Oxidation of Fatty Acids Fatty acids are an important source of energy and adenosine triphosphate (ATP) for many cellular organisms. Excess fatty acids, glucose, and other nutrients can be stored efficiently as fat. Triglycerides yield more than twice as much energy for the same mass as do carbohydrates or proteins.

Oxidation of Fatty Acids There are several types of fatty acids oxidation. (1) β- oxidation of fatty acid (2) α- oxidation of fatty acids (3) ω- oxidation of fatty acids

β- oxidation of fatty acid This type of oxidation was originally discovered by a scientist named knoop in 1905. It is sometimes called knoop's oxidation. It occurs in many tissues including liver kidney and heart. Fatty acids oxidation doesn't occur in the brain, as fatty acid can't be taken up by that organ.

Intracellular, the mitochondria are the principle sites of fatty acids oxidation. Beta-oxidation is the process by which fatty acids, in the form of Acyl-CoA molecules, are broken down in mitochondria and/or in peroxisomes to generate Acetyl-CoA, the entry molecule for the Citric Acid cycle.

The beta oxidation of fatty acids involve three stages: Activation of fatty acids in the cytosol Transport of activated fatty acids into mitochondria (carnitine shuttle) Beta oxidation proper in the mitochondrial matrix

Fatty acids to be oxidized must be entered the following steps: 1) Activation of FA: This proceeds by FA thiokinase (acyl COA synthetase) present in endoplasmic reticulum and in the outer mitochondrial membrane. Thiokinase requires ATP, COA SH, Mg++. The product of this reaction is acyl COA and water.

mitochondrion the mitochondrion contained the enzymes responsible for electron transport and oxidative phosphorylation In inner membrane knobs Impermeable to ions and most other compounds

ATP is converted to AMP + P~P, the energy released is utilized for formation of high energy bond (thioester bond) in acyl COA (RCO ~ S COA). The high energy of P~P is lost by pyrophosphatase thus two high energy phosphates are lost during activation.

2-Transport of fatty acyl CoA from cytosol into mitochondria: Long chain acyl CoA cannot readily traverse the inner mitochondria membrane and so a special transport mechanism called carnitine shuttle is needed.

Carnitine It is synthesized in liver and kidney from lysine. It is essential for oxidation of long chain fatty acids. Carnitine is not required for the permeation of medium chain acyl CoA into the mitochondrial matrix. Carnitine (β-hydroxy-y-trimethyl-ammonium butyrate) is a carrier. N(CH3)3 CH2 H-C-OH COO- + Carnitine

Acyl groups from acyl COA is transferred to hydroxyl group of carnitine to form acyl carnitine, catalyzed by carnitine acyltransferase I, located in the outer mitochondrial membrane.

Acylcarnitine is then shuttled across the inner mitochondrial membrane by a translocase enzyme. The acyl group is transferred back to CoA on the inner border of the matrix side of the inner mitochondrial membrane by carnitine acyl transferase II. Finally, carnitine is returned to the cytosolic side by translocase, in exchange for an incoming acyl carnitine.

FAD is the hydrogen acceptor. 3- Steps of beta oxidation proper in the mitochondrial matrix: The first reaction is the oxidation of acyl CoA by an acyl CoA dehyrogenase to give α-β unsaturarted acyl CoA (enoyl CoA). FAD is the hydrogen acceptor.

The second step is the hydration of the double bond to β-hydroxyacy CoA (p-hydroxyacyl CoA).

Then, the β-hydroxyacyl CoA is oxidized to produce β-Ketoacyl CoA a NAD-dependent reaction.

Finally, cleavage of the two carbon fragment by thiolase enzyme occurs.

The release of acetyl CoA leaves an acyl CoA molecule shortened by 2 carbons. This acyl CoA molecule is the substrate for the next round of oxidation starting with acyl CoA dehydrogenase. Repetition continues until all the carbons of the original fatty acyl CoA are converted to acetyl CoA. In the last round a four carbon acyl CoA (butyryl CoA) is cleaved to 2 acetyl CoA.

Energetics of FA oxidation e.g. Palmitic (16C): B-oxidation of palmitic acid will be repeated 7 cycles producing 8 molecules of acetyl COA. In each cycle FADH2 and NADH+H+ is produced and will be transported to the respiratory chain. FADH2 2 ATP NADH + H+ 3 ATP So 7 cycles 5x7 = 35 ATP

Each acetyl COA which is oxidized in citric cycle gives 12 ATP (8 x 12 = 96 ATP) 2 ATP are utilized in the activation of fatty acid (It occurs once). Energy gain = Energy produced - Energy utilized = 35 ATP + 96 ATP - 2 ATP = 129 ATP

Calculation of Energetics of any FA Oxidation: [(N/2 - 1) x 5 ATP] + [N/2 x 12 ATP] - 2 ATP. Number of carbons of fatty acid.)

α-oxidation This type of oxidation occurs in α-position with the removal of one carbon from the carboxyl end of fatty acids. It occurs in brain but occurs also in liver tissues. Does not require coenzyme A and does not generate ATP.

Function: Formation of a hydroxyl fatty acids which is a constituent of brain lipids. Modification of FA with methyl groups on the 6 carbon which block 6 oxidation e.g. phytanic acid present in certain plants, it has 4 CH3 groups at position 3, 7, 11, 15, by initial a oxidation and removal of one carbon, CH3 groups is at a position, FA undergo 6 oxidation.

Refsum's disease: It is a rare neurological disorder caused by accumulation of phytanic acid, a constituent of chlorophyll found in plant foodstuffs. Phytanic acid contains a methyl group on carbon 3 that blocks (β oxidation). Normally, an initial a oxidation removes the methyl group, but in Refsum's disease there is inherited defect in a oxidation that allows accumulation of phytanic acid

Omega Oxidation: Omega oxidation of fatty acids at the terminal methyl group producing dicarboxylic acid (HOOC R COOH). It occurs in microsomes of the liver. The dicarboxylic acid formed may be shorted from both ends by B oxidation liberating 2 molecules of acetyl COA each time. Oxidation continues usually to adipic (Ce) and suberic (Cg) acids which are excreted in urine

Oxidation of unsaturated Fatty acid Oxidation of the unsaturated FA occurs by the enzymes normally responsible for β-oxidation till the double bond is approached. If the double bond is A -cis, it becomes isomerized to A2-trans, then β-oxidation continues. If the double bond is A4 cis, it first forms A2-trans A4-cis derivative (as usually occurs in β-oxidation). A reductase enzyme reduces the A4-cis double bond forming A2-trans derivative which continues in β-oxidation.