Lecture 16 Finish lipid metabolism (Triglycerides, Isoprenoids/Steroids, Glyoxylate cycle) Amino acid metabolism (Urea cycle) Google Man III
The Powertrain of Human Metabolism (verview) CARBHYDRATES PRTEINS LIPIDS Glucose Amino acids Fatty acids ther Carbohydrates xaloacetate -xidation Fatty Acid Synthesis Glycogen Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Ketogenesis Lactate Ketone bodies Ribose-5-P Cholesterol NADPH NADH p. 21
Biosynthesis of Fatty Acids Carbohydrates Proteins PEP Pyruvate Fatty Acids Acetyl-CoA Pyrimidine Bases Acetyl-CoA (cytosol) Thr Asp xalaoacetate Citrate Ile Met Asn Malate TCA Cycle Isocitrate Glutathione Lys Fumarate -Ketoglutarate Glu rnithine Succinyl-CoA Pro Gln Arg Porphyrines Purine Bases Heme Chlorophyll Vitamin B 12 Review
The Citrate Shuttle MATRIX Mitochondrial Membrane inner outer CYTSL Acetyl CoA 1 CITRATE CITRATE ATP CoA AA 2 7 6 5 MALATE AA 3 MALATE ADP NADH NAD + NADP + HP 4 3- Fatty acid synthesis Acetyl CoA 4 PYRUVATE NADPH + H + PYRUVATE C 2 p. 76 PPP Review
Fatty Acid Biosynthesis I. Activation of Acetyl-CoA Acetyl-CoA + C 2 + ATP Malonyl-CoA + ADP + Pi Acetyl-CoA Carboxylase Review
II. Biosynthesis (Fatty( Acid Synthase Complex) 1. Condensation (Malonyl( Malonyl-CoA C 2 ) 2. Reduction (+ NADPH) 3. Dehydration ( ( H 2 ) 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 (+) Citrate (-) Palmitoyl CoA Acetyl CoA Carboxylase (active) Acetyl CoA Carboxylase (inactive) Acetyl CoA Carboxylase (partially active) Phosphatase HP 3-4 H 2 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 + C 2 + ATP Malonyl-CoA + ADP + Pi Fatty Acid Synthesis Acyl-CoA Cytosol
Biosynthesis of Unsaturated Fatty Acids 18 12 9 1 H 3 C 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 Linolenic acid 18 12 9 1 18 15 12 9 1 C H 3 C - H 3 C C - Introduction of a double bond by desaturases
Mammals convert linoleic acid to arachidonic acid: Desaturase H H C C H H = NADPH/H + 18 H 3 C 12 9 6 Elongation CSCoA C=C H H H 2 H 2 Mixed-function xidases NADP + 20 14 11 8 H 3 C CSCoA Arachidonoyl CoA 20 H 3 C Cyclooxygenase (CX1) 14 Desaturase 11 8 5 CSCoA 20:4 ( ( 5,8,11,14 ) mega-6 6 family Aspirin Cyclization Leukotriene Prostaglandins
Non-specific CX Inhibitors
Specific CX-2 2 Inhibitors CX-1 CX-2
Synthesis of Phospholipids and Triglycerides CH 2 H CH 2 P 2-3 Glycerol-3-P dehydrogenase CH 2 H H H NADH + H + NAD + DHAP Glycerol-3-P CH 2 P 3 2- Glycerol-3-P acyltransferase R 1 C SCoA CoASH CH 2 C R 1 H H Lysophosphatidic Acid CH 2 P 3 2- R 2 C SCoA Glycerol-3-P acyltransferase CoASH R 2 C CH 2 C H CH 2 P 2-3 R 1 Phosphatidic Acid p. 84
Synthesis of Phospholipids and Triglycerides CoASH R 2 C CH 2 H C R 1 Phosphatidic Acid 2- CH 2 P 3 Phosphatase R 2 C CH 2 H CH 2 H C R 1 R 3 C SCoA Diglyceride acyltransferase CoASH Diacylglycerol R 2 C CH 2 H C R 1 CH 2 C R 3 Phospholipids Triacylglycerol p. 84
Ethyl alcohol MATRIX Mitochondrial Membrane inner outer NADPH NADPH CYTSL NADH NADH Acetaldehyde Acetate Acetyl CoA 1 CITRATE CITRATE ATP CoA Acetyl-CoA AA 2 7 6 5 MALATE AA 3 MALATE ADP NADH NAD + NADP + HP 4 3- Fatty acid synthesis Acetyl CoA 4 PYRUVATE NADPH + H + PYRUVATE C 2 Fatty Acid Synthesis
Fatty Liver
Synthesis of Isoprenoids and Steroids Acetyl-CoA Acetoacetyl-CoA HMG-CoA HMG-CoA Lyase Ketone Bodies Lovastatin HMG-CoA Reductase Mevalonic Acid (4 steps) P P Dimethylallyl-PP (DMAPP) (C5) P P Isopentenyl-PP (IPP) p. 85
Synthesis of Isoprenoids and Steroids P P PPi + + P P DMAPP IPP P P Geranyl pyrophosphate (C10) H Farnesyl pyrophosphate (C15) H H H Cholesterol Squalene (C30) (many steps) Cholesterol (C27) p. 85
Important Isoprenoids p. 86
The Glyoxylate Cycle (Bacteria, Fungi, Plants) 2 Acetyl-CoA + NAD + + 2H 2 Succinate + NADH + 2 CoA
In Humans: No Gluconeogenesis from Acetyl-CoA Protein Pyruvate Gluconeogenesis Acetyl-CoA Irreversible C 2 Fatty Acids Glucose xalaoacetate Citrate Malate Fumarate TCA Cycle Isocitrate -Ketoglutarate Irreversible C 2 Succinyl-CoA Irreversible C 2
Glyoxylate Cycle versus TCA Cycle 1. Acetyl-CoA ACETYL-CoA H 3 C C ScoA CH C - CoA-SH + H + CH 2 C - H 2 H 2 CH 2 C - H 2 H C - C C - H 2 C - CH 2 C - 2 CHC - 2 HC C - 1 CITRATE H cis-aconitate enzyme-bound NAD ISCITRATE CC - H 2 C C - 3 NADH + H C 2 NADH + H + XALACETATE 8 HC-CH CH A. H CH 2 C - H C C - -KET- GLUTARATE NAD H H C - C H C H C - B. 4 NAD + CoA-SH NADH + H + C 2 MALATE 2. Acetyl-CoA 7 H 2 H C C -C C - H FADH 2 6 FAD C - CH 2 CH 2 C - CoASH 5 GTP GDP + Pi H CH 2 C - C H ScoA FUMARATE SUCCINATE SUCCINYL-CoA
Unique Reactions of Glyoxylate Cycle A. Isocitrate Lyase Isocitrate Succinate + Glyoxylate HC-CH CH B. Malate Synthase Glyoxylate + Acetyl-CoA + H 2 Malate + CoA-SH
Eukaryotic Glyoxylate Cycle (Plants, Fungi) Triacylglycerols Carbohydrates Lipid Bodies Fatty acids Glucose Fatty acids Gluconeogenesis AA Acetyl-CoA Cytosol Malate AA Citrate Malate AA Acetyl-CoA Malate Glyoxylate Cycle Isocitrate Fumarate TCA Cycle Citrate Acetyl-CoA Glyoxylate Succinate Succinate Glyoxysome Mitochondrion p. 87
Last Diet Change CARBHYDRATES PRTEINS LIPIDS Glucose Amino acids Fatty acids ther Carbohydrates xaloacetate Glycogen Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Lactate Ketone bodies Ribose-5-P Cholesterol NADPH NADH p. 21
CARBHYDRATES Glucose-6-P Pyruvate Acetyl-CoA NADH ATP
CARBHYDRATES Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Excess Calories Glycogen Triacylglycerides
CARBHYDRATES LIPIDS Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Excess Calories Glycogen Triacylglycerides
CARBHYDRATES LIPIDS Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Excess Calories Glycogen Triacylglycerides
PRTEINS CARBHYDRATES LIPIDS Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Excess Calories Glycogen Triacylglycerides
PRTEINS Amino Acids Ammonia (NH 4+ ) Urea CARBHYDRATES Carbon Skeleton LIPIDS xaloacetate Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Excess Calories Glycogen Triacylglycerides
PRTEINS Skeletal Muscle Amino Acids Ammonia (NH 4+ ) Urea CARBHYDRATES Carbon Skeleton LIPIDS xaloacetate Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Excess Calories Glycogen Triacylglycerides
I ll be baaack!
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PRTEINS Skeletal Muscle Amino Acids Ammonia (NH 4+ ) Urea CARBHYDRATES Carbon Skeleton LIPIDS xaloacetate Glucose-6-P Pyruvate Acetyl-CoA NADH ATP Excess Calories Glycogen Triacylglycerides
Dietary Poteins Degradation
Dietary Protein Proteases, Peptidases (e.g., Trypsin,, Pepsin) Amino Acids Blood Liver Hepatocytes (Cytosol) Amino Acid x Aminotransferases (PLP-dependent) + -KGA -Keto Acid x + Glu From and To Mitochondria
Aminotransferases = Transaminases R 1 CH C - R 2 C C - NH 3 Amino Acid (1) -Ketoacid (2) PLP R 1 C C - R 2 CH C - -Ketoacid (1) NH 3 Amino Acid (2) p. 53
Pyridoxal Phosphate Coenzyme of Aminotransferases H R 1 C C - 2-3 PH 2 C HC H AA 1 H 2 R N CH H N H CH 3 1/2 of AT Reaction N H CH 3 H + NH 2 R CH 2 N H H CH 3 Keto acid R R 1 C C - N CH 2 H H + R R 1 C C - N CH H H 2 N H CH 3 N H CH 3 To complete reaction and regenerate PLP, reverse the reactions p. 52
Dietary Protein Proteases, Peptidases (e.g., Trypsin,, Pepsin) Amino Acids Blood Liver Hepatocytes (Cytosol) Amino Acid x Aminotransferases (PLP-dependent) + -KGA -Keto Acid x + Glu From and To Mitochondria
Malate-xaloacetate Shuttle Electron Shuttles Cytosol ASP KGA GLUTAMATE Mitochondria ASP KGA GLUTAMATE AA NADH + H + NADH + H + AA MALATE NAD + NAD + MALATE uter Inner Membranes p. 50
From cytosol Hepatocytes Glu Dehydrogenase Glu + NAD + + H 2 -KGA + NADH + NH 3 Asp Aminotransferase Glu + AA -KGA + Asp Mitochondria To cytosol
Glutamate-xaloacetate Aminotransferase (Transaminase) C - C - C - C - C CH NH 3 CH NH 3 C CH 2 CH 2 CH 2 CH 2 C - CH 2 C - CH 2 AA C - Aspartate (Asp) C - Glutamate (Glu) -Ketoglutarate (KGA) p. 51