstaglandinsEicosanoids (20 C):

Prostaglandins (PG)Thromboxanes (TX)Leukotrienes (LT)

PG Vs Hormones:All cellsLocal acting & Not storedShort half-lifePlasma 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:ConstitutiveMost tissuesImportant for:

Integrity of gastric mucosaRenal homeostasisPlatelet aggregation

COX Isoenzymes

COX-2InducibleLimited No. of tissuesStimulus:

Products of inflammatory & immune cells

Mediates:Inflammatory response:

Pain, Redness & SwellingFever of infection

CONT’D

COX Inhibitors

Cortisol (Steroid):Selective COX-2 (-)Phospholipase A2 (-)

NSAIDS:Both COX-1 and –2 (-)Side effects: Gastric, Renal & ClottingLow-dose Asprin therapy

Celecoxib: Selective COX-2 (-)

Prostaglandin’S Functions