1. Professor Biochemistry Phospholipid Metabolism

2. Learning Objectives At the end of the session the student shall be able to: 1. Define phospholipids and explain the pathways for synthesis and degradation. 2. Enumerates the functions of PL specifically in relation to CNS. 3. Interprets the biochemical basis of lipid storage disorders.

3. Diseases associated with phospholipid metabolism 1. RDS (Respiratory distress syndrome) 2. Niemann-pick diseas 3. Farbers disease 4. Gauchers disease 5. Krabbes disease 6. Tay-sachs disease

4. Phospholipids-Relation to CNS Lecithin (Phosphatidyl choline) : plays important role in the neural transmission. Plasmalogens: Constitutes 10% of the lipid component of the brain. Phosphitidyl Inositol : signal transmission as second messenger. Glycosphingolipids : widely distributed in brain. Gangliosides: abundantly present in the nervous system. Sphingomyelin: chief constituent of myelin sheath.

5. How do phospholipids differ from triacylglycerides (TAGs)? TAGs have three fatty acids hooked to a glycerol molecule. GLYCEROL

6. Phospholipids Phospholipids have two fatty acids hooked to either a glycerol or Sphingosine backbone. A phosphate (polar group) group has replaced one fatty acid of the TAG this is attached by a Phosphodiester bond.

7. Structure of a phospholipids Distribution of phospholipids in the membranes Distribution is asymmetric. PC and Sphingomyelin in the outer layer PS and PE and PI in the inner layer

8. Phospholipids These are triglycerides in which one fatty acid has been replaced by a phosphate group. Phosphate group is soluble in water, while the fatty acid tails are not. Phospholipids are thus hydrophilic at one end and hydrophobic at the other end. Nitrogenous base.

9. Classification Phospholipids: 1. Glycerophospholipids 2. Sphingophospholipids

10. Phospholipids

11. Glycerophospholipids

12. Sphingophospholipids

13. Synthesis of Glycerophospholipids Site: smooth endoplasmic reticulum Synthesized from Phosphatidic acid and 1,2 DAG, intermediates in the production of TAG Metabolism.

14. Formation of Lecithin and Cephalin Choline and Ethanolamine first gets Phosphorylated and then combine with CTP to form, CDP-Choline and CDP-ethanolamine respectively. CDP-Choline and CDP-ethanolamine combine with 1,2DAG to form Phosphotidyl Choline (lecithin) Phosphotidyl Ethanolamine (Cephalin).

15. Significance of Lecithin It is phosphatidylcholine these are most abundant in cell membranes. Dipalmitoyl lecithin is found in lungs acts as a surfactant and prevents the adherence of inner surface of the lungs.

16. Mechanism of RDS

17. Respiratory distress syndrome Is synthesized shortly before parturition in full- term infants. Preterm new-borns have this syndrome due to deficiency of lung surfactant. Respiratory distress syndrome (RDS) in infants is due to absence of phosphatidylcholine. It is Administration of either natural or artificial surfactant has been useful.

18. Significance of Cephalin Phosphotidyl ethanolamine it differs in the base from lecithin. Take part in blood clotting.

19. Formation of Phosphotidyl Serine Phosphotidyl ethanolamine can exchange its ethanolamine group with free serine to produce Phosphotidyl serine.

20. Formation of Phosphotidyl Inositol CDP-DAG produced from Phosphatidic acid combines with Inositol to form PI. PI is important for signal transmission across membranes.

21. Synthesis of Cardiolipin CDP-DAG combines with glycerol-3-phosphate to form Phosphotidyl glycerol, which in turn combines with another molecule of CDP-DAG to produce Cardiolipin. This is the only PL possessing antigenic properties.

23. Formation of Plasmalogens These are PL with fatty acid at carbon 1 bound by an ether linkage instead of ester linkage. An important Plasmalogen, is 1-alkenyl 2 acetyl glycerol 3- Phospho Choline causes platelet aggregation and is referred to as platelet- activating factor.

24. Sphingophospholipids

25. Ganglioside

26. Sphingomyelin synthesis Synthesis: these contain a complex amino alcohol, sphingosine, instead of glycerol. Palmitoyl CoA and Serine combine and undergo a series of reactions to produce sphingosine. which is then acetylated to produce Ceramide. This reacts with CDP- Choline to form Sphingomyelin.

27. Degradation of Sphingomyelin Sphingomyelin Ceramide phosphorylcholine Ceramide Sphingosine Ceramidase Sphingomyelinase Def: Niemann-pick disease Def: Faber’s disease

28. Niemann-pick disease It is an inherited disorder due to defect in Sphingomyelinase. Clinical symptoms: accumulation of Sphingomyelins in liver and spleen, resulting in enlargement of these organs, mental retardation. Cherry red spot in macula. Death usually occurs by 2 years.

29. Farber’s disease Defect in Ceramidase. Clinical symptoms: Skeletal deformities, Subcutaneous nodules, Dermatitis and Mental retardation.

30. Biosynthesis of Glycolipids(Cerebrosides) These are derivatives of Ceramide (sphingosine bound to fatty acid)) most appropriately known as cerebrosides. Galactocerebroside and glucocerebroside are the common glycosphingolipids. These are the major component of membrane lipids in the nervous system.

31. Degradation of Glycolipids(Cerebrosides) Glucocerebrosid e Ceramide Glucose β-glucosidase Def: Gaucher's disease

32. Gaucher's disease This is due to the enzyme β-Glucosidase deficiency. As a result glucocerebroside levels increase.

33. Degradation of Glycolipids(Cerebrosides) Galactocerebrosi de Ceramide Galactose β-galactosidase Def: Krabbe’s disease

34. Krabbe’s disease Enzyme defect is β-Galactosidase results in accumulation of Galactocerebroside. Clinical features: Total absence of myelin in the nervous tissue is a common feature, severe mental retardation, convulsions, Blindness and deafness.

35. Glucocerebroside Galactocerebroside. Sphingomyelin Ceramide

36. Degradation of Phospholipids These are degraded by Phospholipases which will cleave the Phospho di ester bonds. 1. Phospholipase A1: specifically cleaves the fatty acid at C1 position of phospholipids. 2. Phospholipase A2: hydrolyses the fatty acid at C2 position of phospholipids. 3. Phospholipase C (A3): specifically cleaves the bond between phosphate and glycerol of phospholipids. 4. Phospholipase D(A4): hydrolyses and removes the nitrogenous base from the phospholipids.

37. Phospholipases

38. Lecithin-cholesterol acyl transferase LCAT is a plasma enzyme, synthesized in the liver. It is associated with apo A1 of HDL. This enzyme esterifies cholesterol by transferring acyl group from the second position of lecithin. Lecithin + Cholesterol LCAT Lysolecithin + Cholesterol ester. This reaction is responsible for reverse cholesterol transport mediated by HDL.

39. Synthesis of gangliosides

40. Group of glycolipids contain one or more sialic acid residues. Present in high concentrations in CNS and on surface of the membranes. The major gangliosides of brain are GM1, GM2 GM3. For ganglioside synthesis the active form is NANA (N-acetyl neuraminic acid). NANA is attached by the hydroxyl group of its 2 nd carbon to the 3 rd hydroxyl group of sugars.

41. Degradation of Gangliosides Cer-Glc-Gal- NANA Gal-NANACer-Glc Hexosaminidase A Def: Tay-sachs disease

42. Tay-sachs disease Incidence 1 in 6000 births. Deficiency of Hexosaminidase A Mental retardation Cherry red spot in macula. Prognosis is bad.

43. Lysosomal storage diseases

44. 1. These are also called sphingolipidosis. 2. Normally catabolised by a series of bond specific lysosomal hydrolases. 3. Diseases results from failure of breakdown of a particular spingolipid due to deficiency of a single enzyme (gene mutation). 4. Children are affected. 5. These diseases can be diagnosed prenatally by amniocentesis.

45. Phospholipids and Sphingolipids are involved in Multiple Sclerosis (M.S.) MS is a demyelinating disease, caused due to degeneration of myelin sheath. Interfering the nerve conduction. Oligodendroglial cells synthesize the myelin sheath. Clinical symptoms: Presents with tingling and numbness in her fingers and toes. Loss of balance Blurred vision..

46. Guillain-Barre syndrome It is an inflammatory autoimmune neuritis wherein T-cells formed in response to a viral illness mistakenly attack the myelin sheath of peripheral nerves. The myelin sheaths are composed of sphingolipids and phospholipids. They present with progressive weakness of low extremities, loss of deep tendon reflexes, respiratory distress and flu like symptoms. Foods rich in sphingolipids are soy and dairy products.

47. Antiphopsholipid syndrome (Hughes syndrome) Body produces antibodies against its own phospholipids. The major one being anticardiolipin antibody. These antibodies will bind to proteins involved in coagulation and increase the risk of blood clots (thrombosis) Clinical symptoms: repeated miscarriages Thrombocytopenia Deep vein thrombosis.