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Eicosanoids.pptx for first year medical students
- 2. Prostaglandin metabolism Compound lipid metabolism
- 3. Pre-T est 1. Name the essential fatty acids 2. Give 2 egs of phospholipids.
- 4. COMPETENCIES • BI 4.2, 4.3 • PROSTAGLANDIN METABOLISM, • COMPOUND LIPID METABOLISM • LIPID STORAGE DISEASE
- 5. Specific Learning objective • At the end of the interactive lecture the phase I MBBS student should be able to • List the biologically important prostaglandins and their metabolism correctly • Explain the functions of prostaglandins and the clinical applications of eicosanoids correctly.
- 6. Specific Learning objective • Define and classify compound lipids correctly. • Describe the metabolism of phospholipids and glycolipids • Define the various types of lipid storage disease
- 7. Eicosanoids • Derived from C20 polyunsaturated fatty acids • Types: 1) Prostanoids Prostaglandins (PG), thromboxanes (TX) 2) Leukotrienes (LT) lipoxins (LX) • Source: Diet (essential fatty acids) synthesized from arachidonate
- 8. Prostanoic acid • The 5 C ring is saturated • OH group is at 15 C OH
- 9. Synthesis from arachidonate membrane phospholipids PLA2 (inhibited by steroids) arachidonic acid cyclo-oxygenase (aspirin inhibits) prostaglandins synthase lipooxygenase thrombaxanes leukotrienes
- 10. Prostaglandins Most potent Biologically active substances synthesized by all cells except RBC. Acts as local hormones Derived from 20 C cyclicsaturated fattyacid, Prostanoic acid. T ypes:- Series 1:one double bond at 13–14 (Linolenic acid) Series 2:two double bond at13 – 14 &5 – 6 (ArachidonicA) Series 3 :three double bond at13 – 14,5 – 6& 17 – 18 (Eicosapenta –enoicacid)
- 11. Cyclooxygenase (Cox) pathway Arachidonate PGG2 peroxidase PGH2 PG synthase PGI2 PGE2 PGD2 TXA2 PGF2α TX synthase
- 12. Cyclooxygenase (Prostaglandin H2 synthase) • Suicidal enzyme • Inhibited by aspirin, indomethacin and ibuprofen • Mechanism: Aspirin acetylated inhibit COX derivative Indomethacin Ibuprofen compete with arachidonate inhibit COX
- 13. Regulation of PG’s synthesis . Phospholipase – activated by Epinephrine,thrombin,Ang II,Bradykinin Inhibited by Steroids. Cyclo-oxygenase – Activated by :Catcholamines Inhibited byAspirin. Half lifeof PG ‘sis 30 secs. Constitutive form Inducible form
- 14. Functions • Prostacyclin (PGI2) inhibit platelet aggregation vasodilatation • PG F: uterine muscle contraction induce labor bronchoconstrictor • PG E: bronchodilator causes inflammation
- 15. Biological actions CVS Prostacyclin – PGI2 – Synthesized by vascular endothelium Action: 1.Vasodilatation 2.inhibitsplatelet aggregation 3.protective effecton vessel wall
- 17. Ovary & Uterus PGF2 – Stimulatesuterine muscles Use: Medical terminationofpregnancy Inducing labour Arrest post partum hemorrhage LH inducedovulation Effect on Respiratory tract PGF – Constricts Bronchialsmoothmuscle. PGE – PotentBrochodilator
- 18. Immunity & Inflammation PGE2 & D2 – Produces inflammation Increases capillary permeability Causes erythema &wheal at injury site Reduced T-cell &B- cellfunction. GIT Inhibitory effecton Gastric sceretion Increases intestinal motility Use:Acid pepticdisease
- 19. LEUKOTRIENES Conjugated trienes Produced by Neutrophils. Subscript indicates the no of double bonds
- 20. Lipooxygenase pathway Arachidonate 5-HPETE LTA synthetase LTA4 LTB4 LTC4 LTD4 LTE4 15 LOX 15-HPETE Lipoxins (hydroxy peroxy eicosa tetraenoate) 5 LOX
- 21. Functions Mediators of inflammation and anaphylaxis L TB4 most potent chemo tactic agent L TC4, L TD4, L TE4 - Slow reacting substance of anaphylaxis SRS-A Causes: Smooth musclecontraction Constrict bronchioles Produces vasoconstriction
- 22. Lipoxins Conjugated tetraenes produced by leukocytes LXA4 Most common lipoxin They are vasoactive, immunoregulatory & chemo tactic agent
- 24. Compound lipids Ester of fatty acid with alcohol, but in addition contain other groups. A. Phospholipids
- 25. Phospholipids Fatty acid + glycerol or sphingol + phosphoric acid + nitrogenous base Major component of biological membranes Amphipathic lipids Simplest is phosphatidic acid
- 26. Classification of Phospholipid Sphingophospholipid - Sphingomyelins (Cephalin) Glycerophospholipid • Phosphatidylcholine (Lecithin) Phosphatidylethanolamine Phosphatidylserine Phosphatidylinositol Plasmalogens Lysophospholipids Cardiolipins
- 27. Phosphatidic acid Simplest phospholipid Intermediate in the synthesis of TGL and other phosphoglycerols. Fatty acids are esterified to the hydroxyls on C1 and C2. C3 hydroxyl is esterified to phosphoric acid.
- 28. 1. Phosphatidyl choline Also called lecithin choline • Most abundant PL in cell membrane. • Dipalmitoyl lecithin is a component of lung surfactant. • Deficiency – Respiratory Distress Syndrome
- 29. Synthesis of Phosphatidyl choline LECITHIN
- 30. 2. Phosphatidyl Ethanolamine • Phosphatidic acid is esterified to ethanolamine. •Thromboplastin - contains cephalin, which initiates clotting process. • Found in biomembranes of brain and nervous tissue. ethanol amine Function Also called Cephalin
- 33. 3. Phosphatidyl serine •Phosphatidic acid esterified to the amino acid serine. •Component of cell membranes. •Role in cell cycle signalling. •Programmed cell apoptosis Serine Functio n
- 34. Synthesis of Phosphatidyl serine
- 35. 4.PLASMALOGENS Aliphatic long chain in Ether linkage Choline or Ethanolamine Aliphatic long chain (C12 – C18) α, β unsaturated alcohol in ether linkage with the first hydroxyl group of glycerol.
- 37. 5. PHOSPHATIDYL INOSITOL Inositol Functio n •Phosphatidicacid is esterified to inositol. •Involved in signal transduction. • On stimulation by hormone, PIP2 releases inositol 1,4,5-triphosphate (IP3) and DAG - act as second messengers.
- 38. Synthesis of Phosphatidyl Inositol
- 39. Dipalmitoyl lecithin – acts as surface active agents required for formation of lung surfactant reduces surface tension in alveoli prevents alveolar collapse.
- 41. Action of Phospholipases Phospholipases are enzymes that hydrolyse Phospholipids. Phospholipases A2 - acts on second Carbon atom & hydrolyses the esterified fatty acid. Present in the venom of Viper snake. Lecithin Lysolecithin + Fatty acid
- 42. •Also known as Cardiolipins. •Found mainly in the inner membrane of mitochondria. •Consists of two molecules of phosphatidic acid linked together by glycerol. •It was first isolated from cardiac muscle and hence the name. DIPHOSPHATIDYL GLYCEROL Structure
- 43. Cardiolipins • Only phospholipid with antigenic properties. • Major lipid in Mitochondrial membrane. • Decreased Cardiolipin Mitochondrial dysfunction Heart failure. • Used in diagnosis of syphilis. • Identification of antibodies that react with cardiolipins diagnosis of antiphospholipid syndrome.
- 44. Imp: 1.myelin – contains ethanolamine plasmalogens 2.Heart muscle – contains choline plamalogens 3.Platelet Activating Factor – involved in platelet aggregation. PLASMALOGENS
- 47. Phospholipids Lecithin Glycerol Fatty acid Phosphoric acid Choline Cephalin Glycerol Fatty acid Phosphoric acid ethanolamine Phosphatidyl serine Glycerol Fatty acid Phosphoric acid serine Phosphatidyl inositol Glycerol Fatty acid Phosphoric acid inositol Plasmalogens Glycerol Aliphatic long chain Fatty acid (ether bond) Phosphoric acid Choline/etha nolamine/ser ine Cardiolipins Glycerol Fatty acid Phosphoric acid inositol Sphingomyeli n sphingol Fatty acid Phosphoric acid Choline
- 48. Sphingolipids Types: 1. Phosphosphingosides 2. Glycosphingolipids 3. Sulfatides - Has long chain amino alcohol Sphingosine
- 49. Spingomyelins - Phosphosphingosides Does not contain glycerol Instead 18 carbon unsaturatedamino alcohol called‘sphingosine’. Ceramide = sphingosine+ fatty acid Sphingomyelin = fatty acid + phosphoric acid + sphingosine + choline.
- 50. Found in large quantities in Brain & Nervous tissues Found in the membranes, especially in myelin sheath.
- 52. GLYCOLIPIDS
- 53. CERAMIDE Ceramides are amide linkages of fatty acids to the nitrogen of alcohol sphingosine
- 54. GLYCOLIPIDS Do not contain phosphoricacid. Composed of a ceramide backbone with carbohydrate groups (mono- or oligosaccharides) attached to C1 of sphingosine. Types: 1. Cerebrosides 2. Gangliosides 3. Globosides 4. Sulfolipids
- 57. Resemble cerebrosides Contains oligosaccharide carbohydrate units up to 7 sugar moieties. Constituents of RBC membrane & determinants of ABO blood group system Eg: Lactosylceramide isfound in RBC membrane Globosides
- 58. Highest concentration found in Gray matter of brain. Large complex lipids Structure: long chain F A Sphingosine alcohol Galactose or Glucose N- acetylgalactosamine N-acetyl neuraminic acid Gangliosides
- 60. Gangliosides Contains N- acetyl Neuraminic acid – (NANA) Ceramide - Glucose – Galactose –NANA Simplest ganglioside-GM3 IMP: contribute to stability of paranoidal junction &Ion channel clusters in Myelinated nerve fibers.
- 63. Ceramide + Monosaccharide + Sulfate Sulfogalactoceramide – nerve tissue PAPS – 3’-phosphoadenosine- 5’phosphosulfate – sulfatedonor They are present in high concentration in myelin. Sulfolipids
- 64. Constituent of nervous tissue Specific receptors for polypeptide hormones, drugs,viruses Found on specific sites on the nerve ending for neurotransmitter binding Blood group antigens Determinants in immunological reactions Functions of Glycolipids
- 65. Glycolipids Cerebrosides Sphingosine Fatty acid Glucose/ Galactose Globosides Sphingosine Fatty acid Oligosaccharide Gangliosides Sphingosine Fatty acid Oligosaccharide NANA Sulfatides Sphingosine Fatty acid Glucose/ Galactose Sulfate
- 67. Lipid storage disorders Failure of degradation of the complex lipids leads to accumulation in CNS Lipid storage disorders. All are inherited in autosomal recessive mendelian fashion except for the X- linked Fabry’ s disease.
- 70. Disease Enzyme Defect Accumulated Lipid Tissues Involved Tay–Sachs disease HexosaminidaseA GM2 ganglioside Brain, retina Gaucher's disease –Glucosidase (glucocerebrosidase) Glucocerebroside Liver, spleen, bone marrow, brain Neimann–Pick disease Sphingomyelinase Sphingomyelin Brain, liver, spleen Metachromatic leukodystrophy ArylsulfataseA Sulfatide Brain, kidney, liver, peripheral nerves Fabry's disease –Galactosidase Ceramide trihexoside Skin, kidney Krabbe's disease Galactosylceramidase Galactocerebroside Brain
- 71. Tay–Sachs disease INTRO: GM2 Gangliosidosis Accumulation of gangliosides in brain and nervous tissue. ENZYME DEFECT : Hexosaminidase A INHERITANCE:Autosomal recessive Pathology: Normal degradation of GM2 by hydrolyzing enzyme Hexosaminidase A. If enzyme is deficient GM2 accumulation occurs.
- 72. Post-test 1.Name the essential fatty acids. 2.List 2 functions of prostaglandins 3.Name the enzyme defect in Niemann Pick and T aysach’s Disease