Lecture 14 (2009)

Lecture 14(2009) - Midterm 2(in class TUE(5/19 Bring Calculator to Exam Room Assignments(Last Name Initial AN OZ 198 Young Hall 180 Medical

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Unformatted text preview: Midterm 2 (in class), TUE (5/19) Bring Calculator to Exam! Room Assignments (Last Name Initial) AN OZ 198 Young Hall 180 Medical Sciences C Review Sessions Friday (5/15): Monday (5/18): ESSENTIALS Problem Sets Kleiber Hall, 5-7 p.m. Kleiber Hall, 5-7 p.m. posted (3) 4-6 Abel Office Hours: Tomorrow (FRI) (8:30 10 am) (4 5 pm) Lecture 14 Lipid Metabolism -Oxidation of fatty acids Ketogenesis Lipid biosynthesis Activation and Transport of Fatty Acids Fatty Acid Activation (Cytosol) Fatty Acid + CoA + ATP Acyl-CoA + AMP + PPi PPi + H2O 2 Pi Outer Membrane Intermembrane Space Inner Membrane Mitochondrial Matrix Matrix Acyl-CoA Carnitine Transporter Acyl-CoA -Oxidation CoA-SH O-Acyl Carnitine CoA-SH Carnitine acyltransferase I Carnitine acyltransferase II Review I. Fatty Acid Activation (Acyl-CoA) II. Successive -Oxidation of Acyl-CoA 1. Oxidation ( FADH2) 2. Hydration (+ H2O) 3. Oxidation ( NADH) 4. Cleavage (+ CoA, Acetyl-CoA) Acyl(C-2)-CoA Review R Mitochondrial matrix 1 O C S CoA FAD FADH2 O C S CoA -Oxidation of Saturated Fatty Acids Acyl CoA Acyl CoA:FAD oxidoreductase Acyl-CoA Dehydrogenase Acyl- R 2 -OXIDATION H R OH Additional rounds of -oxidation 3 trans-2-enoyl CoA H2O L-3-hydroxyacyl CoA hydro-lyase Enoyl-CoA Hydratase Enoyl- O C S CoA NAD+ NADH + H O C S CoA + L-3()-hydroxyacyl CoA O L-3-hydroxyacyl CoA:NAD+ oxidoreductase -hydroxyacyl-CoA Dehydrogenase hydroxyacyl3 ()-ketoacyl CoA R 4 O R C S CoA + CoA 3-Keto acyl CoA: CoA acyltransferase (Thiolase) Acyl-CoA acetyltransferase Acyl- O H3C C S CoA Acetyl CoA Acyl CoA ( 2 carbons) TCA Cycle Review ATP Yield 148 ATP 2 ATP (fatty acid activation) = 146 ATP per 18:0 8.2 ATP per carbon fatty acid Compare to glucose oxidation: 38 ATP per hexose 6.3 ATP per carbon carbohydrate Water Yield 52 H2O 18 H2O (TCA) 8 H2O (-Oxidation) = 26 H2O per 18:0 ~1.6 g H2O per gram fatty acid Review -Oxidation of Unsaturated Fatty Acids O 12 18 H3C 9 1 C SCoA 3 turns of -oxidation 12 18 H3C 3 Acetyl CoA O 9 7 C SCoA cis-3, cis6 Enoyl CoA isomerase 12 18 H3C 9 7O SCoA H2O 12 -oxidation step 2 (skip step 1) 18 H3C OH C trans-2, cis6 7O C SCoA NAD+ p. 77 -Oxidation of Unsaturated Fatty Acids 12 18 H3C OH + 7O C SCoA NAD 12 -oxidation step 3 18 H3C NADH + H+ O 7 O C SCoA CoA 1 Acetyl CoA O -oxidation step 4 18 H3C SCoA -oxidation step 1 18 H3C FAD FADH2 C O SCoA C trans-2, cis4 p. 77 -Oxidation of Unsaturated Fatty Acids H3C -oxidation step 1 18 H3C FAD FADH2 C O SCoA C trans-2, cis4 2,4-Dienoyl-CoA reductase NADPH + H+ NADP+ O SCoA C 18 H3C trans-3 Enoyl CoA isomerase O 18 H3C -oxidation starting with step 2, SCoA C trans-2 then 4 complete cycles 5 Acetyl CoA p. 77 -Oxidation of Unsaturated Fatty Acids: Summary Linoleic Acid: 18:2 (9,12) after 3 regular rounds of -oxidation O 12 18 H3C 9 7 C SCoA cis-3, cis6 Enoyl CoA isomerase 12 18 H3C 9 7O SCoA H O C trans-2, cis6 -oxidation step 1 18 H3C FAD FADH2 O SCoA C trans-2, cis4 2,4-Dienoyl-CoA reductase NADPH + H+ NADP+ O SCoA C 18 H3C trans-3 Enoyl CoA isomerase cis-3 (or trans-3) trans-2 p. 77 SCoA H3C H2 C C O + HCO3+ Fate of Propionyl-CoA ATP Propionyl CoA 1. HO C H3C C H C O ADP HO O SCoA "Left-over" from the -oxidation of odd-numbered fatty acids L-Methyl malonyl CoA SCoA C O 2. H3C H C C D-Methyl malonyl CoA + HPO42+ O Glucose 3. SCoA H2C C O OH H2 C C O Succinyl CoA PEP + CO2 TCA Cycle PEP-CK OAA "4CO2" p. 78 Robert B. Woodward (Nobel Prize, 1965) Ketogenesis Synthesis of "Ketone Bodies" from Acetyl-CoA under certain physiological and pathological conditions: Starvation Diabetes mellitus Glycogen (muscles, liver) is already depleted ! Starvation Protein Pyruvate Gluconeogenesis Acetyl-CoA Glucose Oxalaoacetate Citrate Malate TCA Cycle Isocitrate Fumarate -Ketoglutarate Succinyl-CoA (Severe) Starvation Protein Ketone Bodies CoA Pyruvate CoA Acetyl-CoA Fatty Acids Fatty Acids Fatty Acids Glucose Oxalaoacetate Citrate FADH2 NADH Malate TCA Cycle Isocitrate ETC Fumarate -Ketoglutarate ATP Succinyl-CoA Google Man II Diabetes mellitus "Excessive excretion of sweet urine" (glucosuria) glucosuria Metabolic disease caused by a deficiency in the secretion or action of insulin (6-10 million in the US) Type I: insufficient insulin production (10% of cases) Type II: insulin-insensitivity (defective response, 90%) Many complications Glycation (non-enzymatic protein modification) Cataracts (glucose sorbitol, rupture of lens cells) sorbitol Excessive and incomplete -oxidation (ketogenesis) ketogenesis Insufficient glucose uptake: cells are "starved" Diabetes mellitus Protein Ketone Bodies CoA Pyruvate CoA Acetyl-CoA Fatty Acids Fatty Acids Fatty Acids Glucose Oxalaoacetate Citrate NADH FADH2 Malate TCA Cycle Isocitrate ETC Fumarate -Ketoglutarate ATP Succinyl-CoA Fate of Excess Acetyl-CoA O 2 x CH3 C SCoA Acetyl CoA CoASH -Ketoacyl thiolase O CH3 C CH2 O C SCoA Acetoacetyl CoA Acetyl CoA HMG-CoA synthase CoASH OH OOC CH2 C CH3 -hydroxy--methyl glutaryl CoA (HMG-CoA) CH2 O C SCoA p. 79 Brain (Starvation) OOC CH2 OH C CH3 CH2 O C SCoA Muscles -hydroxy--methyl glutaryl CoA (HMG-CoA) HMG-CoA lyase Acetyl CoA O OOC CH2 C CH3 CO2 CH3 O C Acetone CH3 Blood NADH + H+ Acetoactetate -Hydroxybutrate dehydrogenase Danger of Acidosis (Ketosis) NAD+ OH CH2 C H CH3 OOC Ketone Bodies Blood -Hydroxybutyrate p. 79 -Hydroxybutyrate Acetoacetate Blood -Hydroxybutyrate NAD+ NADH Acetoacetate Succinyl-CoA Succinate Acetoacetyl-CoA CoA Brain TCA Cycle 2x Acetyl-CoA Cut-off for Second Midterm (show video clip) Lipid Biosynthesis (Cytosol) Biosynthetic Functions of the TCA Cycle PEP Pyruvate Fatty Acids Acetyl-CoA Steroids Pyrimidine Bases Acetyl-CoA (cytosol) Acetyl- Thr Asp Oxalaoacetate Citrate 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 p. 46 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 Pentose-P Pathway p. 80 Biosynthesis of Saturated Fatty Acids Activation of Acetyl-CoA Acetyl-CoA Carboxylase O H3C C S CoA Acetyl CoA H O C C S CoA O + HCO3- + ATP C O- + ADP HPO43- H Malonyl CoA Transfer of Malonyl-CoA onto an "Acyl Carrier Protein (ACP)" H O C OO C C S CoA H Malonyl CoA Malonyll-CoA:ACP transacetylase O H O C C S ACP H + ACP C O- + CoASH p. 81 Transfer of Acetyl-CoA onto a second Acyl Carrier Protein (ACP) O C S CoA Acetyl-CoA:ACP transacetylase H3C + ACP O H3C C S ACP Acetyl ACP + CoASH Acetyl CoA Acyl carrier protein Malonyl-ACP Acetyl-ACP p. 81 Coenzyme A (CoA-SH) NH2 N N N N Pantothenic Acid (Vitamin B5) O O HS CH2 CH2 H N C CH2 CH2 H N O C H C CH3 C CH2 O O P O O CH2 O O P O O O O P OH O OH CH3 Simple Model of the Fatty Acid Synthase Complex Malonyl-ACP Acetyl-ACP -Ketobutyryl-ACP H H3C O C S CoA O + 1 C O- O C C S ACP H -Ketoacyl ACP synthase CO2 CH3 O O C S ACP Use of growing chain instead of acetyl ACP in next rounds 2 Acetoacetyl ACP (Acetoacyl ACP) + NADPH + H NADP + -Ketoacyl ACP reductase OH O H3C C S ACP H 3 CH3 O C S ACP D-3()-hydroxyacyl ACP H2O 3-Hydroxyacyl ACP dehydratase 3 ()-ketoacyl ACP NADPH + H+ 4 NADP+ O C S ACP Enoyl ACP reductase Butyryl ACP p. 79 H H3C O C S CoA O + 1 C O- O C C S ACP H -Ketoacyl ACP synthase CO2 CH3 O O C S ACP Use of growing chain instead of acetyl ACP in next rounds 2 Acetoacetyl ACP (Acetoacyl ACP) + NADPH + H NADP + -Ketoacyl ACP reductase OH O H3C C S ACP H 3 CH3 O C S ACP D-3()-hydroxyacyl ACP H2O 3-Hydroxyacyl ACP dehydratase 3 ()-ketoacyl ACP NADPH + H+ 4 NADP+ O C S ACP Enoyl ACP reductase Butyryl ACP p. 79 I. Activation of Acetyl-CoA (Malonyl-ACP) II. Successive Condensation of Acetyl-Units 1. Condensation ( CO2) 2. Reduction (+ NADPH) 3. Dehydration ( H2O) 4. Reduction (+ NADPH) Acyl(C+2)-ACP Typically stops at 16:0 (Palmitoyl-CoA) Activation 7Acetyl-CoA + 7CO2 + 7ATP 7Malonyl-CoA + 7ADP + 7Pi Biosynthesis (7 rounds) Acetyl-CoA + 7Malonyl-CoA + 14NADPH Palmitoyl-CoA (16:0) + 7CO2 + 7CoA +14NADP+ + 7H2O Sum 8Acetyl-CoA + 7ATP + 14NADPH 16:0 (free acid) + 8CoA + 7ADP + 7Pi + 14 NADP+ + 6H2O ...
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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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