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Biosynthesis of membrane lipids and steroids 1

Biosynthesis of membrane lipids and steroids 1. Léránt István. BIOSYNTHESIS OF MEMBRANE LIPIDS. Fatty acid 1. Fatty acid 1. Glycerol. Fatty acid 2. Glycerol. Fatty acid 2. Phosphatydic acid is a COMMON INTERMEDIER of biosynthesis of phospholipids Neutral fats. Fatty acid 3. P.

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Biosynthesis of membrane lipids and steroids 1

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  1. Biosynthesis of membrane lipids and steroids 1 Léránt István

  2. BIOSYNTHESIS OF MEMBRANE LIPIDS • Fattyacid 1 • Fattyacid 1 • Glycerol • Fattyacid 2 • Glycerol • Fattyacid2 Phosphatydic acid is a COMMON INTERMEDIER of biosynthesis of phospholipids Neutral fats • Fattyacid3 P Alcohol Glycerol-phosphate acyltransferase Neutralfats Phospholipids Biosynthesis of membrane lipids and steroids 1

  3. In most tissues Glycerol / glycerol-kinase LIver Adiposetissue: Glycolysis - DHAP Biosynthesis of membrane lipids and steroids 1

  4. SYNTHESIS of MEMBRANE LIPIDS and TRIGLYCERIDS Phosphatydic acid is a COMMON INTERMEDIER of biosynthesis of phospholipids Neutral fats ACYL-GLYCEROL-SYNTHETASE COMPLEX ENDOPLASMIC RETICULUM Phosphatase Diacylglycerol acyltransferase Biosynthesis of membrane lipids and steroids 1

  5. SYNTHESIS OF MEMBRANE LIPIDS BIOSYNTHESIS OF PHOSPHOLIPIDS ACTIVATION OF PHOSPHATIDIC ACID / ALCOHOL Biosynthesis of membrane lipids and steroids 1

  6. SYNTHESIS OF PHOSPHATIDYLINOSITOL 4,5 BISPHOSPHATE CDP-diacylglycerol Phosphatidyl-inositol Phosphatidyl-inositol 4,5 bisphosphate Phospholipase C Biosynthesis of membrane lipids and steroids 1

  7. Cardiolipin - component of the mitochodrial membranes Phosphatidyl - glycerol Diophosphatidyl – glycerol; Cardiolipin P- P- pH ~ / = 7,0 pK’ H3PO4 ~ / = 1 - 2 Mitochondria / Lues Biosynthesis of membrane lipids and steroids 1

  8. Cardiolipin - component of the mitochodrial membranes CTP CDP P- P- Biosynthesis of membrane lipids and steroids 1

  9. PHOSPHATIDYL-CHOLINE CHOLINE: Foodsources Circulation Presynapticcholinergicmembrane Choline-transport - highaffinitySynthesis of phosphatidyl-cholinein hepatocytesfromphosphatidyl-ethanolamine Cytoplasm Endoplasmicreticulum CTP:phosphocholine cytidyliltranspherase Choline-kinase CDP-CHOLINE: 1,2-diglyceride Phosphocholineltranspherase Endoplasmicreticulum Biosynthesis of membrane lipids and steroids 1

  10. CHOLINE PHOSPHATIDYLETHANOLAMINE&PHOSPHATIDYL-CHOLINELIVER CHOLINE-P CDP-CHOLINE PHOSPHATIDYL- CHOLINE CO2 3 S-adenosyl- homocysteine 3 SAM PHOSPHATIDYL SERINE Biosynthesis of membrane lipids and steroids 1

  11. CHOLINE PHOSPHATIDYLETHANOLAMINE&PHOSPHATIDYL-CHOLINELIVER CHOLINE-P RATE LIMITING STEP: CTP:phosphocholine cytidylil-transferase Cytoplasm – Endoplasmic reticulum Translocation - activation + fatty acid – fatty -acyl-CoA / DAG cAMP dependent protein kinase Lipid transport – PCh dependent Choline deficiency / VLDL / fatty liver CDP-CHOLINE PHOSPHATIDYL- CHOLINE CO2 3 S-adenosyl- homocysteine 3 SAM PHOSPHATIDYL SERINE Biosynthesis of membrane lipids and steroids 1

  12. Sphingolipids Sphingosine Sphingosine • Fattyecid • Fattyacid Ceramide Glu / Gal P Choline Sphingosine (4-sphingenene) • X Sphingomyeline P Choline Glu Glucosyl-cerebroside Sphingosine • Fattyacid Glu Gal Lactosyl-cerebrozide NeuNAc • X GM2ganglioside Glu Gal GalNAc Biosynthesis of membrane lipids and steroids 1

  13. Sphingomyelin Fattyacid Phosphoricacid Sphingosine Ceramide Choline Biosynthesis of membrane lipids and steroids 1

  14. Synthesis of sphigolipids Galactocerebrosides Glucocerebrosides Gangliosides sphyngomyeline Biosynthesis of membrane lipids and steroids 1

  15. Biosynthesis of membrane lipids and steroids 1

  16. Glucosyl-ceramide / Glucocerebroside Monohexoside Glu Ceramide Dihexoside Gal Glu Ceramide Trihexoside Gal Gal Glu Ceramide Biosynthesis of membrane lipids and steroids 1

  17. Galactosyl – ceramide / Galactocerebroside Monohexoside Gal Ceramid Dihexozid Gal Gal Ceramid Biosynthesis of membrane lipids and steroids 1

  18. ABO blood group system Glu Gal GalNAc Gal „O” (H) antigen Fuc Glu Gal GalNAc Gal GalNAc „A” antigen Fuc Glu Gal GalNAc Gal Gal „B” antigen Fuc Biosynthesis of membrane lipids and steroids 1

  19. Gangliosides Glu Gal Ceramide GM3 NANA GM2 GalNAc Gal Glu Ceramide NANA GM1 GalNAc Gal Glu Ceramide Cholera toxin Gal NANA Biosynthesis of membrane lipids and steroids 1

  20. Inborn errors of phospholipid, sphingolipid metabolism • Demyelination: Sclerosis multiplex • White matter decrease of [phospholipid], [plasmenyl ethanolamine], [sphingolipid] • Sphingolipidosis: • Accumulation of complex lipids • Synthesis of complex lipids is not effected • Lack of specific (hydrolytic) lysomal enzymes • All tissues are effected • Multiple sulfatase deficiency Biosynthesis of membrane lipids and steroids 1

  21. Sphingolipidoses sphingomyelinase Niemann-Pick Ceramid P-Kol • Accumulation of sphingomyelin Biosynthesis of membrane lipids and steroids 1

  22. Gaucher’s - disease • Accumulation of glucocerebrosides in reticuloendothelial cells of spleen, liver, and bone marrow • the most common of lysosomal storage disease • Mental retardation Glu b-glukozidáz Gaucher Ceramid Biosynthesis of membrane lipids and steroids 1

  23. Krabbe disease • Accumulation of Galactosyl ceramide Gal b-galaktosidase Krabbe Ceramid Biosynthesis of membrane lipids and steroids 1

  24. Tay – Sachs Disease • Deficiency of Hexosaminidase A • Hexosaminidase A • hydrolyses the N-acetyl-galactosamine of GM2 ganglioside • Mental retardation • Macrocephalia • Death at age 2-4 • Frequency: Ashkenazi Jewish population 1:3500 Biosynthesis of membrane lipids and steroids 1

  25. Tay – Sachs Disease Glu Gal GalNAc Tay - Sachs Ceramid NANA hexosaminidase Biosynthesis of membrane lipids and steroids 1

  26. Sphingolipidoses Glu Gal Gal Fabry Ceramide a-galactosidase Biosynthesis of membrane lipids and steroids 1

  27. CHOLESTEROL “Cholesterol is the most highly decorated small molecule in biology. Thirteen Nobel Prizes have been awarded to scientists who devoted major parts of their careers to cholesterol. Ever since it was isolated from gallstones in 1784, cholesterol has exerted an almost hypnotic fascination for scientists from the most diverse areas of science and medicine…. Cholesterol is a Janus-faced molecule. The very property that makes it useful in cell membranes, namely its absolute insolubility in water, also makes it lethal.” Michael Brown and Joseph Goldstein Nobel Lectures (1985) Biosynthesis of membrane lipids and steroids 1

  28. CHOLESTEROL “Cholesterol is the most highly decorated small molecule in biology. Thirteen Nobel Prizes have been awarded to scientists who devoted major parts of their careers to cholesterol. Ever since it was isolated from gallstones in 1784, cholesterol has exerted an almost hypnotic fascination for scientists from the most diverse areas of science and medicine…. Cholesterol is a Janus-faced molecule. The very property that makes it useful in cell membranes, namely its absolute insolubility in water, also makes it lethal.” Michael Brown and Joseph Goldstein Nobel Lectures (1985) Biosynthesis of membrane lipids and steroids 1

  29. CHOLESTEROL “Cholesterol is the most highly decorated small molecule in biology. Thirteen Nobel Prizes have been awarded to scientists who devoted major parts of their careers to cholesterol. Ever since it was isolated from gallstones in 1784, cholesterol has exerted an almost hypnotic fascination for scientists from the most diverse areas of science and medicine…. Cholesterol is a Janus-faced molecule. The very property that makes it useful in cell membranes, namely its absolute insolubility in water, also makes it lethal.” Michael Brown and Joseph Goldstein Nobel Lectures (1985) Biosynthesis of membrane lipids and steroids 1

  30. CHOLESTEROL • SYNTHESIS OF • Active isoprenoid-units – isopentenyl-pirophosphate • Acetyl-CoA à3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) • HMG-CoA àmevalonate • Mevalonate àisopentenyl-PP • 6 isopentenyl-pyrophosphate àsqualen • Cyclisation of squalen àcholesterol Acetyl CoA – C27 Synthesis – cytosolic compartment Endoplasmic reticulum bound enzymes All cells LIVER Adrenal cortex Testis Ovaries Intestinal epithelia Biosynthesis of membrane lipids and steroids 1

  31. Steps of cholesterol biosynthesis I Koleszterin-bioszintézis Ketontest-képzés Biosynthesis of membrane lipids and steroids 1

  32. Steps of cholesterol biosynthesis II Rate limiting step in cholesterol biosynthesis Biosynthesis of membrane lipids and steroids 1

  33. Steps of cholesterol biosynthesis III Mevalonicacid + ATP à 5-pyrophospho-mevalonate 5-pyrophospho-mevalonate àdecarboxylation + activeisoprenoid unit Prenylatedproteins, ubiquinon, heme, Biosynthesis of membrane lipids and steroids 1

  34. Steps of cholesterol biosynthesis IV 5 5 Dimethylallyl-PP + isopentenyl-PP = Geranyl-PP (5 + 5) = 10 Geranyl –PP + isopentenyl-PP = farnesyl-PP (10 + 5) = 15 Farnesyl-PP + Farnesyl-PP = Squalene (15 + 15 )= 30 NADPH + H+ PPi Squalene -syntase – Endoplasmic reticulum 10 5 15 15 30 Biosynthesis of membrane lipids and steroids 1

  35. Steps of cholesterol biosynthesis V Cyclization Monooxygenase C2,3 epoxide Transfer of Methylgroups 14-13, 8 – 14 Sterol carrier protein 1 (SCP1) Squalene Sterol carrier protein 2 (SCP2) Lanosterol Biosynthesis of membrane lipids and steroids 1

  36. Steps of cholesterol biosynthesis V 1 molecule of cholesterol 18 acetyl-CoA 36 ATP 16 NADPH Biosynthesis of membrane lipids and steroids 1

  37. Regulation of cholesterol biosynthesis • Regulation of HMG-CoA biosynthesis • HMG-CoA reductase mRNS synthesis (transcription) • HMG-CoA reductase mRNS translation • HMG-CoA reductase degradation • covalent modification - phosphorylation Cholesterol - food de novo synthesis Liver Intestine Rate of biosynthesis is influenced by Intracellular cholesterin synthesis Comitted step: HMG-CoA reductase Biosynthesis of membrane lipids and steroids 1

  38. Cholesterolá Cholesterolâ REGULATION OF CHOLESTEROL BIOSYNTHESIS Regulation of biosynthesisofHMG-CoA HMG-CoA reductase mRNSsynthesis (transcription) HMG-CoA reductase mRNStranslation HMG-CoA reductase degradation covalentmodification - phosphorylation Sterolregulatoryelementbinding protein (SREBP) SREBP cleavageactivating protein (SCAP) INSIG-1 HMG-CoA reductase Biosynthesis of membrane lipids and steroids 1

  39. REGULATION OF CHOLESTEROL BIOSYNTHESIS Regulation of biosynthesisofHMG-CoA HMG-CoA reductase mRNSsynthesis (transcription) HMG-CoAreductase mRNStranslation HMG-CoA reductase degradation covalentmodification - phosphorylation Sterolregulatoryelementbinding protein (SREBP) SREBP cleavageactivating protein (SCAP) X formedfrommevalonate cholesterol of foodorigin Biosynthesis of membrane lipids and steroids 1

  40. REGULATION OF CHOLESTEROL BIOSYNTHESIS Regulation of biosynthesisofHMG-CoA HMG-CoA reductase mRNSsynthesis (transcription) HMG-CoA reductase mRNStranslation HMG-CoA reductase degradation covalentmodification - phosphorylation Sterolregulatoryelementbinding protein (SREBP) SREBP cleavageactivating protein (SCAP) HMG-CoA reductase Cytoplasmatic domain – katalysis Membrane domain – sensor cholesterol cc Enzyme proteolytic cleavage, ubiquitine, proteasome Biosynthesis of membrane lipids and steroids 1

  41. REGULATION OF CHOLESTEROL BIOSYNTHESIS Regulation of biosynthesisofHMG-CoA HMG-CoA reductase mRNSsynthesis (transcription) HMG-CoA reductase mRNStranslation HMG-CoA reductase degradation covalentmodification - phosphorylation Sterolregulatoryelementbinding protein (SREBP) SREBP cleavageactivating protein (SCAP) Biosynthesis of membrane lipids and steroids 1

  42. Hepatocyta - VLDL LIPIDTRANSPORT Biosynthesis of membrane lipids and steroids 1

  43. Biosynthesis of membrane lipids and steroids 1

  44. Chylomicrons Biosynthesis of membrane lipids and steroids 1

  45. VLDL Biosynthesis of membrane lipids and steroids 1

  46. HDL Biosynthesis of membrane lipids and steroids 1

  47. LDL Biosynthesis of membrane lipids and steroids 1

  48. Biosynthesis of membrane lipids and steroids 1

  49. Biosynthesis of membrane lipids and steroids 1

  50. Biosynthesis of membrane lipids and steroids 1

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