Lecture 20 Ch 27 28 Fatty Acid Metabolism Fatty acid catabolism oxidation of saturated even C fatty acids and the ATP count oxidation of saturated uneven C fatty acids oxidation of polyunsaturated fatty acids Ketone bodies Fatty acid biosynthesis How the cell ensures supply of the precursors acetyl CoA and NADPH Steps of biosynthesis Overall equation for the synthesis of one molecule of palmitic acid 16 0 Regulation of fatty acid metabolism 1 Triglyceride as Fuel Ester 2 Lipid Degradation 3 4 Hydrolysis Lipolysis of Triacylglycerols in an Adipocyte Adipose cell ATGL albumin FA DAG lipase MAG lipase 5 Glycerol can enter the glycolysis gluconeogenesis pathway 6 7 Fatty Acid Catabolism 1 Activation of Fatty acid with CoA by Acyl CoA synthase on outer membrane of mitochondria 2 Transport of activated fatty acid into mitochondrial matrix via Translocase 3 oxidation cycle of saturated even C fatty acid 4 Catabolism of uneven C saturated fatty acid 5 Catabolism of unsaturated fatty acid double bonds 8 Activation of Fatty acids Acyl CoA synthase Pi orthophosphate PPi pyrophosphate 9 Fatty Acids are linked to Coenzyme A before they are oxidized 10 Long Chain Fatty Acid CoA Synthetase 11 The Acyl CoA Synthetase activates fatty acids for oxidation ATP Acyl CoA AMP P P G for acyl CoA synthesis 31 5 kJ mol AMP PP 32 3 kJ mol Net G 0 8 kJ mol G for ATP 12 Transfer of acyl CoA to inner mitochondrial space Acyl CoA Acyl carnitine 13 14 Transfer of Acyl carnitine from inner mitochondrial space to matrix Acyl CoA 15 oxidation converts the carbon of Fatty acid Chain from reduced to oxidized form oxidation Reduced H H C FAD NAD FADH2 NADH Oxidized O C 16 One cycle of oxidation for saturated FA Acyl CoA ETC trans 2 Enoyl CoA L 3 Hydroxyacyl CoA ETC 3 Ketoacyl CoA Acyl CoA Acetyl CoA 17 Acyl CoA Dehydrogenase Enoyl CoA hydratase 18 Each cycle of oxidation involves four reactions 19 The first two rounds in the degradation of palmitate Last round 7 CoA 20 oxidation Total ATP yield on complete oxidation of one molecule of palmitic acid 16 carbons Total ATP yield 77 5 22 5 8 2 106 123 H2O 31 NADH x 2 5 ATP NADH 77 5 ATP 15 FADH2 x 1 5 ATP FADH2 22 5 ATP Note Subtracting 2 ATP equivalent that was used up for the fatty acid activation Each round of TCA cycle produces 3 NADH 1 FADH2 and 1 ATP 21 How Are Odd Carbon Fatty Acids Oxidized Some of the intermediate steps require biotin and B12 derivatives 22 Propionyl CoA carboxylase bicarbonate ATP Proprionyl CoA carboxyphosphate Biotin 23 Methylmaolyl CoA Methylmalonyl CoA Epimerase D Methylmalonyl CoA Resonance stabilized carbanion intermediate L Methylmalonyl CoA 24 Methylmalonyl CoA Mutase Cobalamin Vit B12 25 Fatty acids can be Saturated or Unsaturated Saturated Mono or poly Unsaturated Tail has only single C C bonds One or more C C bonds in the tail are double bonds 16 0 18 2 26 1 2 3 Hydrate Oxidize Thiolase 27 cis 3 Enoyl CoA Isomerase 28 Acyl CoA Dehydrogenase Glutamate 29 2 4 Dienoyl CoA Reductase NADPH 30 Fatty acid breakdown lipolysis TG FA lipase stimulated by glucagon and epinephrine inhibited by insulin FA 1 Coupled to CoA acyl CoA needs ATP PPi Acyl CoA synthetase 2 Transported into mitochondrial matrix carnitine transporter 3 oxidation separate enzymes in mitochondrial matrix oxidation FADH2 hydration oxidation NADH cleavage acetyl CoA acyl CoA TCA even double bond two steps 2 4 Dienoyl CoA reductase Another round of oxidation odd double bond one step cis 3 enoyl CoA isomerase31 Ketone and diabetes 32 Ketone Bodies B hydroxybutyrate dehydrogenase Thiolase HMG CoA synthase HMG CoA lyase 33 Diabetic ketosis results when insulin is absent 34 Fatty Acid Metabolism Fatty acid catabolism Fatty acid anabolism 1 Intermediates are linked covalently to the SH group of CoA 1 Intermediates are linked covalently to the SH group of Acyl Carrier proteins ACPs 2 Occurs in the mitochondrial matrix 2 Occurs in the cytosol 3 Enzymes of fatty acid breakdown are all separate proteins 3 All enzymes except for one required to synthesize a molecule of fatty acid are components different domains of one long polypeptide chain called Fatty Acid Synthase FAS 1 The coenzyme for oxidationreduction reactions is the NAD NADH couple 4 The coenzyme for oxidationreduction reactions is the NADP NADPH couple 35 Fatty Acid Synthesis takes place in 3 stages Step 1 Preparatory step transfer of acetyl CoA from mitochondria to cytoplasm Step 2 Activation of acetyl CoA acetyl CoA converted to malonyl CoA Steps 3 7 Fatty acid synthesis Synthesis occurs on an acyl carrier protein a molecular scaffold 36 Fatty acid biosynthesis depends on acetyl CoA cytosolic 37 Step 2 Acetate Units Are Committed to Fatty Acid Synthesis by Formation of Malonyl CoA The acetyl CoA carboxylase ACC reaction Acetyl CoA Malonyl CoA 38 Step 2 Part 1 The Carboxylation of Biotin carbonylphosphate intermediate Biotin Enzyme ATP HCO3 CO2 Biotin ADP Pi H 39 Step 2 Part 2 The transcarboxylation Reaction Acetyl CoA Malonyl CoA CO2 Biotin Enzyme acetyl CoA malonyl CoA Biotin Enyzme 40 Step 3 acetyl and malonyl units are transferred from CoA to Acyl Carrier Protein ACP Catalyzed by the enzyme malonyl CoA acetyl CoA transacylase MAT Acetyl CoA ACP Acetyl ACP CoA Malonyl CoA ACP Malonyl ACP CoA 41 Step 4 Condensation of Acetyl ACP and Malonyl ACP Ketoacyl synthase KS 42 Step 5 Reduction of the keto group to form a OH group Ketoacyl reductase KR 43 Step 6 Dehydration 3 Hydroxyacyl dehydratase DH 44 Step 7 Reduction to saturate the fatty acid chain Enoyl reductase ER 45 Step 8 Condensation of Acyl ACP and Malonyl ACP Acyl such as butyryl ACP Ketoacyl synthase KS Ketoacyl Repeat Steps 8 5 6 and 7 until a 16 C fatty acid chain is formed 46 The thioesterase acts as a ruler to determine fatty acid length 47 Fatty acid Synthesis All enzymatic activity part of the same protein 1 Acetyl CoA matrix OAA citrate cytoplasm 2 Acetyl CoA ATP malonyl CoA 3 Acetyl CoA acetyl ACP Malonyl CoA Malonyl ACP 4 Condensation Acetyl Acyl ACP malonyl ACP ketoacyl ACP CO2 KS 5 Reduction NADPH KR 6 Dehydration DH 7 Reduction Acyl ACP 2 Cs ER 1 Continue steps 5 7 until reach 16 carbons 8 Cleave of ACP from 16 C fatty acid chain TE 48 Overall equation for synthesis of a molecule of palmitic acid Acetyl CoA 7 malonyl CoA 14 NADPH 7H 2 C 7 x 3 C Palmitoly 16 C 7 CO2 14 NADP 8 CoA 6 H2O Formation of 7 molecules of malonyl CoA requires 7 acetyl CoA 7 CO2 7 ATP 7 malonyl CoA 7 ADP 7 Pi 7 H Adding the above two reactions gives the overall equation for
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