Lecture 20 Chapters 27 28 Fatty Acid Metabolism The hummingbird s tremendous capacity to store and use fatty acids enables it to make migratory journeys of remarkable distances 1 Outline 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 Overview 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 allosteric covalent hormonal 2 Triaglyceride as Fuel Ester O R C OR Triglyceride triacylglycerols 3 Adipocyte 4 Lipid Degradation 5 6 Hydrolysis Lipolysis of Triacylglycerols in an Adipocyte Adipose cell ATGL albumin FA HS lipase glucose MAG lipase 7 Glycerol can enter the glycolysis gluconeogenesis pathway 8 Hydrolysis Lipolysis of Triacylglycerols in an Adipocyte Muscle kidney and heart Adipose cell ATGL albumin FA HS lipase glucose MAG lipase 9 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 10 Activation of Fatty acids Acyl CoA synthase Pi orthophosphate PPi pyrophosphate 11 Fatty Acids are linked to Coenzyme A before they are oxidized 1 2 12 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 13 Transfer of acyl CoA to inner mitochondrial space Acyl CoA Acyl carnitine 14 Fig 23 8a p 703 Transfer of Acyl carnitine from inner mitochondrial space to matrix Acyl carnitine Acyl CoA 15 Fig 23 8b p 703 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 Palmitic acid C 16 saturated even C C 14 fatty acid Acetyl CoA 17 Each cycle of oxidation involves four reactions FADH2 oxidation cleavage oxidation NADH oxidation hydration 18 Reactions 1 2 Dehydrogenation Oxidation Hydration 1 Acyl CoA dehydrogenase 2 Enoyl CoA hydratase 19 Reactions 3 4 Dehydrogenation Cleavage of the C C bond 3 L 3 Hydroxyacyl Co A dehydrogenase 4 ketothiolase 20 The first two rounds in the degradation of palmitate Last round 7 CoA 21 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 x1 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 22 Fatty Acid Oxidation is an Important Source of Metabolic Water for Some Animals 23 How Are Odd Carbon Fatty Acids Oxidized Some of the intermediate steps require biotin and B12 derivatives TCA Can be used to regenerate OAA 24 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 25 oxidation of fatty with double bond on ODD carbon 3 2 1 Oxidation FADH X 3 2 Acyl CoA dehydrogenase 3 2 2 Hydration H2O 3 Oxidation NADH 4 Cleavage of AcetyCoA 26 oxidation of fatty with double bond on Even carbon 4 3 2 1 Oxidation FADH Acyl CoA dehydrogenase 4 4 3 2 X 2 Hydration H2O 3 Oxidation NADH 3 2 reductase NADPH NADP 27 oxidation of fatty with double bond on Even carbon 4 3 2 1 Oxidation FADH Acyl CoA dehydrogenase 4 4 3 3 2 2 2 Hydration H2O 3 Oxidation NADH 28 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 isomerase29 Fat burns in the flame of carbohydrates 30 Ketone and diabetes catabolism In the liver http www elmhurst edu chm vchembook 623acetylCoAfate html 31 Ketone Bodies Acetyl CoA Acetoacetic acid Acetyl CoA 2 CoA H CO2 3 hydroxybutanoic acid acetone http www elmhurst edu chm vchembook 623acetylCoAfate html 32 Diabetic ketosis results when insulin is absent 33 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 34 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 35 Fatty acid biosynthesis depends on acetyl CoA cytosolic matrix cytoplasm Inner mitochondrial membrane 36 mito cytosol ATP CoA ADP OAA AcCoA or OAA NADPH Pentose Phosphate Pathway37 Step 2 Acetate Units Are Committed to Fatty Acid Synthesis by Formation of Malonyl CoA Acetyl CoA The acetyl CoA carboxylase ACC reaction Malonyl CoA 38 Step 2 Part 1 The Carboxylation of Biotin carbonylphosphate intermediate 39 Step 2 Part 2 The transcarboxylation Reaction Acetyl CoA Malonyl CoA 40 Acetyl CoA carboxylase ACC enzyme in E coli acetylCoA carbonylphosphate intermediate 41 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 Malonyl CoA ACP Acetyl ACP CoA Malonyl ACP CoA 42 Step 4 Condensation of Acetyl ACP and Malonyl ACP Ketoacyl synthase KS 43 Step 5 Reduction of the keto group to form a OH group H Ketoacyl reductase KR
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