Lipid Synthesis Biosynthesis of Membrane Phospholipds

Lipid Biosynthesis Biosynthesis of Membrane Phospholipds Glycerophospholipid Biosynthesis requires Attach head group by condensation here: Activation by CTP • Begin with phosphatidic acid (microorganisms) or 1,2 Diacylglycerol (mammals) • Both activate precursors using CTP • Bacteria use phosphatidate and attach head group to C-3 phosphate group mammals bacteria – Make CDP-diacylglycerol from CTP and phosphatidic acid • Mammals use CDP-alcohol and attach Example: head group to diacylglycerol – Make CDP-alcohol from CTP and choline or ethanolamine 1 Lipid Biosynthesis Synthesis of Phosphatidylcholine, -ethanolamine, and serine and in Mammals • Either one of the alcohols is activated by attaching to CDP. Mammals use CDP-alcohol • CDP-alcohol is used to couple this to diacylglycerol • Phosphatidyl-serine is made “backwards” from phosphatidyl-ethanolamine or phosphatidyl-choline via head-group exchange reactions. • catalyzed by specific synthases • pathway “salvages” the choline Lipid Biosynthesis Synthesis of Phosphatidylcholine, -ethanolamine, and serine and in Mammals • Either one of the alcohols is activated by attaching to CDP. Mammals use CDP-alcohol • CDP-alcohol is used to couple this to diacylglycerol • Phosphatidyl-serine is made “backwards” from phosphatidyl-ethanolamine or phosphatidyl-choline via head-group exchange reactions. • catalyzed by specific synthases • pathway “salvages” the choline 2 Lipid Biosynthesis Synthesis of Phosphatidyl-choline, -ethanolamine, -serine, -inositol, and -diglycerol in Yeast “Bacterial” pathways “Mammalian” pathways Head-group exchange reactions that interconvert PE, PS, & PC in mammals are not shown. Lipid Biosynthesis Synthesis of Sphingolipids dihydroceramide desaturase 1 O2 2H2 O • Sphingosine comes from amino acids + fatty acids; serine + palmitate • Condensation of palmitoyl-CoA and serine, forms β-ketosphinganine • Reduction, acylation, oxidase yields N-acylsphinganine (a ceramide). 3 Lipid Biosynthesis Synthesis of Sphingolipids dihydroceramide desaturase 1 O2 2H2 O • Sphingosine comes from amino acids + fatty acids; serine + palmitate • Condensation of palmitoyl-CoA and serine, forms β-ketosphinganine • Reduction, acylation, oxidase yields N-acylsphinganine (a ceramide). ANABOLISM II: Biosynthesis of Fatty Acids & Lipids Lipid Biosynthesis Fatty Acid Synthesis Isoprene Biosynthesis Fat Catabolism Fatty Acid Degradation Ketone body Utilization 4 ANABOLISM II: Biosynthesis of Fatty Acids & Lipids 1. Biosynthesis of fatty acids 2. Regulation of fatty acid degradation and synthesis 3. Assembly of fatty acids into triacylglycerol and phospholipids 4. Metabolism of isoprenes a. Ketone bodies and Isoprene biosynthesis b. Isoprene polymerization i. Cholesterol ii. iii. Steroids & other molecules Regulation iv. Role of cholesterol in human disease Cholesterol and Steroid Biosynthesis Fates of Acetyl CoA (HMG-CoA) Amino acid (L) Importance of cholesterol: Dr. Kornberg: Lecture 04.05.17 (12:0117:12) 5 min Amino acids 1. Oxidation to CO2 2. Lipid metabolism 3. Amino acid metabolism • Nearly all the remaining lipids have a chemical relationship, and their biosynthesis are built on, the 5-carbon isoprene unit • Isoprene is made through the intermediate, mevalonate 1912-2000 Nobel Prize 1964 5 Cholesterol and Steroid Biosynthesis “Fat burns in the flame of sugar” Fatty Acids NADH Acetyl-CoA NADH FADH2 Pyruvate Pyruvate CO2 Ketone Bodies Citrate Oxaloacetate Malate Isocitrate a -Ketoglutarate Fumarate Succinyl-CoA Succinate Cholesterol and Steroid Biosynthesis Ketone Body Biosynthesis • The first step is reverse of the last step in the b oxidation: thiolase reaction joins two acetate units. • A second step incorporates a third acetyl-CoA. • Together, two CoASH are freed from three acetyl-CoA. • In the liver, this synthesis occurs regardless of excess acetyl-CoA • HMG-CoA is a metabolic junction 6 Cholesterol and Steroid Biosynthesis Ketone Body Biosynthesis • The first step is reverse of the last step in the b oxidation: thiolase reaction joins two acetate units. • A third acetyl-CoA is incorporated in the second step. • Together, two CoASH are freed from three acetyl-CoA. • In the liver, this synthesis occurs regardless of excess acetyl-CoA • HMG-CoA is a metabolic junction Cholesterol and Steroid Biosynthesis Ketone Body Biosynthesis • In order to traffic to other tissues, CoA must be removed. This is done by removing as acetyl-CoA leaving Acetoacetate. This along with Acetone and b-hydroxybutyrate can then travel through the blood to other tissues for energy (catabolism). Ø In the mitochondria • Acetone is removed as a gas and exhaled (although some species or tissues can metabolize acetone), but acetoacetate and b-hydroxybutyrate can traffic to the heart, kidney, muscle, and adapted brain for use in energy production. HMG-CoA & ketone bodies: Dr. Kornberg: Lecture 03.01.17 (27:35-32:16) 4.5 min 7 Cholesterol and Steroid Biosynthesis Ketone Body Biosynthesis • In order to traffic to other tissues, CoA must be removed. This is done by removing as acetyl-CoA leaving Acetoacetate. This along with Acetone and b-hydroxybutyrate can then travel through the blood to other tissues for energy (catabolism). Ø In the mitochondria • Acetone is removed as a gas and exhaled (although some species or tissues can metabolize acetone), but acetoacetate and b-hydroxybutyrate can traffic to the heart, kidney, muscle, and adapted brain for use in energy production. HMG-CoA & ketone bodies: Dr. Kornberg: Lecture 03.01.17 (27:34-32:16) 4.5 min ANABOLISM II: Biosynthesis of Fatty Acids & Lipids 8 Cholesterol and Steroid Biosynthesis Liver as a fuel source: Ketone Bodies & Glucose This all occurs in the liver mitochondria ANABOLISM II: Biosynthesis of Fatty Acids & Lipids Lipid Biosynthesis Fatty Acid Synthesis Isoprene Biosynthesis Fat Catabolism Fatty Acid Degradation Ketone body Utilization 9 Cholesterol and Steroid Biosynthesis IN THE CYTOSOL Formation of Mevalonate from HMG-CoA • HMG-CoA (from 3 acetyl-CoAs) is reduced to form mevalonate. • HMG-CoA reductase is a common target of cholesterol-lowering drugs; called Statins Cholesterol and Steroid Biosynthesis Mevalonate to Activated Isoprenes • Two phosphates are transferred stepwise from ATP to mevalonate. • A third phosphate from ATP is added at the hydroxyl, followed by decarboxylation and elimination catalyzed by pyrophosphomevalonate decarboxylase creates a diphosphorylated 5-C product; D3-isopentyl pyrophosphate (IPP) (isoprene). • Isomerization to a second isoprene dimethylallylpyrophosphate (DMAPP) gives two activated isoprene compounds that act as precursors for all of the other lipids in this class D 3-isopentyl pyrophosphate Isopentyl-D-pyrophosphate isomerase 10