Fatty Acid Catabolism 2024 PDF

Fatty acid catabolism Learning objectives 1. Explain the significance of fatty acid catabolism 2. Understand the reactions steps for fatty acid β-oxidation (enzymes, metabolites, chemical changes, utilization of ATP, generation of ATP, NADPH, FADH2) 3. Describe how unsaturated fatty acids an...

Fatty acid catabolism Learning objectives 1. Explain the significance of fatty acid catabolism 2. Understand the reactions steps for fatty acid β-oxidation (enzymes, metabolites, chemical changes, utilization of ATP, generation of ATP, NADPH, FADH2) 3. Describe how unsaturated fatty acids and “odd” fatty acids are oxidized – what is the yield of ATP? 4. Recognize the significance of ketone body formation 5. Explain how plants (but not humans) may convert lipids to carbohydrates  Fatty acid catabolism - Fatty acid is an excellent energy source - Fatty acids are packaged as triacylglycerols acyl chain Glycerol backbone A triacylglycerol - Fatty acid oxidation releases a tremendous amount of energy Example: Palmitic acid – C16 saturated fatty acid CH3(CH2)14COOH + 23O2 16CO2 + 16H2O G' = -2340 kcal/mol (This is coupled to formation of 106 ATPs) - Fatty acid oxidation generate reduced electron carriers and acetyl-CoAs - Fatty acids provide 80% of the energetic needs in heart and liver 2 3 Degradation of triacylglycerol Lipase Fatty acids 4 Conversion of glycerol to glycolytic metabolites: (DHAP) 5 Fatty acid activation - The acyl chain of fatty acid must be joined to co-enzyme A to become substrates of the β-oxidation enzymes in mitochondria - Enzyme: acyl-CoA synthetase (Acyl-AMP) 6 Transport of fatty acyl CoA into mitochondria - Fatty acyl-CoA cannot pass through the inner membrane of mitochondria - Requires carnitine as a carrier of the fatty acyl chain - Acyl-carnitine can pass through a specific translocase - Fatty acyl-CoA is formed inside the matrix 7 -Oxidation of saturated fatty acids: a spiral pathway = acetyl CoA 8 9 β-Oxidation of palmitic acid (16:0) Palmitic acid 2 1 + CoA-SH (Co-enzyme A) 1 oxidation QH2 Complex III β α 2 1 2 hydration β 3 oxidation Complex I β 10 - A new co-enzyme A (CoA-SH) then reacts with the beta-carbon, releasing acetyl-CoA which contains two carbons from the acyl chain: β α 4 Thiolysis Next β-oxidation cycle 1 2 3 11 4 Overall changes: C16 Fatty acid 7 β-oxidation cycles 8 Acetyl-CoA - The product of each cycle of reactions become a substrate for the next cycle - A spiral pathway - Final cycle of β-oxidation: CH3(CH2)2CO-S-CoA + CoA-SH 2 acetyl-CoA C 16 12 ATP formation from completion oxidation of C16:0 - For each cycle of -oxidation: 1 FADH2 (1.5 ATP) + 1 NADH (2.5 ATP) = 4 ATPs - For palmitic acid (C16 saturated), 7 cycles of -oxidation are required to produce 8 acetyl-CoA - Number of ATPs derived from -oxidation: 7 x 4 = 28 - For each acetyl-CoA entering the citrate acid cycle, 10 ATPs are generated (1 GTP, 1 FADH2, 3 NADH) - Number of ATPs derived from oxidation of acetyl-CoA: 8 x 10 = 80 - Total number of ATPs from complete oxidation of palmitic acid: 108 13 From p. 1: - Fatty acid oxidation releases a tremendous amount of energy Example: Palmitic acid – C16 saturated fatty acid CH3(CH2)14COOH + 23O2 16CO2 + 16H2O (This is coupled to formation of 106 ATPs) – Why only 106 ATPs? -ATP-consuming step: Palmitic acid + ATP + CoA-SH Acyl-CoA + AMP + 2Pi - Free energies of hydrolysis: G' ATP + H2O AMP + PPi -45.6 PPi + H2O 2Pi -19.2 _________________________________ ATP + 2H2O AMP + 2Pi -64.8 vs ATP + H2O ADP + Pi -32.8 - Thus, energetically, the hydrolysis of 1 ATP to AMP is equivalent to the 14 hydrolysis of 2 ATP to 2 ADP ATP generation – glucose vs fatty acid oxidation If we start from glucose (6 carbon): - Glycolysis to 2 pyruvate yields: 2 ATP 2 NADH [2 X 2.5 = 5 ATP] - Conversion of 2 pyruvate to 2 acetyl-CoA: 2 NADH [2 X 2.5 = 5 ATP] - Oxidation of 2 acetyl-CoA in the TCA cycle: 2 x 10 = 20 ATP 32 ATP for complete oxidation of glucose to CO2 Net yield = __________ 96 ATP for 3 glucose (18 carbons) 15 -For a C18 saturated fatty acid (18:0): 8 cycles of -oxidation are required to produce 9 acetyl-CoA -For each series of -oxidation: 1 FADH2 (1.5 ATP); 1 NADH (2.5 ATP) -Number of ATPs derived from -oxidation: 8 x 4 = 32 -For each acetyl-CoA entering the citrate acid cycle, 10 ATPs are generated (1 GTP, 1 FADH2, 3 NADH) -Number of ATPs derived from oxidation of acetyl-CoA: 9 x 10 = 90 -Net profit of ATPs from complete oxidation = 32 + 90 – 2 = 120 vs. 96 ATP for 3 glucose (18 carbons) 16 Oxidation of unsaturated fatty acids (1) Oxidation of monounsaturated fatty acid: - One additional enzyme is required: 2, 3-enoyl-CoA isomerase 3 x 4 = 12 ATPs ← → TCA cycle → 3 x 10 = 30 ATPs 2 4 – 1.5 = 2.5 ATPs ← β oxidation 3 (last 3 steps) 4 (substrate for enoyl-CoA hydratase) Step 1 is skipped Acetyl-CoA (no FADH2 formation) TCA cycle → 1 x 10 = 10 ATPs 1 4 x 4 = 16 ATPs ← β oxidation 2 (4 full cycles) 3 4 5 Acetyl-CoA → TCA cycle → 5 x 10 = 50 ATPs 17 Net ATP yield = 120.5 -2 (formation of acyl-CoA) = 118.5  (2) Oxidation of polyunsaturated fatty acids: - 2 additional enzymes are required: 2, 3-enoyl-CoA isomerase, 2, 4-dienoyl-CoA reductase 3 x 4 = 12 ATPs ← TCA cycle → 3 x 10 = 30 ATPs cis-∆3 to trans- ∆2 conversion 2 4 – 1.5 = 2.5 ATPs ← β oxidation (substrate for enoyl-CoA hydratase) 3 (last 3 steps) 4 Step 1 is skipped Acetyl-CoA → TCA cycle → 1 x 10 = 10 ATPs (no FADH2 formation) 4 SCoA 10 C O cis-4 18  4 SCoA 10 C cis-4 O FAD 1 First step of β-oxidation cycle 1.5 ATP ← FADH2 (acyl-CoA dehydrogenase) -2.5 ATP [equivalent to 1 NADH] trans-∆3 to trans- ∆2 conversion 2 (substrate for enoyl-CoA hydratase) 4 – 1.5 = 2.5 ATPs ← β oxidation 3 (last 3 steps) 4 Step 1 is skipped Acetyl-CoA → TCA cycle → 1 x 10 = 10 ATPs (no FADH2 formation) 19 More β oxidation cycles (full cycles) [3 more β-oxidation cycles + release of 4 acetyl CoAs] Oxidation of “odd” fatty acids - Fatty acids with an odd number of carbons are rare in mammals, but many plants and bacteria do contain these lipids - Substrate of the last -oxidation is a 5-C acyl-CoA, giving rise to one acetyl- CoA and one propionyl-CoA (3-C unit) 20 How can succinyl-CoA be completely oxidized for ATP formation? 21 Formation of ketone bodies - During starvation, TCA cycle intermediates in liver are depleted by gluconeogenesis to make glucose - Acetyl-CoA released from fatty acid β- oxidation will be in excess - Ketone bodies are then formed - Co-enzyme A is released for further fatty acid β-oxidation 22 Ketone bodies: acetoacetate, acetone, β-hydroxybutyrate 23 Ketone body formation and export from the liver: starvation 24 Utilization of ketone bodies - In non-hepatic tissues (brain, heart, kidney, skeletal muscle) - Under starvation conditions - After depletion of glucose supply absence in liver 25 β-Oxidation and glyoxylate cycle in plant seeds - In glyoxysomes – organelles in developing seeds (fat reserves) - Plant mitochondria do not contain β-oxidation pathway enzymes. - Acetyl-CoA produced by β-oxidation enters the glyoxylate cycle to make succinate. - Succinate is exported to mitochondria for use as a TCA cycle intermediate or a gluconeogenesis precursor. 26 The glyoxylate cycle - Three enzymes are also found in the citric acid cycle - Two unique enzymes - One unique metabolite - Not in animals or humans 27 Conversion of lipids to carbohydrates in plant seeds 28