Chapter 17 – Fatty Acid Catabolism- Acetyl-CoA fates:o Oxidized to CO2 in the citric acid cycle for energy conservationo In liver, it may be converted to ketone bodies – water soluble fuels exported to the brain and other tissues when glucose is not availableo In higher plants, it serves as a biosynthetic precursor- Oxidation – a repetitive four-step process by which fatty acids are converted into acetyl-CoA- Because they are insoluble in water, ingested triacylglycerols must be emulsified before they can be digested by water-soluble enzymes in the intestineo Triacylglycerols absorbed in the intestine or mobilized from storage tissues must be carried in the blood bound to proteins that counteracttheir insolubility- The complete oxidation of fatty acids to CO2 and H2O takes place in three stages:o The oxidation of long-chain fatty acids to two-carbon fragments, in theform of acetyl-CoA ( oxidation)o Oxidation of acetyl-CoA to CO2 in the citric acid cycleo The transfer of electrons from reduced electron carriers to the mitochondrial respiratory chain17.1 Digestion, Mobilization, and Transport of Fats- Cells can obtain fatty acid fuels from three sources:o Fats consumed in the dieto Fats stored in cells as lipid dropletso Fats synthesized in one organ for export to another- Triacylglycerols are virtually the sole source of energy in hibernating animalsand migrating birds- Triacylglycerols provide more than half the energy requirements of some organso Livero Hearto Resting skeletal muscle- Protists obtain fats by consuming organisms lower in the food chain, and some store fats as cytosolic lipid droplets- Vascular plants mobilize fats stored in seeds during germinationDietary Fats Are Absorbed in the Small Intestine- Before being absorbed through the intestinal wall, triacylglycerols must be solubilized into microscopic micelles by bile saltso Bile salts are synthesized from cholesterol in the liver, stored in the gallbladder, and released into the small intestine after ingestion of a fatty mealo Bile salts are amphipathic compounds that act as biological detergents, converting dietary fats into mixed micelles of bile salts and triacylglycerols- Lipase action converts triacylglycerols to monoacylglycerols and diacylglycerols, free fatty acids, and glycerolo Micelles are more accessible to lipases- Chylomicrons – lipoprotein aggregates into which triacylglycerols are packedafter being converted back to this form in the intestine- Apolipoproteins – lipid-binding proteins in the blood, responsible for the transport of triacylglycerols, phospholipids, cholesterol, and cholesteryl esters between organs- Lipoprotein – spherical aggregates with hydrophobic lipids at the core and hydrophilic protein side chains and lipid head groups at the surfaceo Apolipoproteins combine with lipids to form several classes of these- Chylomicrons move from the intestinal mucosa into the lymphatic system, and then enter the blood, which carries them to muscle and adipose tissueo Lipoprotein lipase – an extracellular enzyme activated by apoC-II that hydrolyzes triacylglycerols to fatty acids and glycerol, which are takenup by cells in the target tissueso In muscle, fatty acids are oxidized for energyo In adipose tissue, fatty acids are esterified for storage as triacylglycerolsHormones Trigger Mobilization of Stored Triacylglycerols- Neutral lipids are stored in adipocytes as lipid droplets, with a core of sterol esters and triacylglycerols surrounded by a monolayer of phospholipids- Perilipins – a family of proteins that restrict access to lipid droplets, preventing untimely lipid mobilizationo Coats the surface of lipid droplets- Epinephrine and glucagon, secreted in response to low blood glucose levels, activate the enzyme adenylyl cyclase in the adipocyte plasma membrane, which produces cAMPo CAMP-dependent PKA phosphorylates perilipin A, which causes hormone-sensitive lipase to move to the lipid droplet surface, where ithydrolyzes triacylglycerols to free fatty acids and glycerol Also phosphorylates hormone-sensitive lipase, increasing its activity- Free fatty acids (FFA) – fatty acids released from lipid dropletso Pass from the adipocyte into the blood, where they bind to serum albumin, which carries them to other tissues- Glycerol kinase – phosphorylates the glycerol released by lipase action forming glycerol 3-phosphate, which is oxidized to dihydroxyacetone phosphateo Triose phosphate isomerase converts dihydroxyacetone phosphate to glyceraldehyde 3-phosphate, which is oxidized via glycolysisFatty Acids Are Activated and Transported into Mitochondria- The enzymes of fatty acid oxidation are located in the mitochondrial matrix- Fatty acids with 14 or more carbons cannot pass directly through the mitochondrial membranes – they must first undergo three enzymatic reactions of the carnitine shuttle:o Esterification to CoA: Acyl-CoA synthetases – catalyze the formation of a thioester linkage between the fatty acid carboxyl group and the thiol group of coenzyme A to yield fatty acyl-CoA- Coupled to the cleavage of ATP to AMP and PPi- Two steps- Involves a fatty acyl-adenylate intermediate- Fatty acyl-CoAs are high energy compoundso Transesterification to carnitine followed by transport: Fatty acids are transiently attached to the hydroxyl group of carnitine to form fatty acyl-carnitine- Catalyzed by carnitine acyltransferase I in the outer membrane- The fatty acyl-carnitine ester then enters the matrix by facilitated diffusion through the acyl carnitine/carnitinetransporter of the inner mitochondrial membraneo Transesterification back to CoA: The fatty acyl group is enzymatically transferred from carnitine to intramitochondrial coenzyme A by carnitine acyl-transferase II – an isozyme located on the inner face of the inner mitochondrial membrane that regenerates fatty acyl-CoAand releases it, along with carnitine, into the matrix- Coenzyme A in the mitochondrial matrix is largely used in oxidative degradation of pyruvate, fatty acids, and some amino acids- Cytosolic coenzyme A is used in the biosynthesis of fatty acids- Fatty acyl-CoA in the cytosolic pool can be used for membrane lipid synthesisas well17.2 Oxidation of Fatty Acids- Three stages:o Oxidation – fatty acids undergo oxidative removal of successive two-carbon units in the form of acetyl-CoA, starting from the carboxyl end of the fatty acyl chaino The acetyl groups
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