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Energy release from fat. Fatty acids are key constituents of lipids. Why are cell membranes needed? Fatty acids are degraded and synthesised by different pathways.
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Energy release from fat Fatty acids are key constituents of lipids. Why are cell membranes needed? Fatty acids are degraded and synthesised by different pathways. Describe the process of fatty acid activation including why the free energy change overall for the formation of acetyl CoA is favourable. Explain the mechanism of fatty acid transport into mitochondria, especially the role of carnitine. Outline the four steps in the b-oxidation of fatty acids. Discuss the role of peroxisomes in fat metabolism. Explain the conditions under which ketone bodies are formed and why? Refer to chapters 12 & 22, Stryer, 5e and chapter 17, Lehninger, 4e Lecture 26, Michael Schweizer
A 16-C fatty acid, with numbering conventions, is shown. Most naturally occurring fatty acids have an even number of carbon atoms. The pathway for catabolism of fatty acids is referred to as the b-oxidation pathway, because oxidation occurs at the b-carbon (C-3).
Triacylglycerols (triglycerides) are the most abundant dietary lipids, & the form in which we store reduced carbon for energy. Each triacylglycerol has a glycerolbackbone to which is esterified 3 fatty acids. Most are mixed, with different fatty acids varying in chain length & double bonds.
Glycerol is converted to the Glycolysis intermediate dihydroxyacetone phosphate, by reactions catalyzed by: 1 Glycerol Kinase 2 Glycerol-3-Phosphate Dehydrogenase.
Acetyl CoA is a key intermediate between fat and carbohydrate metabolism
Fatty Acid Activation • fatty acid + ATP acyladenylate + PPi PPi 2 Pi • acyladenylate + HS-CoA acyl-CoA + AMP Overall: fatty acid + ATP + HS-CoA acyl-CoA + AMP + 2 Pi Exergonic hydrolysis of PPi (P~P), catalyzed by pyrophosphatase, makes the coupled reaction spontaneous. 2 ~P bonds of ATP are cleaved. The acyl-CoA product includes one "~" thioester linkage. Different acyl-CoA synthases exist for fatty acids of different chain lengths.
Fatty acid activation: Acyl-CoA Synthases (Thiokinases), of ER & outer mitochondrial membranes, catalyze fatty acid activation. Esterification of a fatty acid to coenzyme A is ATP-dependent, & occurs in 2 steps.
Carnitine Palmitoyl Transferase catalyzes transfer of a fatty acid between the CoA thiol and the OH on carnitine.
1. Carnitine Palmitoyl Transferase I, and enzyme on the cytosolic surface of the outer mitochondrial membrane, transfers a fatty acid from CoA to the OH on carnitine. 2. An antiporter in the inner mitochondrial membrane mediates exchange of carnitine for acylcarnitine.
3. Carnitine Palmitoyl Transferase II, an enzyme within the mitochondrial matrix, transfers the fatty acid from carnitine to CoA. (Carnitine exits the matrix in step 2.) Fatty acyl-CoA is now in the matrix.
One round of four reactions by which a fatty acyl CoA is shortened by two carbon atoms with the production of acetyl CoA • C-C bond in a and b region already weakened by C=O • Introduction of a cabonyl bond into the fatty acyl chain weakens the molecule further
b Oxidation Pathway The b oxidation pathway is cyclic. The product, 2 C shorter, is the input to another round of the pathway. If the fatty acid contains an even number of C atoms, the final reaction cycle (for which the substrate is butyryl-CoA) yields 2 copies of acetyl CoA. Summary of one round of the b-oxidation pathway: fatty acyl-CoA + FAD + NAD+ + HS-CoA fatty acyl-CoA (2C less) + FADH2 + NADH + H+ + acetyl-CoA
The b-oxidation pathways. 7 molecules of of acetyl CoA are formed from myristoyl CoA (C14:0).
ATP Production FADH2 of Acyl-CoA Dehydrogenase is reoxidized by transfer of 2e- via ETF to CoQ of the respiratory chain. Transfer of 2e- from CoQ to oxygen is accompanied by H+ pumping, leading to production of approx. 1.5ATP. NADH is reoxidized by transfer of 2e- to the respiratory chain complex I. H+ pumping associated with transfer of 2e- from complex I to oxygen yields approx. 2.5ATP. Acetyl-CoA can enter Krebs cycle, yielding additional NADH, FADH2, and GTP (ATP). Fatty acid oxidation is a major source of cell ATP. (complete oxidation of palmitate yields 106 molecules of ATP (see Stryer 5e, p610)),
Peroxisomal b-Oxidation b-Oxidation of long-chain fatty acids also occurs within peroxisomes.
Peroxisomal b-Oxidation FAD is e- acceptor for peroxisomal Acyl-CoA dehydrogenase, which catalyzes the 1st oxidative step of the pathway. FADH2 is reoxidized in the peroxisome producing hydrogen peroxide: FADH2 + O2 FAD + H2O2 The peroxisomal enzyme Catalase degrades H2O2: 2H2O2 2H2O + O2 These reactions produce no ATP.
Formation of ketone bodies During CHO starvation, oxaloacetate in liver is depleted due to gluconeogenesis. This impedes acetyl-CoA entry to Krebs cycle. Acetyl-CoA in liver mitochondria is converted then to ketone bodies, acetoacetate & b-hydroxybutyrate.
