PowerPoint PresentationSlide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16One cycle of β-oxidation – for saturated FASlide 18Slide 19Slide 20Slide 21How Are Odd-Carbon Fatty Acids Oxidized?Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Slide 32Slide 33Slide 34Slide 35Slide 36Slide 37Slide 38Step 2 - Part 1 - The Carboxylation of BiotinSlide 40Slide 41Slide 42Slide 43Slide 44Slide 45Slide 46Slide 47Slide 48Slide 49Slide 50Slide 51Slide 52Slide 53Slide 54Slide 55 Fatty acid catabolism:- β-oxidation of saturated (even C) fatty acids and the ATP count - β-oxidation of saturated (uneven C) fatty acids- β-oxidation of polyunsaturated fatty acids- Ketone bodiesFatty 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 metabolism1Lecture 20 (Ch. 27 & 28) – Fatty Acid MetabolismTriglyceride as Fuel2EsterLipid Degradation34Hydrolysis (Lipolysis) of Triacylglycerols in an AdipocyteATGLDAG lipaseMAG lipasealbuminFAAdipose cell5Glycerol can enter the glycolysis/gluconeogenesis pathway67Fatty Acid Catabolism1. Activation of Fatty acid with CoA by Acyl CoA synthase on outer membrane of mitochondria2. Transport of activated fatty acid into mitochondrial matrix via Translocase3. β-oxidation cycle of saturated even-C fatty acid4. Catabolism of uneven-C saturated fatty acid5. Catabolism of unsaturated fatty acid (double bonds)8Activation of Fatty acidsαβγAcyl CoA synthasePPi = pyrophosphatePi = orthophosphate9Fatty Acids are linked to Coenzyme A before they are oxidized1011Long Chain Fatty Acid CoA SynthetaseThe Acyl-CoA Synthetase activates fatty acids for β-oxidation. Acyl-CoA + AMP +PPATP∆G°’ for ATPAMP + PP= -32.3 kJ/mol∆G°’ for acyl-CoA synthesis = +31.5 kJ/molNet ∆G°’ = -0.8 kJ/mol12+Transfer of acyl CoA to inner mitochondrial spaceAcyl CoAAcyl carnitine1314Transfer of Acyl carnitine from inner mitochondrial space to matrixAcyl CoA15Reduced Oxidizedβ-oxidation converts the β-carbon of Fatty acid Chain from reduced to oxidized formCHHβOCβFAD+NAD+FADH2+NADHβ-oxidation16One cycle of β-oxidation – for saturated FA17Acyl CoAtrans-2-Enoyl CoAL-3-Hydroxyacyl CoA3-Ketoacyl CoAAcyl CoAAcetyl CoAETCETC18Acyl CoA DehydrogenaseEnoyl CoA hydrataseEach β cycle of oxidation involves four reactions19The first two rounds in the degradation of palmitate.Last round (#7)CoA20β oxidation: Total ATP yield on complete oxidation of one molecule of palmitic acid (16 carbons)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 ATP31 NADH x 2.5 ATP/NADH = 77.5 ATP15 FADH2 x 1.5 ATP/FADH2 = 22.5 ATPTotal ATP yield = 77.5 + 22.5 + 8 -2* = 106+ 123 H2O21How Are Odd-Carbon Fatty Acids Oxidized?Some of the intermediate steps require biotin and B12 derivatives2223Propionyl-CoA carboxylaseATPbicarbonatecarboxyphosphateBiotinProprionyl-CoAMethylmaolyl-CoA24Methylmalonyl-CoA-EpimeraseD-Methylmalonyl CoAL-Methylmalonyl CoAResonance stabilized carbanion intermediate25Methylmalonyl-CoA-MutaseCobalamin (Vit B12)Fatty acids can be Saturated or UnsaturatedOne or more C-C bonds in the tail are double bondsSaturated Mono- or poly-UnsaturatedTail has only single C-C bonds16:0 18:226271. Hydrate2. Oxidize3. Thiolase28cis-3-Enoyl CoA Isomerase29Acyl CoA DehydrogenaseGlutamate302,4 Dienoyl-CoA ReductaseNADPHFatty acid breakdown (lipolysis)TG FA (lipase) stimulated by glucagon and epinephrine, inhibited by insulinFA 1)Coupled to CoA (acyl CoA ) needs ATP + PPi (Acyl CoA synthetase)2)Transported into mitochondrial matrix (carnitine transporter)3) β-oxidation: (separate enzymes in mitochondrial matrix)oxidation+ FADH2hydrationoxidation + NADHcleavage: acetyl CoA + acyl CoATCAAnother round of β-oxidation∆odd double-bond:(one step)cis-∆3-enoyl CoA isomerase∆even double bond:(two steps) 2,4-Dienoyl CoA reductase31Ketone and diabetes3233Ketone BodiesThiolaseHMG-CoAsynthaseHMG-CoAlyaseB-hydroxybutyratedehydrogenaseDiabetic ketosis results when insulin is absent34Fatty acid catabolism Fatty acid anabolism1. Intermediates are linked covalently to the –SH group of CoA2. Occurs in the mitochondrial matrix3. Enzymes of fatty acid breakdown are all separate proteins1. The coenzyme for oxidation-reduction reactions is the NAD+/NADH couple1. Intermediates are linked covalently to the –SH group of Acyl Carrier proteins (ACPs)2. Occurs in the cytosol3. 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)4. The coenzyme for oxidation-reduction reactions is the NADP+/NADPH coupleFatty Acid Metabolism35Fatty Acid Synthesis takes place in 3 stages:Step 1. Preparatory step: transfer of acetyl CoA from mitochondria to cytoplasmStep 2. Activation of acetyl CoA: acetyl CoA converted to malonyl CoASteps 3-7. Fatty acid synthesis. Synthesis occurs on an acyl carrier protein, a molecular scaffold.36Fatty acid biosynthesis depends on acetyl-CoA (cytosolic)37Step 2. Acetate Units Are Committed to Fatty Acid Synthesis by Formation of Malonyl-CoAThe acetyl-CoA carboxylase (ACC) reactionAcetyl CoAMalonyl CoA38Step 2 - Part 1 - The Carboxylation of Biotincarbonylphosphate intermediate39Biotin-Enzyme + ATP + HCO3- CO2-Biotin + ADP + Pi + H+Step 2 -Part 2 - The transcarboxylation ReactionMalonyl-CoAAcetyl-CoA40CO2-Biotin-Enzyme + acetyl-CoA malonyl-CoA + Biotin-EnyzmeStep 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 + CoAMalonyl-CoA + ACP Malonyl-ACP + CoA41Step 4 – Condensation of Acetyl ACP and Malonyl ACPβ-Ketoacyl synthase (KS)42β-Ketoacyl reductase (KR)Step 5 – Reduction of the β-keto group to form a β-OH group433-Hydroxyacyl dehydratase (DH)Step 6 – Dehydration44Enoyl reductase (ER)Step 7 – Reduction to saturate the fatty acid chain45Step 8 – Condensation of Acyl ACP and Malonyl ACPβ-Ketoacyl synthase (KS) AcylKetoacyl(such as butyryl ACP)46Repeat Steps 8, 5,
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