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Biosynthesis of membrane lipids and steroids 1 Léránt István.

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Presentation on theme: "Biosynthesis of membrane lipids and steroids 1 Léránt István."— Presentation transcript:

1 Biosynthesis of membrane lipids and steroids 1 Léránt István

2 BIOSYNTHESIS OF MEMBRANE LIPIDS Phosphatydic acid is a COMMON INTERMEDIER of biosynthesis of phospholipids Neutral fats Biosynthesis of membrane lipids and steroids 1 2 Glycerol Fatty acid 1 Fatty acid 2 Fatty acid 3 Glycerol Fatty acid 1 Fatty acid 2 P P Alcohol Neutral fats Phospholipids Glycerol-phosphate acyltransferase Glycerol-phosphate acyltransferase

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

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 4

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

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

7 Cardiolipin - component of the mitochodrial membranes Biosynthesis of membrane lipids and steroids 1 7 Phosphatidyl - glycerol Diophosphatidyl – glycerol; Cardiolipin P-P-P-P- P-P-P-P- pH ~ / = 7,0 pK’ H 3 PO 4 ~ / = Mitochondria / Lues

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

9 PHOSPHATIDYL-CHOLINE CHOLINE: Food sources Circulation Presynaptic cholinergic membrane Choline-transport - high affinity Synthesis of phosphatidyl-choline in hepatocytes from phosphatidyl- ethanolamine Biosynthesis of membrane lipids and steroids 1 9 Choline-kinase CTP:phosphocholine cytidyliltranspherase CTP:phosphocholine cytidyliltranspherase Cytoplasm Endoplasmic reticulum Cytoplasm Endoplasmic reticulum CDP-CHOLINE: 1,2-diglyceride Phosphocholine ltranspherase CDP-CHOLINE: 1,2-diglyceride Phosphocholine ltranspherase

10 PHOSPHATIDYLETHANOLAMINE & PHOSPHATIDYL-CHOLINE LIVER Biosynthesis of membrane lipids and steroids 1 10 CHOLINE CHOLINE-P CDP-CHOLINE PHOSPHATIDYL- CHOLINE PHOSPHATIDYL- CHOLINE PHOSPHATIDYL SERINE PHOSPHATIDYL SERINE CO 2 3 SAM 3 S-adenosyl- homocysteine 3 S-adenosyl- homocysteine

11 PHOSPHATIDYLETHANOLAMINE & PHOSPHATIDYL-CHOLINE LIVER 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 Biosynthesis of membrane lipids and steroids 1 11 CHOLINE CHOLINE-P CDP-CHOLINE PHOSPHATIDYL- CHOLINE PHOSPHATIDYL- CHOLINE PHOSPHATIDYL SERINE PHOSPHATIDYL SERINE CO 2 3 SAM 3 S-adenosyl- homocysteine 3 S-adenosyl- homocysteine

12 Sphingolipids Biosynthesis of membrane lipids and steroids 1 12 P P Choline X X Sphingomyeline Glu Glucosyl-cerebroside GluGal Lactosyl-cerebrozide GluGalGalNAc NeuNAc G M2 ganglioside Sphingosine Fatty ecid P P Choline Sphingosine Fatty acid Glu / Gal Ceramide Sphingosine Fatty acid X X Sphingosine (4-sphingenene)

13 Sphingomyelin Biosynthesis of membrane lipids and steroids 1 13 Sphingosine Ceramide Choline Phosphoric acid Fatty acid

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

15 Biosynthesis of membrane lipids and steroids 1 15

16 Glucosyl-ceramide / Glucocerebroside Biosynthesis of membrane lipids and steroids 1 16 Ceramide Glu Monohexoside Ceramide GluGal DihexosideCeramide GluGalGal Trihexoside

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

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

19 Gangliosides Biosynthesis of membrane lipids and steroids 1 19 Ceramide Glu Gal NANA G M3 Ceramide GluGal NANA GalNAc G M2 Ceramide GluGal NANA GalNAc G M1 Gal Cholera toxin

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 20

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

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 Biosynthesis of membrane lipids and steroids 1 22 Ceramid Glu Gaucher  -glukozidáz

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

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

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

26 Sphingolipidoses Biosynthesis of membrane lipids and steroids 1 26 CeramideFabry GluGalGal  -galactosidase

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 27

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 28

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 29

30 CHOLESTEROL SYNTHESIS OF Active isoprenoid-units – isopentenyl-pirophosphate Acetyl-CoA  3-hydroxy-3-methyl- glutaryl-CoA (HMG-CoA) – HMG-CoA  mevalonate – Mevalonate  isopentenyl-PP 6 isopentenyl-pyrophosphate  squalen Cyclisation of squalen  cholesterol 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 30

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

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

33 Steps of cholesterol biosynthesis III Mevalonic acid + ATP  5-pyrophospho-mevalonate 5-pyrophospho-mevalonate  decarboxylation + active isoprenoid unit Biosynthesis of membrane lipids and steroids 1 33 Prenylated proteins, ubiquinon, heme,

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

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 35

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

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 37

38 REGULATION OF CHOLESTEROL BIOSYNTHESIS Regulation of biosynthesis of HMG- CoA HMG-CoA reductase mRNS synthesis (transcription) HMG-CoA reductase mRNS translation HMG-CoA reductase degradation covalent modification - phosphorylation Sterol regulatory element binding protein (SREBP) SREBP cleavage activating protein (SCAP) Biosynthesis of membrane lipids and steroids 1 38 HMG-CoA reductase HMG-CoA reductase Cholesterol  Cholesterol  INSIG-1

39 REGULATION OF CHOLESTEROL BIOSYNTHESIS Regulation of biosynthesis of HMG- CoA HMG-CoA reductase mRNS synthesis (transcription) HMG-CoA reductase mRNS translation HMG-CoA reductase degradation covalent modification - phosphorylation Sterol regulatory element binding protein (SREBP) SREBP cleavage activating protein (SCAP) Biosynthesis of membrane lipids and steroids 1 39 X formed from mevalonate cholesterol of food origin

40 REGULATION OF CHOLESTEROL BIOSYNTHESIS Regulation of biosynthesis of HMG- CoA HMG-CoA reductase mRNS synthesis (transcription) HMG-CoA reductase mRNS translation HMG-CoA reductase degradation covalent modification - phosphorylation Sterol regulatory element binding protein (SREBP) SREBP cleavage activating 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 40

41 REGULATION OF CHOLESTEROL BIOSYNTHESIS Regulation of biosynthesis of HMG- CoA HMG-CoA reductase mRNS synthesis (transcription) HMG-CoA reductase mRNS translation HMG-CoA reductase degradation covalent modification - phosphorylation Sterol regulatory element binding protein (SREBP) SREBP cleavage activating protein (SCAP) Biosynthesis of membrane lipids and steroids 1 41

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

43 Biosynthesis of membrane lipids and steroids 1 43

44 Chylomicrons Biosynthesis of membrane lipids and steroids 1 44

45 VLDL Biosynthesis of membrane lipids and steroids 1 45

46 HDL Biosynthesis of membrane lipids and steroids 1 46

47 LDL Biosynthesis of membrane lipids and steroids 1 47

48 Biosynthesis of membrane lipids and steroids 1 48

49 Biosynthesis of membrane lipids and steroids 1 49

50 Biosynthesis of membrane lipids and steroids 1 50

51 Bile acids Biosynthesis of membrane lipids and steroids 1 51 CholesterolCholesterol Primary bile acid Secondary bile acids Cholic acid Chenodeoxycholic acid Deoxycholic acid Litocholic acid Tauro ~ Glyco ~ Tauro ~ Glyco ~ Tauro ~ Gliko ~

52 Biosynthesis of bile acids Biosynthesis of membrane lipids and steroids 1 52

53 Enterohepatic circulation Biosynthesis of membrane lipids and steroids 1 53

54 Bile: bile acids, phosphatidyl-choline, cholesterol Biosynthesis of membrane lipids and steroids 1 54 cholesterol % phosphatidylcholine % Bile acid % 5, 15, 80 %


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