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David L. Nelson and Michael M. Cox LEHNINGER PRINCIPLES OF BIOCHEMISTRY Fifth Edition CHAPTER 17 Fatty Acid Catabolism © 2008 W. H. Freeman and Company Introduction 1. The oxidation of long-chain fatty acids to acetyl-CoA as a central energy-yielding pathway- in mammalian heart and liver; it provide 80% of energetic need 2. Fatty acid are converted into acetyl-CoA by repetitive fourstep processes, b-oxidation 3. Advantage of fatty acid as storage fuel - highly reduced structure with high energy - do not raise the osmolarity - no undesired chemical reaction with other cellular constituents 4. Fatty acid oxidation in mitochondria 1. Three sources: in the diet, in cells as lipid droplet, synthesized in one organ (liver) 2. Dietary Fats are absorbed in the small intestine When low levels of glucose in the blood trigger the release of glucagon, 1 the hormone binds its receptor in the adipocyte membrane and thus 2 stimulates adenylyl cyclase, via a G protein, to produce cAMP. This activates PKA, which phosphorylates 3 the hormone-sensitive lipase and 4 perilipin molecules on the surface of the lipid droplet. Phosphorylation of perilipin permits hormone-sensitive lipase access to the surface of the lipid droplet, where 5 it hydrolyzes triacylglycerols to free fatty acids. 6 Fatty acids leave the adipocyte, bind serum albumin in the blood, and are carried in the blood; they are released from the albumin and 7 enter a myocyte via a specific fatty acid transporter. 8 In the myocyte, fatty acids are oxidized to CO2, and the energy of oxidation is conserved in ATP, which fuels muscle contraction and other energy-requiring metabolism in the myocyte. 1. The enzymes of fatty acid oxidation in animal cells are located in the mitochondrial matrix. 2. Fatty acid are activated. Fatty acid are transported into mitochondria Three stages 1. Fatty acids undergo oxidative removal of successive twocarbon units in the form of acetyl –CoA, starting from the carboxyl end of the fatty acyl chain 2. Aceyl-CoA are oxidized to CO2 in the citric acid cycle 3. Electrons from first and second stage are transferred to ETS chain, passing to oxygen with the formation of ATP. 1. Acyl-CoA dehydrogenase: dehydrogenation of fatty-acyl CoA produces a double bond between a and b carbon, FAD is a prosthetic group. Similar to succinate dehydrogenation system (bound inner membrane of Mito.; transfer electron to ETS) 2. Enoyl-CoA hydratase: water is added to the double bond of the trans-enoyl-CoA, analogous to the fumarase reaction 3. b-Hydroyacyl-CoA deghydrogenase NADH formed and then transfer electorn to NADH dehydrogenase in ETS. Analogous to the malate dehydrogenase 4. Thiolase thiolysis reaction 1. C>12, trifunctional protein (TFP(a4b4)), multienzyme complex associated with inner membrane, catalyzed the reaction 2. a subunit: enoyl-CoA hadratase and b-hydroxyacyl-CoA dehydrogenase activities 3. b-subunit: thiolase substrate channeling 4. C<12, catalyzed by four soluble enzyme 5. Methylene group (-CH2-) in fatty acid is relatively stable first three step create a much less stable C-C bond, in which the a carbon is bonded to two carbonyl carbon then b-carbon makes it a good target for nucleophilic attack by the – SH of CoA 6. The four b-oxidation steps are repeated to yield Acetyl-CoA and ATP palmitoyl-CoA + 7CoA + 7 FAD + 7NAD + 7H2O - 8acetyl-CoA + 7FADH2 + 7NADH + 7H+ -8acetyl-CoA + 28 ATP + 7H+ 7. Acetyl-CoA can be further oxidized in the citric acid cycle - 10 ATP/1turn 80 ATP -108 ATP/palmitoryl-CoA - for activation of palmitoryl, 2 phosphoanhydride bond was used - 106 ATP/palmitate Oxidation of unsaturated fatty acid Oxidation of unsaturated fatty acid Complete oxidation of odd number fatty acids requires three extra reactions Fatty acid oxidation is tightly regulated 1. The three step process (carnitine shuttle) is rate-limiting for fatty acid oxidation and is an important point of regulation 2. Malonyl-CoA, the first intermediate in the cytosolic biosynthesis of fatty acid from acetyl-CoA, inhibits carnitine acyltransferase I. 3. [NADH]/[NAD+] ration is high, b-hydroxyl-CoA dehydrogenase is inhibited. 4. High concentrations of aceyl-CoA inhibit thiolase. 5. [AMP] is high, AMPK is activated and phosphorylated acetyl-CoA carboxylase, which catalyze the formation of malonyl-CoA, thereby decreasing the malonyl-CoA concentration. allowing b-oxidation 6. Transcription factors turn on the synthesis of proteins for lipid catabolism: - PPARa acts in muscle, adipose tissue, and liver to turn on a set of genes essential for fatty acid oxidation. - Glucagon [cAMP] CREB turn on a set of genes essential for fatty acid. Coordinate regulation of fatty acid synthesis and breakdown Two enzymes are key to the coordination of fatty acid metabolism: acetyl-CoA carboxylase (ACC), the first enzyme in the synthesis of fatty acids, and carnitine acyltransferase I, which limits the transport of fatty acids into the mitochondrial matrix for b-oxidation. Ingestion of a high-carbohydrate meal raises the blood glucose level and thus 1 triggers the release of insulin. 2 Insulin-dependent protein phosphatase dephosphorylates ACC, activating it. 3 ACC catalyzes the formation of malonyl-CoA (the first intermediate of fatty acid synthesis), and 4 malonyl-CoA inhibits carnitine acyltransferase I, thereby preventing fatty acid entry into the mitochondrial matrix . When blood glucose levels drop between meals, 5 glucagon release activates cAMP-dependent protein kinase (PKA), which 6 phosphorylates and inactivates ACC. The concentration of malonyl-CoA falls, the inhibition of fatty acid entry into mitochondria is relieved, and 7 fatty acids enter the mitochondrial matrix and 8 become the major fuel. Because glucagon also triggers the mobilization of fatty acids in adipose tissue, a supply of fatty acids begins arriving in the blood. Peroxisome also carry out b oxidation 1. Peroxisome: membrane-inclosed organelles of animal and plant cells. 2. Dehydrogenation, addition of water, oxidation of b-hydroxyacyl-CoA to a ketone, thiolytic cleavage by conezyme A. 3. Difference between peroxisome and mitochondria. - In peroxisome, the flavoprotein acyl-CoA oxidase passes electrons directly to O2, producing H2O2 and cleaved to H2O and O2 by catalase - Specificity for fatty acyl-CoA: much more active on very-long cahin fatty acid such as hexacosanoic acid (26:0). 4. In mammal, high concentration of fats in the diet result in increase synthesis of the enzymes of peroxisomal b-oxidation in liver. long fatty acids are catabolized to shorter-chain products and then are exported to mitochondria. Plant peroxisome and glyoxysome use acetyl-CoA from boxation as a biosynthetic precursor 1. In plant, fatty acid oxidation does not occur primarily in mitochondria but in the peroxisomes of leaf tissue and in the glyoxysomes of germinating seeds 2. The biological role of b-oxidation is to use stored lipid primarily to provide biosynthetic precursors. 3. Glyoxylate cycle to four-carbon precursors for gluconeogenesis. 4. Glyoxysomes contain high concentrations of catalase. Omega-oxidation of fatty acids occurs in the endoplasmic reticulum 1. There is another pathway in some species, including vertebrates, that involves oxidation of the omega carbon. 2. The enzymes unique to omega oxidation are located the ER of liver and kidney 3. The preferred substrate are fatty acid of 10 to 12 carbon. 4. The first step introduces a hydroxyl group on to omega carbon by mixed function oxidase involved in cytochrome p450 and NADPH 5. Produce a carboxyl group at each end. 6. In each pass through the b-oxidation pathway, the double-ended fattyacid yield dicarboxylic acid such as succinic acid, which can enter citric acid cycle. Ketone bodies 1. In human and most other mammals, acetyl-CoA formed in the liver during fatty acid oxidation can either enter the citric acid cycle or undergo conversion to the ketone bodies. 2. Acetoacetate and bhydorxybutyrate are transported by the blood to extrahepatic tissues, where they converted to acetylCoA and oxidized in citric acid cycle. 3. The brain can adapt to the use for acetoacetate or b-hydorxybutyrate under starvation condition. Ketone bodies are overproduced in diabetes and starvation 1. During starvation, gluconeogenesis depletes citric acid cycle intermediates, diverting acetyl-CoA to ketone body production. 2. Untreated DM insulin down cannot uptake glucose malonyl-Co A fall fatty acid oxidation increase ketone body acidosis (ketosis) 3. Individual on very low-calorie diets, using the fats stored in adipose tissue as their major energy source, also have increased level of ketone bodies in their blood and urine.