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Clinical biochemistry second stage OXIDATION OF FATTY ACIDS (LIPOLYSIS) Fatty acids stored in adipose tissue, in form of neutral TAG, serve as the body's major fuel storage. The main oxidations of fatty acid are: α - Oxidation Β- Oxidation ω- Oxidation Quantitatively β oxidation of fatty acids is the most important pathway which occurs in the mitochondria. However α and ω also occur,βoxidation of fatty is the most important pathway for fatty acid oxidation. The initial event in the utilization of fat as an energy source is the hydrolysis of triacylglycerol .This process is initiated by hormonesensitive lipase (HSL), which removes a fatty acid from carbon 1 and/or carbon 3 of the TAG. Epinephrine (as well as norepinephrine) and glucagon stimulate fatty acid release from triglycerides stored in adipocyte fat droplets, whereas insulin action is to counter the responses to these two hormones, and conversely, to induce fat storage. Epinephrine and glucagon binding to their respective receptors triggers activation of adenylate cylcase which lead to activation of HSL, this enzyme is 'activated when phosphorylated by 3',5'-cydie AMP-dependent protein kinase while in the presence of high plasma levels of insulin, HSL is dephosphorylated, and becomes inactive. 1 Clinical biochemistry second stage Then free fatty acids move through the cell membrane of the adipocyte, and immediately bind to albumin in the plasma. They are transported to the tissues, where the fatty acids enter cells, get activated to their CoA derivatives, and are oxidized for energy. Fatty acids are both oxidized to acetyl-CoA and synthesized from acetylCoA. Although the staring material of one process is identical to the product of the other, fatty acid oxidation is not the simple reverse of fatty acid biosynthesis. It is an entirely different process taking place in separate compartment of the cell. This allows each process to be individually controlled. Stages of fatty acid oxidation (1) Activation of fatty acids (2) Transport into the mitochondria (3) Degradation (B-oxidation pathway) 2 Clinical biochemistry second stage Activation of Fatty Acids Fatty acids are converted to CoA thioesters by acyl-CoA synthetase (two ATP equivalents) are consumed to activate one fatty acid to a thioester. Transport of Fatty Acyl CoA into Mitochondria Fatty acids are activated in the cytoplasm; but the beta oxidation is in mitochondria. So transport of fatty acids through the mitochondrial membrane is essential. The long chain fatty acyl CoA cannot pass through the inner mitochondrial membrane. Therefore a transporter, carnitine is involved in transfer of fatty acids The enzyme carnitine acyl transferase-I (CAT-I) will transfer the fatty acyl group to the hydroxyl group of carnitine to form acyl carnitine . translocase will carry the acyl carnitine across the membrane to the matrix of mitochondria.On the matrix side of the membrane another enzyme, carnitine acyl transferase-II (CAT-II) will transfer the acyl group back to co-enzyme A molecule. Carnitine is returned to the cytosolic side by the translocase. Fatty acids shorter than twelve carbons can cross the inner mitochondrial membrane without the aid of carnitine 3 Clinical biochemistry second stage The Reactions of B oxidation The oxidation of the hydrocarbon chain (fatty acyl) occurs by a sequential cleavage of two carbon atoms (as acetyl CoA) in the mitochondrial matrix. This process is known as beta oxidation, because the oxidation and splitting of two carbon units occur at the beta-carbon atom β-oxidation is consists of a sequence of four reactions that result in shortening the fatty acid chain by two carbons. The steps include an oxidation that produces FADH2 ,a hydration step, a second oxidation that produces NADH, and a thiolytic cleavage that releases a molecule of acetyl CoA. These four steps are repeated for saturated fatty acids of even-numbered carbon chains (n/2)-1times (where n is the number of carbons), each cycle producing an acetyl group plus one NADH and one FADH2.The final thiolytic cleavage produces two acetyl groups. 1. Oxidation of acyl CoA by an acyl CoA dehydrogenase to give an enoyl CoA Coenzyme - FAD 2. Hydration of the double bond between C-2 and C-3 by enoyl CoA hydratase with the 3-hydroxyacyl CoA (-hydroxyacyl CoA) formation 4 Clinical biochemistry second stage 3. Oxidation of 3-hydroxyacyl CoA to 3-ketoacyl CoA by 3-hydroxyacyl CoA dehydrogenase Coenzyme – NAD+ 4. cleavage reaction catalyzed by Thiolase Each round (4 enzyme steps) generates one molecule of: FADH2 NADH Acetyl CoA Fatty acyl CoA (2 carbons shorter each round) Fates of the products of B-oxidation NADH and FADH2 - are used in electron respiratory chain acetyl CoA - enters the citric acid cycle acyl CoA – undergoes the next cycle of oxidation Energy yield from fatty acid oxidation The energy yield from the β-oxidation pathway is high. For example, the oxidation of amolecule of palmitoyl CoA(16 carbon) yields 129 ATPs 8 acetyl CoA 7 FADH2 8x12=96 7x2=14 5 Clinical biochemistry second stage 7 NADH 7x3=21 131 ATP ATP expended to activate palmitate Net yield: -2 129 ATP Oxidation of fatty acids with an odd number of carbons: The β-oxi-dation of a saturated fatty acid with an odd number of carbon atoms proceeds by the same reaction steps as that of fatty acids with an even number, until the final three carbons are reached. This compound, propionyl CoA, is metabolized by a three-step pathway Propionyl CoA Is Converted into Succinyl CoA 1. Propionyl CoA is carboxylated to yield the D isomer of methylmalonyl CoA. The hydrolysis of an ATP is required. Enzyme: propionyl CoA carboxylase Coenzyme: biotin 2. The D isomer of methylmalonyl CoA is racemized to the L isomer Enzyme: methylmalonyl-CoA racemase 3. L isomer of methylmalonyl CoA is converted into succinyl CoA by an intramolecular rearrangement Enzyme: methylmalonyl CoA mutase Coenzyme: vitamin B12 (cobalamin) 6 Clinical biochemistry second stage β Oxidation of Unsaturated Fatty Acids The oxidation of unsaturated fatty acids provides less energy than that of saturated fatty acids because they are less highly reduced and, therefore, fewer reducing equivalents can be produced from this oxidation. Comparism between synthesis and degradation of fatty acids Ketone Bodies Are Fuel That Are Synthesized in the liver Unbalanced metabolism of fats and carbohydrate changes the flow of nutrients pathways Common factors in abnormal metabolic conditions Lack of carbohydrates Impaired use of carbohydrates Fasting Starvation Untreated diabetes Response to a Fast and Starvation The natural response to glucose and energy deficiency is involves two metabolic processes. Firstly the adrenal cortex secretes glucocorticoids to stimulate gluconeogenesis. Secondly growth hormone is secreted to accelerate lipolysis in adipose tissue to provide fatty acids for oxidation. Liver glycogen stores are depleted .Fatty acids can be used by heart, kidney skeletal muscle and liver. Fatty acids are not used as fuel by the brain because they do not cross the blood brain barrier. Survival during starvation is mainly determined by the size of the stored triacylglycerol pool .After several days of starvation acetyl CoA is made in abnormally 7 Clinical biochemistry second stage high amounts due to excessive fatty acid breakdown since glucose/glycogen is not available, glucose is the primary source of fuel for the human brain therefore the rate of gluconeogenesis has to increase during fasting or carbohydrate starvation, oxaloacetate in liver is depleted from the TCA cycle because it is used for gluconeogenesis(making glucose for the brain) impedes entry of acetyl CoA into the TCA cycle. Excessive Acetyl CoA is converted in liver mitochondria to ketone bodies.Ketone bodies can be thought of as “soluble fats exported to cells that need it. Synthesis of the ketone bodies 1. β Ketothiolase condensing 2 acetyl CoA to produce acetoacetyl CoA, with release of one CoA 2. HMG CoA Synthase catalyzes condensation of a third acetate moiety (from acetyl CoA) with acetoacetyl CoA to form hydroxymethylglutaryl CoA (HMG CoA). 3. HMG CoA Lyase cleaves HMG CoA to yield acetoacetate plus acetyl CoA 4. β Hydroxybutyrate dehydrogenase catalyzes inter conversion of the ketone bodies acetoacetate and β hydroxybutyrate. 8 Clinical biochemistry second stage Ketone Bodies are oxidized in mitochondria of many tissues other than liver .Liver cannot use ketone bodies because the activating enzyme required for ketone body utilization is absent in the liver. While ketogenesis is an important survival mechanism that maintains high rates of fatty acid oxidation when carbohydrates stores are depleted, it can also lead to pathological conditions if acetoacetate and D-βhydroxybutyrate levels in the blood get too high. Acidosis is a condition referring to low blood pH which can occur when ketogenesis produces more acetoacetate and D-β- hydroxybutyrate than what can be utilized by the peripheral tissues. In patients with undiagnosed diabetes, which is a metabolic form of carbohydrate"starvation," elevated concentrations of acetoacetate and D-β-hydroxybutyrate in the blood and urine can be several orders of magnitude higher than normal causing nausea, vomiting and stomach pain. Moreover, these individuals also have high levels of acetone in their blood which can be detected on their breath as a fruity odor. Acetone is a spontaneous breakdown product of acetoacetate 9