Chapter 27 Fatty Acid Metabolism Fatty acids stored as triacylglycerols in adipose tissue Fatty acids are processed in three stages o Lipids must be mobilized in this process triacylglycerols are degraded to fatty acids and glycerol which are released from the adipose tissue and transported to the energy requiring tissues o Then the fatty acids must be activated and transported into mitochondria for degradation o Finally the fatty acids are broken down in a step by step fashion into acetyl CoaA which is then processed in the citric acid cycle Triacylglycerols are hydrolyzed by hormone stimulated lipases o After a night s fast glycogen stores are low however lipids are readily available How are they mobilized o Triacylglycerols are stored in an adipocyte as a lipid droplet an intracellular compartment surrounded by a single layer of phospholipids and proteins required for fatty acid metabolism Triacylglycerol mobilization and deposition take place on surface of the droplet o Triacylglycerol in storage form must be hydrolyzed to yield isolated fatty acids o Hormones glucagon and epinephrine trigger 7TM receptors that activate adenylate cyclase The increased level of cyclic AMP then stimulates protein kinase A which phosphorylates perilipin and hormone sensitive lipase Phosphorylation of perilipin Restructures the fat droplet so that the triacylglycerols are more accessible to the mobilization Triggers the release of a coactivator for adipose triglyceride lipase ATGL ATGL initiates the mobilization of triacylglycerols by releasing a fatty acid from triacylglycerol forming a diacylglycerol Diacylglycerol a free fatty acid and monoacylglycerol by hormone sensitive lipase Monoglycerol lipase completes the mobilization of fatty acids with the production of a free fatty acid and glycerol Thus epinephrine and glucagon induce lipolysis Probably also regulate the use of triacylglycerol stores in that tissue o Released fatty acids are not soluble inblood plasma Serum albumin binds the FAs and carries them to be accessible o Glycerol formed by lipolysis is absorbed by the liver and phosphorylated Then oxidized to dihydroxyacetone phosphate then isomerized to glyceraldehyde 3 phosphate intermediate in both glycolytic and gluconeogenic so glycerol can be converted into pyruvate or glucose in the liver glyverol and glycolytic intermediates are interconvertible Fatty acids are linked to coenzyme A before they are oxidized o Transport proteins assist fatty acids diffusion across cell membrane o Fatty acid oxidation takes place in the mitochondria degradation Fatty acids must b activated by reacting with CoA to form acyl CoA takes place in outer mitochondrial membrane Enzyme is catalyzed by acyl CoA synthetase Activation takes place in 2 steps 1 fatty acid reacts with ATP to form acyl adenylate and the other two phosphoryl groups of the ATP substrate are released as pyrophosphate 2 Sulfhydryl group of CoA then attacks the acyl adenylated to form acyl CoA and AMP These 2 partial reactions are freely reversible equilibrium constant for the sum is close to 1 energy levels of reactants and products are about equal Reaction driven forward by the hydrolysis of pyrophosphate by pyrophosphatase Again we see many biosynthetic reactions are made irreversibly by hydrolysis of inorganic pyrophosphate o Transport across the inner mitochondrial membranes requires that the fatty acids be linked to carnitine The acyl groups is transferred from the sulfur atom of CoA to the hydroxyl group of carnitine to form acyl carnitine Caatalyzed by carnitine acyltransferase I o Acyl carnitine shuttled across inner mitochondrial membrane by a o The acyl group is transferred back to CoA by carnitine acyltransferase translocase II o Finally the translocase returns carnitine to the cytoplasmic side in exchange for an incoming acyl carnitine restarting the process Clinical insight Pathological conditions result if FA can t enter mitochondria o Symptoms of carnitine deficiency mild muscle cramping to severe weakness and even death muscle kidney and heart are primary tissues impaired o Diseases illustrate that the impaired flow of a metabolite from one compartment of a cell to another can lead to a pathological condition o Carnitine dietary supplement now Can increase endurance enhances brain function and promotes weight loss Acety CoA NADH and FADH2 are generated by fatty acid oxidation o Goal of FA degradation oxidize the FA two carbons at a time to acetyl CoA and to gather the released high energy electrons to power oxidative phosphorylation o Degradation of saturated acyl CoA Oxidation by FAD Hydration Oxidation by NAD Thiolysis by CoA o Fatty acid is shortened by two carbon atoms as a result and FADH2 NADH and acetyl CoA are generated o Because oxidation takes place at the beta carbon atom its called the beta oxidation pathway Steps of beta oxidation o Oxidation of acyl COA Done by acyl CoA dehydrogenase to give an enoyl CoA with a trans double bond between C2 and C3 FAD is the electron acceptor because the deltaG for this reaction is insufficient to reduce NAD Electrons picked up by FAD are transferred to ETC and eventually ubiquinone reducing it to ubiquinol Ubiquinol delivers its high potential electrons to the second proton pumping site of the respiratory chain o Hydration of the double bond between C2 and C3 Done by enoyl CoA hydratase Hydration of enoyl CoA is stereospecific only L isomer of 3 hydroxyacyl CoA is formed when the trans DB is hydrated o Oxidation by NAD Hydration of enoyl CoA converts the hydroxyl group at C3 into a keto group and generates NADH Catalyzed by L 3 hydroxyacyl CoA dehydrogenase o Thiolysis by CoA Cleavage of 3 ketoacyl CoA by a thio group of a second CoA molecule This yields acetyl CoA and an acyl CoA shortened by two carbon atoms Thiolytic cleavage is catalyzed by B ketothiolase The complete oxidation of palmitate yields 106 molecules of ATP o In each reaction cycle An acyl is shortened by two carbon atoms One molecule of FADH2 NADH and acetyl CoA is formed o The degradation of palmitoyl CoA requires seven reaction cycles and in the seven cycle C4 ketoacyl CoA is thiolyzed to 2 molecules of acetyl CoA o 2 5 molecules of ATP are generated when the respiratory chain oxidizes each of these NADH molecules whereas 1 5 molecules of ATP are formed for each FADH2 because e enter chain at ubiquinol o Oxidation of acetyl COA by CAC yields 10 molecules of ATP So number of ATP molecules formed in