Lecture 16 (2009)

Lecture 16 (2009) - Lecture 16 Finish lipid metabolism...

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Unformatted text preview: Lecture 16 Finish lipid metabolism (Triglycerides, Isoprenoids/Steroids, Glyoxylate cycle) cycle Amino acid metabolism (Urea cycle) cycle Google Man III The "Powertrain" of Human Metabolism (Overview) CARBOHYDRATES PROTEINS LIPIDS Glucose Amino acids Fatty acids Other Carbohydrates Oxaloacetate -Oxidation Fatty Acid Synthesis Glycogen Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Ketogenesis Lactate Ketone bodies Ribose-5-P NADPH NADH Cholesterol p. 21 Biosynthesis of Fatty Acids Carbohydrates Proteins PEP Pyruvate Fatty Acids Acetyl-CoA Pyrimidine Bases Acetyl-CoA (cytosol) Oxalaoacetate Citrate Thr Asp Ile Met Lys Asn Malate TCA Cycle Isocitrate Glutathione -Ketoglutarate Fumarate Glu Ornithine Succinyl-CoA Pro Gln Arg Porphyrines Purine Bases Heme Chlorophyll Vitamin B12 Review The Citrate Shuttle Mitochondrial Membrane inner outer MATRIX CYTOSOL Acetyl CoA 1 CITRATE CITRATE ATP OAA 5 7 6 MALATE 2 ADP OAA 3 MALATE NADP+ 4 NADPH + H+ PYRUVATE PYRUVATE CO2 HPO43Acetyl CoA CoA NADH NAD+ Fatty acid synthesis p. 76 PPP Review Fatty Acid Biosynthesis I. Activation of Acetyl-CoA Acetyl-CoA + CO2 + ATP Malonyl-CoA + ADP + Pi Acetyl-CoA Carboxylase Review II. Biosynthesis (Fatty Acid Synthase Complex) 1. Condensation (Malonyl-CoA CO2) 2. Reduction (+ NADPH) 3. Dehydration ( H2O) 4. Reduction (+ NADPH) Acyl(C+2)-ACP Typically stops at Palmitoyl-CoA (16:0) Review Regulation of Acetyl-CoA Carboxylase ATP (+) AMP (-) ATP ADP Protein kinase Acetyl CoA Carboxylase (active) (+) Citrate (-) Palmitoyl CoA Acetyl CoA Carboxylase (inactive) Acetyl CoA Carboxylase (partially active) Phosphatase HPO43- H2O p. 83 Regulation of Acetyl-CoA Carboxylase Acetyl-CoA Carboxylase Dephosphorylated Activity Highly phosphorylated Citrate Concentration p. 83 Reciprocal Regulation of Synthesis and Degradation Acyl-CoA Cytosol Carnitine acyltransferase I Mitochondria Acetyl-CoA + CO2 + ATP Malonyl-CoA + ADP + Pi Fatty Acid Synthesis Acyl-CoA Cytosol Biosynthesis of Unsaturated Fatty Acids O H3C 18 12 9 1 C SCoA Plants, but not humans, have enzymes that introduce double bonds at n>9 Mammals have enzymes that can introduce double bonds at n<9 Essential fatty acids for humans: Linoleic acid 18 H3C 12 9 O 1 C Linolenic acid O18 H3C 15 12 9 1 O C O- Introduction of a double bond by "desaturases" Mammals convert linoleic acid to arachidonic acid: Desaturase 18 H3C 12 9 6 O CSCoA H H C--C H H C=C H H O=O NADPH/H+ H2O H2O NADP+ Elongation 20 H3C 14 11 8 O CSCoA Mixed-function Oxidases Desaturase Arachidonoyl CoA 20 H3C 14 11 8 5 O CSCoA 20:4 (5,8,11,14) Omega-6 family Cyclooxygenase (COX1) Cyclization Leukotriene Aspirin Prostaglandins Non-specific COX Inhibitors Specific COX-2 Inhibitors COX-1 COX-2 Synthesis of Phospholipids and Triglycerides CH2OH O CH2OPO3 2- DHAP NADH + H+ Glycerol-3-P dehydrogenase NAD+ CH2OH HO H CH2OPO32O R1 C SCoA Glycerol-3-P Glycerol-3-P acyltransferase CoASH O CH2O HO H CH2OPO32R2 O C SCoA C R1 Lysophosphatidic Acid Glycerol-3-P acyltransferase CoASH O O R2 C O CH2O H CH2OPO32C R1 Phosphatidic Acid p. 84 Synthesis of Phospholipids and Triglycerides CoASH O O R2 C O CH2O H CH2OPO32C R1 Phosphatidic Acid Phosphatase O O R2 C O CH2O H CH2OH O O R2 C O CH2O H CH2O C O C R3 R1 C R1 R3 O C SCoA Diglyceride acyltransferase CoASH Diacylglycerol Phospholipids Triacylglycerol p. 84 Ethyl alcohol NADPH Mitochondrial Membrane inner outer NADH Acetaldehyde MATRIX NADPH CYTOSOL NADH Acetate Acetyl CoA 1 CITRATE CITRATE ATP OAA 5 7 6 MALATE 2 ADP OAA 3 MALATE HPO43Acetyl CoA CoA Acetyl-CoA NADH NAD+ NADP+ Fatty acid synthesis 4 NADPH + H+ PYRUVATE PYRUVATE CO2 Fatty Acid Synthesis Fatty Liver Synthesis of Isoprenoids and Steroids Acetyl-CoA Acetoacetyl-CoA HMG-CoA Lyase HMG- HMG-CoA Lovastatin HMG-CoA Reductase HMG- Ketone Bodies Mevalonic Acid (4 steps) P P Dimethylallyl-PP (DMAPP) (C5) P P Isopentenyl-PP (IPP) p. 85 Synthesis of Isoprenoids and Steroids PPi + P P DMAPP + IPP P P P P Geranyl pyrophosphate (C10) H Farnesyl pyrophosphate (C15) H H HO Cholesterol Squalene (C30) (many steps) Cholesterol (C27) p. 85 Important Isoprenoids p. 86 The Glyoxylate Cycle (Bacteria, Fungi, Plants) 2 Acetyl-CoA + NAD+ + 2H2O Succinate + NADH + 2 CoA In Humans: No Gluconeogenesis from Acetyl-CoA Protein Pyruvate Irreversible CO2 Gluconeogenesis Acetyl-CoA Fatty Acids Glucose Oxalaoacetate Citrate Malate TCA Cycle Isocitrate Irreversible Fumarate -Ketoglutarate CO2 Succinyl-CoA Irreversible CO2 Glyoxylate Cycle versus TCA Cycle CoA-SH + H+ 1. Acetyl-CoA ACETYL-CoA O C ScoA H3C H2O CH2COOHO COOCH2COOCITRATE H2O CH2COOC COOCHCOO - H2O 2 2 1 CH2COOH COOHC COOOH NAD ISOCITRATE cis-aconitate enzyme-bound O C COO H2C COO- 3 NADH + H CO2 OXALOACETATE NADH + H+ 8 NAD HOOC-CHO A. CH2COOH H C COOO -KETOGLUTARATE COO HO C H H C H COOMALATE - 4 NAD + CoA-SH NADH + H + CO2 B. 7 H 2. Acetyl-CoA H2O -OOC C C COOH FADH2 6 COOCH2 CH2 COOFAD SUCCINATE CoASH 5 CH2COOH H C ScoA O GTP GDP + Pi SUCCINYL-CoA FUMARATE Unique Reactions of Glyoxylate Cycle A. Isocitrate Lyase Isocitrate Succinate + Glyoxylate HOOC-CHO B. Malate Synthase Glyoxylate + Acetyl-CoA + H2O Malate + CoA-SH Eukaryotic Glyoxylate Cycle (Plants, Fungi) Triacylglycerols Carbohydrates Lipid Bodies Fatty acids Gluconeogenesis Glucose OAA Fatty acids Malate Cytosol Acetyl-CoA OAA Citrate Malate OAA Acetyl-CoA Malate Glyoxylate Cycle Isocitrate Fumarate TCA Cycle Citrate Acetyl-CoA Glyoxylate Succinate Succinate Glyoxysome Mitochondrion p. 87 Last Diet Change ... CARBOHYDRATES PROTEINS LIPIDS Glucose Amino acids Fatty acids Other Carbohydrates Oxaloacetate Glycogen Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Lactate Ketone bodies Ribose-5-P NADPH NADH Cholesterol p. 21 CARBOHYDRATES Glucose-6-P Pyruvate Acetyl-CoA NADH ATP CARBOHYDRATES Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Excess Calories Glycogen Triacylglycerides CARBOHYDRATES LIPIDS Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Excess Calories Glycogen Triacylglycerides CARBOHYDRATES LIPIDS Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Excess Calories Glycogen Triacylglycerides PROTEINS CARBOHYDRATES LIPIDS Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Excess Calories Glycogen Triacylglycerides PROTEINS Amino Acids Ammonia (NH4+) Urea CARBOHYDRATES Carbon Skeleton LIPIDS Oxaloacetate Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Excess Calories Glycogen Triacylglycerides PROTEINS Skeletal Muscle Amino Acids Ammonia (NH4+) Urea CARBOHYDRATES Carbon Skeleton LIPIDS Oxaloacetate Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Excess Calories Glycogen Triacylglycerides "I'll be baaack!" Viewers Discretion Is Advised "Oh, my back ..." Downh ill PROTEINS Skeletal Muscle Amino Acids Ammonia (NH4+) Urea CARBOHYDRATES Carbon Skeleton LIPIDS Oxaloacetate Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Excess Calories Glycogen Triacylglycerides Dietary Poteins Degradation Proteases, Peptidases Dietary Protein (e.g., Trypsin, Pepsin) Amino Acids Blood Liver Hepatocytes (Cytosol) Aminotransferases Amino Acidx + -KGA (PLP-dependent) -Keto Acidx + Glu From and To Mitochondria Aminotransferases = Transaminases O R1 CH NH3 C OR2 C O O C O- Amino Acid (1) -Ketoacid (2) PLP O R1 C O C OR2 CH NH3 COO - -Ketoacid (1) Amino Acid (2) p. 53 Pyridoxal Phosphate Coenzyme of Aminotransferases H R1 2HC O 3POH2C O N OH AA 1 H 2O CH R CH3 N H CH3 H+ OH C COO - N H 1/2 of AT Reaction NH2 CH2 R OH R1 N H CH3 C N CH2 H+ OH CH3 CH R OH COO N R1 C COO - Keto acid H 2O R N H CH3 N H To complete reaction and regenerate PLP, reverse the reactions p. 52 Proteases, Peptidases Dietary Protein (e.g., Trypsin, Pepsin) Amino Acids Blood Liver Hepatocytes (Cytosol) Aminotransferases Amino Acidx + -KGA (PLP-dependent) -Keto Acidx + Glu From and To Mitochondria Electron Shuttles Malate-Oxaloacetate Shuttle Cytosol ASP KGA GLUTAMATE OAA NADH + H+ NAD+ MALATE Outer Inner Membranes Mitochondria ASP KGA GLUTAMATE OAA NADH + H+ NAD+ MALATE p. 50 From cytosol Hepatocytes Glu Dehydrogenase Glu + NAD+ + H2O -KGA + NADH + NH3 Mitochondria Asp Aminotransferase Glu + OAA -KGA + Asp To cytosol Glutamate-Oxaloacetate Aminotransferase (Transaminase) COO- COO- COO- COO- C O CH NH3 CH NH3 C O CH2 CH2 CH2 CH2 COO- CH2 COO- COO- CH2 COO- OAA Aspartate (Asp) Glutamate (Glu) -Ketoglutarate (KGA) p. 51 ...
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This note was uploaded on 09/06/2009 for the course BIS 103 taught by Professor Abel during the Spring '08 term at UC Davis.

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