Transcript Gal
Biosynthesis of membrane lipids and steroids 1 Léránt István phospholipids Neutral fats Fatty acid 1 Fatty acid 2 Fatty acid 3 Glycerol Phosphatydic acid is a COMMON INTERMEDIER of biosynthesis of Glycerol BIOSYNTHESIS OF MEMBRANE LIPIDS Fatty acid 1 Fatty acid 2 P Alcohol Glycerol-phosphate acyltransferase Biosynthesis of membrane lipids and steroids 1 Neutral fats 2 Phospholipids In most tissues Glycerol / glycerol-kinase LIver Adipose tissue: Glycolysis - DHAP Biosynthesis of membrane lipids and steroids 1 3 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 SYNTHESIS OF MEMBRANE LIPIDS BIOSYNTHESIS OF PHOSPHOLIPIDS ACTIVATION OF PHOSPHATIDIC ACID / ALCOHOL Biosynthesis of membrane lipids and steroids 1 5 SYNTHESIS OF PHOSPHATIDYLINOSITOL 4,5 BISPHOSPHATE CDP-diacylglycerol Phosphatidyl-inositol Phosphatidyl-inositol 4,5 bisphosphate Phospholipase C Biosynthesis of membrane lipids and steroids 1 6 Cardiolipin - component of the mitochodrial membranes O H2C R2 C O O C H2C O O C R1 H2C H O H O P O C O P O OH CH2 CH2 O H C O C R3 O R4 C O CH2 O O Phosphatidyl - glycerol Diophosphatidyl – glycerol; Cardiolipin P- P- pH ~ / = 7,0 pK’ H3PO4 ~ / = 1 - 2 Mitochondria / Lues Biosynthesis of membrane lipids and steroids 1 7 Cardiolipin - component of the mitochodrial membranes glycerol-3- phosphate acyltranspherase Glycerol- 3 - P 2 phosphatidat e - DAG synthase phosphatidat e CDP CDP diacylglycerol synthase CDP diacylglycerol PGP phosphatidylglycerol- P (P GP ) phosphatidylglycerol- P (P GP )dephosphor ylation phosphatidylglycerol CDP -diacylglycerol phosphatidylglycerol cardiolipin CTP P- PCDP Biosynthesis of membrane lipids and steroids 1 8 PHOSPHATIDYL-CHOLINE CHOLINE: Food sources Circulation Presynaptic cholinergic membrane Choline-transport - high affinity Synthesis of phosphatidyl-choline in hepatocytes from phosphatidylethanolamine Choline-kinase Cytoplasm Endoplasmic reticulum CTP:phosphocholine cytidyliltranspherase CDP-CHOLINE: 1,2-diglyceride Phosphocholine ltranspherase Endoplasmic reticulum Biosynthesis of membrane lipids and steroids 1 9 CHOLINE PHOSPHATIDYLETHANOLAMINE & PHOSPHATIDYL-CHOLINE LIVER CHOLINE-P CDP-CHOLINE PHOSPHATIDYLCHOLINE CO2 3 SAM PHOSPHATIDYL Biosynthesis of membrane lipids and steroids 1 SERINE 3 S-adenosylhomocysteine 10 CHOLINE PHOSPHATIDYLETHANOLAMINE & PHOSPHATIDYL-CHOLINE LIVER CHOLINE-P RATE LIMITING STEP: CTP:phosphocholine cytidyliltransferase Cytoplasm – Endoplasmic reticulum Translocation - activation CDP-CHOLINE + fatty acid – fatty -acyl-CoA / DAG cAMP dependent protein kinase Lipid transport – PCh dependent Choline deficiency / VLDL / fatty liver PHOSPHATIDYLCHOLINE CO2 3 SAM PHOSPHATIDYL Biosynthesis of membrane lipids and steroids 1 SERINE 3 S-adenosylhomocysteine 11 Sphingolipids Sphingosine Sphingosine Fatty ecid Fatty acid Ceramide H H 3 P Choline 2 1 CH CH C C CH2OH Glu / Gal + O NH3 H szfingozin (4-szfingenin) Sphingosine (4-sphingenene) X P Choline Sphingomyeline Glu Glucosyl-cerebroside Glu Gal Lactosyl-cerebrozide Sphingosine Fatty acid NeuNAc X Glu Gal GalNAc GM2 ganglioside Biosynthesis of membrane lipids and steroids 1 12 Sphingomyelin H 3 H O 2 CH CH C O H + N H2 C 1 CH2 C R Fatty acid O O P O O Sphingosine Ceramide Choline CH3 + CH2 CH2 N Biosynthesis of membrane lipids and steroids 1 CH3 CH3 Phosphoric acid 13 Synthesis of sphigolipids Galactocerebrosides Glucocerebrosides Gangliosides sphyngomyeline Biosynthesis of membrane lipids and steroids 1 14 Biosynthesis of membrane lipids and steroids 1 15 Glucosyl-ceramide / Glucocerebroside Glu Ceramide Gal Glu Ceramide Gal Glu Ceramide Monohexoside Dihexoside Trihexoside Gal Biosynthesis of membrane lipids and steroids 1 16 Galactosyl – ceramide / Galactocerebroside Monohexoside Dihexozid Gal Biosynthesis of membrane lipids and steroids 1 Gal Ceramid Gal Ceramid 17 ABO blood group system Glu Gal GalNAc Gal „O” (H) antigen Fuc Glu Gal GalNAc Gal GalNAc „A” antigen Gal „B” antigen Fuc Glu Gal GalNAc Gal Fuc Biosynthesis of membrane lipids and steroids 1 18 Gangliosides Gal GM3 Glu Ceramide NANA GM2 GalNAc Gal Glu Ceramide Glu Ceramide NANA GM1 GalNAc Gal Gal Cholera toxin NANA Biosynthesis of membrane lipids and steroids 1 19 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 Sphingolipidoses Niemann-Pick Ceramid P-Kol sphingomyelinase • Accumulation of sphingomyelin Biosynthesis of membrane lipids and steroids 1 21 Gaucher’s - disease • Accumulation of glucocerebrosides in reticuloendothelial cells of spleen, liver, and bone marrow • the most common of lysosomal storage disease • Mental retardation Gaucher Ceramid Glu Biosynthesis of membrane lipids and steroids 1 b-glukozidáz 22 Krabbe disease • Accumulation of Galactosyl ceramide Krabbe Ceramid Gal Biosynthesis of membrane lipids and steroids 1 b-galaktosidase 23 Tay – Sachs Disease • Deficiency of Hexosaminidase A • Hexosaminidase A • hydrolyses the N-acetylgalactosamine of GM2 ganglioside • Mental retardation • Macrocephalia • Death at age 2-4 • Frequency: Ashkenazi Jewish population 1:3500 Biosynthesis of membrane lipids and steroids 1 24 Tay – Sachs Disease Tay - Sachs Ceramid Glu Gal GalNAc NANA hexosaminidase Biosynthesis of membrane lipids and steroids 1 25 Sphingolipidoses Fabry Ceramide Glu Gal Gal a-galactosidase Biosynthesis of membrane lipids and steroids 1 26 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 Janusfaced 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 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 Janusfaced 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 Janusfaced 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 Acetyl CoA – C27 Synthesis – cytosolic compartment Endoplasmic reticulum bound enzymes All cells LIVER Adrenal cortex Testis Ovaries Intestinal epithelia • SYNTHESIS OF • Active isoprenoid-units – isopentenyl-pirophosphate • Acetyl-CoA 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) – HMG-CoA mevalonate – Mevalonate isopentenyl-PP • 6 isopentenyl-pyrophosphate squalen • Cyclisation of squalen cholesterol Biosynthesis of membrane lipids and steroids 1 30 Steps of cholesterol biosynthesis I 2 acetyl- CoA thiolase acetoacety l CoA CoA syntase acetoacety l CoA acetyl- CoA HMG 3 hydroxy 3 methyl glutaryl CoA -CoA - reduktase 3 hydroxy 3 methyl glutaryl CoA HMG mevalonate Koleszterin-bioszintézis Ketontest-képzés Biosynthesis of membrane lipids and steroids 1 31 Steps of cholesterol biosynthesis II Rate limiting step in cholesterol biosynthesis 2 NADPH+H+ 2 NADP+ H3 C -OOC H3C OH O CoA 3-Hidroxi-3metil-glutaril-CoA OH OH -OOC CoASH mevalonát HMG-CoA reduktáz Biosynthesis of membrane lipids and steroids 1 32 Steps of cholesterol biosynthesis III Mevalonic acid + ATP 5-pyrophospho-mevalonate 5-pyrophospho-mevalonate decarboxylation + active isoprenoid unit Prenylated proteins, ubiquinon, heme, Biosynthesis of membrane lipids and steroids 1 33 5 Steps of cholesterol biosynthesis IV 5 Dimethylallyl-PP + isopentenyl-PP = Geranyl-PP (5 + 5) = 10 10 Geranyl –PP + isopentenyl-PP = farnesyl-PP (10 + 5) = 15 5 Farnesyl-PP + Farnesyl-PP = Squalene (15 + 15 )= 30 NADPH + H+ -PPi 15 Squalene -syntase – Endoplasmic reticulum 15 Biosynthesis of membrane lipids and steroids 1 30 34 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 Steps of cholesterol biosynthesis V 1 molecule of cholesterol 18 acetyl-CoA 36 ATP 16 NADPH Biosynthesis of membrane lipids and steroids 1 36 Regulation of cholesterol biosynthesis Cholesterol - food de novo synthesis Liver Intestine Rate of biosynthesis is influenced by Intracellular cholesterin synthesis Comitted step: HMG-CoA reductase • Regulation of HMG-CoA biosynthesis – HMG-CoA reductase mRNS synthesis (transcription) – HMG-CoA reductase mRNS translation – HMG-CoA reductase degradation – covalent modification phosphorylation Biosynthesis of membrane lipids and steroids 1 37 REGULATION OF CHOLESTEROL BIOSYNTHESIS Cholesterol Cholesterol Regulation of biosynthesis of HMGCoA HMG-CoA reductase mRNS synthesis (transcription) HMG-CoA reductase mRNS translation HMG-CoA reductase degradation covalent modification phosphorylation INSIG-1 HMG-CoA reductase Sterol regulatory element binding protein (SREBP) SREBP cleavage activating protein (SCAP) Biosynthesis of membrane lipids and steroids 1 38 REGULATION OF CHOLESTEROL BIOSYNTHESIS Regulation of biosynthesis of HMGCoA 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) X formed from mevalonate cholesterol of food origin Biosynthesis of membrane lipids and steroids 1 39 REGULATION OF CHOLESTEROL BIOSYNTHESIS Regulation of biosynthesis of HMGCoA 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 REGULATION OF CHOLESTEROL BIOSYNTHESIS Regulation of biosynthesis of HMGCoA 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 Hepatocyta - VLDL LIPIDTRANSPORT Biosynthesis of membrane lipids and steroids 1 42 Biosynthesis of membrane lipids and steroids 1 43 Chylomicrons Biosynthesis of membrane lipids and steroids 1 44 VLDL Biosynthesis of membrane lipids and steroids 1 45 HDL Biosynthesis of membrane lipids and steroids 1 46 LDL Biosynthesis of membrane lipids and steroids 1 47 Biosynthesis of membrane lipids and steroids 1 48 Biosynthesis of membrane lipids and steroids 1 49 Biosynthesis of membrane lipids and steroids 1 50 Bile acids Tauro ~ Gliko ~ H N CH2 CH2 SO3H H N CH2 COOH COOH HO Tauro ~ Glyco ~ Cholesterol HO OH H COOH Chenodeoxycholic acid HO COOH HO HO H OH H Litocholic acid Cholic acid HO COOH Primary bile acid Deoxycholic acid HO H Biosynthesis of membrane lipids and steroids 1 Secondary bile acids 51 Biosynthesis of bile acids Biosynthesis of membrane lipids and steroids 1 52 Enterohepatic circulation Biosynthesis of membrane lipids and steroids 1 53 Bile: bile acids, phosphatidyl-choline, cholesterol phosphatidylcholine % cholesterol % 5, 15, 80 % Bile acid % Biosynthesis of membrane lipids and steroids 1 54