Fatty Acid Oxidation PDF

Oxidation of fatty acids Objectives: After studying this topic, you should be able to: Describe the processes by which fatty acids are transported in the blood, activated and transported into the matrix of the mitochondria for breakdown to obtain energy. Outline the β-oxidation pathway by which...

Oxidation of fatty acids Objectives: After studying this topic, you should be able to: Describe the processes by which fatty acids are transported in the blood, activated and transported into the matrix of the mitochondria for breakdown to obtain energy. Outline the β-oxidation pathway by which fatty acids are metabolized to acetyl- CoA and explain how this leads to the FAs are both oxidized to acetyl-CoA and synthesized from acetyl-CoA. FA oxidation is not the simple reverse of FA biosynthesis but an entirely different process taking place in a separate compartment of the cell. FA oxidation takes place in mitochondria. FA oxidation is an aerobic process, requiring the presence of oxygen. Utilize NAD and FAD as coenzymes and generates ATP. FAs are transported in the blood as free FAs. FFA of longer-chain FA are combined with albumin, and in cell they are attached to a FA binding protein. Steps of FA oxidation: 1. Activation:  This is only step in the complete degradation of FA that requires energy from ATP FA+ATP+CoA ( Acyl-CoA synthatase ( thiokinase) ) Acyl CoA+PPi+AMP  Several acyl-CoA synthatase have been described each specific for FAs of different chain length. 2.Transport of long chain FAs into the mitochondria:-  Activation of short-chain fatty acid and their oxidation within the mitochondria may occur independently of carnitine, but long chain acyl–CoA will not penetrate the inner membrane of mitochondria and become oxidized unless they form acyl carnitine.  Long-chain FAs penetrate the inner mitochondrial membrane as carnitine derivatives.  Carnitine (β-hydroxy γ-trimethyl ammonium butyrate ), is abundant in muscle.  Carnitine can be obtained from the diet, where it is found primarily in meat products.  Carnitine can be also synthesized from the amino acids lysine and methionine in the liver and kidney. 3. β-oxidation of fatty acids:  In β-oxidation, two carbons are activated at a time from acyl-CoA molecules starting at the carboxyl end.  The chain is broken between α(2) and β(3) carbon. ( β-oxidation).  The two-carbon units formed are acetyl-CoA, thus palmitoyl-CoA forms (8 ) acetyl-CoA molecules.  Several enzymes are catalyzed the reaction, known collectively as FA oxidase, are found in the mitochondrial matrix or inner membrane adjacent to the respiratory chain in the inner membrane. These catalyze the oxidation of acyl-CoA, the system being coupled with the phosphorylation of ADP to ATP. Oxidation of odd number FA: FAs with an odd number of carbon atoms are oxidized by pathway of β-oxidation, producing acetyl-CoA until a three-carbon (propionyl-CoA) residue remains. Propionyl-CoA is converted to succinyl-CoA, a constituent of the citric acid cycle.  The propionyl residue from an odd-chain FA is the only part of FA that is glucogenic. β-oxidation in the peroxisomes: Very long chain FAs, (20) carbons & longer, undergo a preliminary β-oxidation in peroxisomes, lead to formation of acetyl-CoA and H2O2. In contrast to mitochondrial β-oxidation the initial dehydrogenation in peroxisomes is catalyzed by an FAD-containing acyl-CoA oxidase. The FADH2 produced is oxidized by molecular oxygen, which is reduced to H2O2 H2O2 is reduced to H2O by catalase. This dehydrogenation in peroxisomes is not linked directly to phosphorylation and the generation of ATP. Further role of peroxisomal β-oxidation is to shorten the side chain of cholesterol in bile acid formation, &take part in the synthesis of plasmalogen, cholesterol, and dolichol. α-oxidation of FAs:  It is removal of one carbon at a time from the carboxyl end of the molecule. ( brain tissue) The branched-chain FAs, ( phytanic) is not substrate for acyl-CoA dehydrogenase due to methyl group on its third (β) carbon. Instead, it is hydroxylated at the α-carbon by FA α- hydroxylase ,the product is decarboxylated and then activated to its CoA derivative, which is substrate for the enzymes of β- oxidation. Does not generate high-energy phosphate.  ω- oxidation of FAs ω- oxidation of FAs: Minor pathway &is brought about by hydroxylase enzymes involving cytochrome P450 in the ER. The -CH3 group is converted to –CH2OH group that subsequently is oxidized to –COOH ,thus forming a dicarboxylic acid. Oxidation of unsaturated FAs: Oxidation of unsaturated FAs provides less energy than that of saturated FAs because they are less highly reduced and therefore, fewer reducing equivalents can be produced from these structures. Oxidation of monounsaturated FAs ( oleic acid) are requires additional enzyme 2,3- enoylCoA isomerase, which converts the 3-cis derivative obtained after 3 rounds of β- oxidation to the 2-trans derivative that can serve as substrate for the hydroxylase. Oxidation of polyunsaturated FAs, such as lenoleic acid, requires NADPH-dependent reductase in addition to the isomerase. Clinical conditions: 1. Carnitine deficiency: Occur in : Preterm infants Liver diseases Malnutrition Vegetarians Pregnancy Severe infections Burns, or trauma, Hemodialysis Organic aciduria patients. Signs &symptoms of carnitine deficiency episodic periods of hypoglycemia with muscular weakness. Treatment is by oral supplementation of carnitine. Inherited defects in the enzymes of β-oxidation lead to nonketotic hypoglycemia, coma and fatty liver. Dicarboxylic aciduria:  Characterized by the excretion of C6-C10 ω- dicarboxylic acids and by nonketotic hypoglycemia.  It is caused by lack of mitochonderial medium chain acyl-Co A dehydrogenase This impairs β-oxidation but increases ω- oxidation of long and medium chain FA which are then shortened by β-oxidation to medium chain dicarboxlyic acid ,which are excreted. Refsum disease:  Is a rare, autosomal recessive disorder caused by a deficiency of α-hydroxylase. This results in the accumulation of phytanic acid in the plasma and tissues.  The symptoms are primarily neurologic. Zelleweger’ s (cerebrohepatorenal) syndrome:  Inherited absence of peroxisomes in all tissues.  Lead to accumulation of very long chain FA in the blood and tissues. The