Lecture 20 Chapters 27 28 Fa4y Acid Metabolism The hummingbird s tremendous capacity to store and use fa4y acids enables it to make migratory journeys of remarkable distances 1 Outline v Fa4y acid catabolism oxidaKon of saturated even C fa4y acids and the ATP count oxidaKon of saturated uneven C fa4y acids oxidaKon of polyunsaturated fa4y acids Ketone bodies v Fa4y acid biosynthesis Overview How the cell ensures supply of the precursors acetyl CoA and NADPH Steps of biosynthesis Overall equaKon for the synthesis of one molecule of palmiKc acid 16 0 RegulaKon of fa4y acid metabolism allosteric covalent hormonal 2 Triaglyceride as Fuel Ester O R C OR Triglyceride triacylglycerols 3 Adipocyte 4 Lipid DegradaKon 5 6 Hydrolysis Lipolysis of Triacylglycerols in an Adipocyte Adipose cell ATGL albumin FA HS lipase MAG lipase glucose 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 MAG lipase glucose 9 Fa4y Acid Catabolism 1 AcKvaKon of Fa4y acid with CoA by Acyl CoA synthase on outer membrane of mitochondria 2 Transport of acKvated fa4y acid into mitochondrial matrix via Translocase 3 oxidaKon cycle of saturated even C fa4y acid 4 Catabolism of uneven C saturated fa4y acid 5 Catabolism of unsaturated fa4y acid double bonds 10 AcKvaKon of Fa4y acids Acyl CoA synthase Pi orthophosphate PPi pyrophosphate 11 Fa4y Acids are linked to Coenzyme A before they are oxidized 1 2 12 The Acyl CoA Synthetase acKvates fa4y acids for oxidaKon ATP Acyl CoA AMP P P G for acyl CoA synthesis 31 5 kJ mol G for ATP AMP PP 32 3 kJ mol Net G 0 8 kJ mol 13 Transfer of acyl CoA to inner mitochondrial space Acyl CoA Acyl carniKne 14 Fig 23 8a p 703 Transfer of Acyl carniKne from inner mitochondrial space to matrix Acyl carniKne Acyl CoA 15 Fig 23 8b p 703 oxidaKon converts the carbon of Fa4y acid Chain from reduced to oxidized form oxidaKon Reduced H H C FAD NAD FADH2 NADH Oxidized O C 16 One cycle of oxidaKon for saturated FA Acyl CoA PalmiKc acid C 16 saturated even C C 14 fa4y acid Acetyl CoA 17 Each cycle of oxidaKon involves four reacKons FADH2 oxidaKon cleavage oxidation NADH oxidaKon hydraKon 18 ReacKons 1 2 DehydrogenaKon OxidaKon HydraKon 1 Acyl CoA dehydrogenase 2 Enoyl CoA hydratase 19 ReacKons 3 4 DehydrogenaKon Cleavage of the C C bond 3 L 3 Hydroxyacyl Co A dehydrogenase 4 ketothiolase 20 The rst two rounds in the degradaKon of palmitate Last round 7 CoA 21 oxidaKon Total ATP yield on complete oxidaKon of one molecule of palmiKc 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 Fa4y Acid OxidaKon is an Important Source of Metabolic Water for Some Animals 23 How Are Odd Carbon Fa4y Acids Oxidized Some of the intermediate steps require bioKn and B12 derivaKves TCA Can be used to regenerate OAA 24 Fa4y 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 oxida on of fa y with double bond on ODD carbon 3 2 1 OxidaKon FADH X 3 2 Acyl CoA dehydrogenase 3 2 2 HydraKon H2O 3 OxidaKon NADH 4 Cleavage of AcetyCoA 26 oxida on of fa y with double bond on Even carbon 4 3 2 1 OxidaKon FADH Acyl CoA dehydrogenase 2 3 4 4 3 2 X 2 HydraKon H2O 3 OxidaKon NADH reductase NADPH NADP 27 oxida on of fa y with double bond on Even carbon 4 3 2 1 OxidaKon FADH Acyl CoA dehydrogenase 4 3 4 3 2 2 2 HydraKon H2O 3 OxidaKon NADH 28 Fa4y acid breakdown lipolysis TG FA lipase sKmulated 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 carniKne transporter 3 oxidaKon separate enzymes in mitochondrial matrix oxidaKon FADH2 hydraKon oxidaKon NADH cleavage acetyl CoA acyl CoA TCA even double bond two steps 2 4 Dienoyl CoA reductase Another round of oxidaKon odd double bond one step 29 cis 3 enoyl CoA isomerase Fat burns in the ame of carbohydrates 30 Ketone and diabetes catabolism In the liver h4p www elmhurst edu chm vchembook 623acetylCoAfate html 31 Ketone Bodies Acetyl CoA AcetoaceKc acid Acetyl CoA 2 CoA H CO2 3 hydroxybutanoic acid acetone h4p www elmhurst edu chm vchembook 623acetylCoAfate html 32 Diabe c ketosis results when insulin is absent 33 Fa4y Acid Metabolism Fa4y acid catabolism Fa4y acid anabolism 1 Intermediates are linked covalently 1 Intermediates are linked covalently to the SH group of CoA to the SH group of Acyl Carrier proteins ACPs 2 Occurs in the mitochondrial matrix 2 Occurs in the cytosol 3 Enzymes of fa4y acid breakdown are all separate proteins 3 All enzymes except for one required to synthesize a molecule of fa4y acid are components di erent domains of one long polypep de chain called Fa4y Acid Synthase FAS 4 The coenzyme for oxidaKon reducKon reacKons is the NAD NADH couple 4 The coenzyme for oxidaKon reducKon reacKons is the NADP NADPH couple 34 Fa4y Acid Synthesis takes place in 3 stages Step 1 Preparatory step transfer of acetyl CoA from mitochondria to cytoplasm Step 2 AcKvaKon of acetyl CoA acetyl CoA converted to malonyl CoA Steps 3 7 Fa4y acid synthesis Synthesis occurs on an acyl carrier protein a molecular sca old 35 Fa4y 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 Pathway 37 Step 2 Acetate Units Are Commi4ed to Fa4y Acid Synthesis by FormaKon of Malonyl CoA Acetyl CoA The acetyl CoA carboxylase ACC reacKon Malonyl CoA 38 Step 2 Part 1 The CarboxylaKon of BioKn carbonylphosphate intermediate 39 Step 2 Part 2 The transcarboxylaKon ReacKon 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 Acetyl ACP CoA Malonyl CoA ACP Malonyl ACP CoA 42 Step 4 CondensaKon 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 44 Step 6 DehydraKon 3 Hydroxyacyl dehydratase DH 45 Step 7 ReducKon to saturate the fa4y acid chain H Enoyl
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