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 β-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 α-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
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 Review
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 (Δ( 5,8,11,14 ) mega-6 6 family Aspirin Cyclization Leukotriene Prostaglandins Review
Non-specific CX Inhibitors
Specific CX-2 2 Inhibitors CX-1 CX-2
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 Carnitine acyltransferase I Mitochondria Acetyl-CoA + C 2 + ATP Malonyl-CoA + ADP + Pi Fatty Acid Synthesis Acyl-CoA
Synthesis of Phospholipids and Triglycerides H P 2-3 Glycerol-3-P dehydrogenase H H H NADH + H + NAD + DHAP Glycerol-3-P P 3 2- Glycerol-3-P acyltransferase R 1 C SCoA CoASH C R 1 H H Lysophosphatidic Acid P 3 2- R 2 C SCoA Glycerol-3-P acyltransferase CoASH R 2 C C H P 2-3 R 1 Phosphatidic Acid p. 84
Synthesis of Phospholipids and Triglycerides CoASH R 2 C H C R 1 Phosphatidic Acid 2- P 3 Phosphatase R 2 C H H C R 1 R 3 C SCoA Diglyceride acyltransferase CoASH Diacylglycerol R 2 C H C R 1 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 α-ketoglutarate Irreversible C 2 Succinyl-CoA Irreversible C 2
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
Glyoxylate Cycle versus TCA Cycle 1. Acetyl-CoA ACETYL-CoA H 3 C C ScoA CH C - CoA-SH + H + C - H 2 H 2 C - H 2 H C - C C - H 2 C - 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 C - H C C - α-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 - C - CoASH 5 GTP GDP + Pi H 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
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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Downhill
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) + α-kga α-keto Acid x + Glu From and To Mitochondria
Glutamate-xaloacetate Aminotransferase (Transaminase) C - C - C - C - C CH NH 3 CH NH 3 C C - C - AA C - Aspartate (Asp) C - Glutamate (Glu) α-ketoglutarate (KGA) p. 51
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 N H H CH 3 α Keto acid R R 1 C C - N 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
Aminotransferases = Transaminases R 1 CH C - R 2 C C - NH 3 Amino Acid (1) α-ketoacid (2) PLP R 1 C C - R 2 CH C - α-ketoacid (1) NH 3 Amino Acid (2) p. 53
Malate-xaloacetate Shuttle Electron Shuttles Cytosol ASP αkga GLUTAMATE Mitochondria ASP αkga GLUTAMATE AA NADH + H + NADH + H + AA MALATE NAD + NAD + MALATE uter Inner Membranes p. 50
Dietary Protein Proteases, Peptidases (e.g., Trypsin,, Pepsin) Amino Acids Blood Liver Hepatocytes (Cytosol) Amino Acid x Aminotransferases (PLP-dependent) + α-kga α-keto Acid x + Glu From and To Mitochondria
From cytosol Hepatocytes Glu Dehydrogenase Glu + NAD + + H 2 α-kga + NADH + NH 3 Asp Aminotransferase Glu + AA α-kga + Asp Mitochondria To cytosol
D. Positively Charged R-Groups Amino Acids H 2 N CH C H H 2 N CH C H H 2 N CH C H N NH NH Histidine His, H C NH NH 2 Arginine Arg R NH 2 Lysine Lys, K E. Negatively Charged R-Groups H 2 N CH C H H 2 N CH C H C H Aspartate Asp, D C H Glutamate Glu, E p. 13
Amino Acid Degradation (Urea Cycle) GLU + NAD + 1 + H αkga + NADH + H + 2 + NH 3 NH 3 + HC 3- + 2 ATP 2 3-2 ADP + HP 4 + 2-3 P C NH 2 Carbamoyl-P p. 88
2-3 P C NH 2 3 The Urea Cycle NH 2 C HP 4 3- NH Citrulline rnithine H H 2 NH 2 C C - NH 3 + 6 H 2 N UREA C NH 2 H C C - NH 3 + 4 ATP Aspartate AMP + PPi Arginine H 2 N H C NH 2 + NH C C - NH 3 + C - HC CH C - 5 Fumarate HN C NH H C C - NH 3 + NH 2 + C - CH C - Argininosuccinate p. 88
Urea Cycle Net Reaction ATP Requirement NH 3 + HC - 3 + Asp + 3ATP Urea + Fumarate + 2ADP + AMP + 4Pi (4 P~bonds cleaved = 44 ATP ) But NADH Generation Glu + NAD + + H 2 α-kga + NADH + NH 3 Malate + NAD + AA + NADH 6 ATP (ETC) Net Gain of 2ATP/Urea