Biochemistry and Molecular Biology - Belyasova N.A. 2002

Metabolism. Energy-Yielding Processes
Catabolic Pathways
Fatty Acid Oxidation

The Biological Oxidation of Fatty acids can be compared to the combustion of Hydrocarbons: in both cases, the maximum yield of Free energy is observed. During the biological ß-Oxidation of the hydrocarbon portion of fatty acids, two-carbon activated components are formed—which undergo further oxidation in the TCA cycle—along with A large number of reducing equivalents that drive ATP Synthesis in the Respiratory Chain. Most aerobic Cells are capable of the Complete oxidation of fatty acids to carbon dioxide and Water.

Exogenous or endogenous Lipids serve as the source of fatty acids. The latter are most commonly represented by triacylglycerols, which are stored in cells as a reserve source of energy and carbon. In addition, cells utilize polar Membrane Lipids, which undergo constant metabolic renewal. Lipids are cleaved into glycerol and free fatty acids by specific Enzymes called lipases.

β-Oxidation of Fatty acids. This primary process of Fatty acid oxidation takes place in the Cell/35.html">Mitochondria of eukaryotes. Carnitine (γ-trimethylamino-β-hydroxybutyrate) facilitates The transport of fatty acids across the mitochondrial membranes by binding the fatty acid molecule in a specific manner. As a result, the positive charge (on the nitrogen atom) and the negative charge (on the oxygen atom of the carboxyl group) are brought into close proximity and neutralize each other.

Following transport into the mitochondrial matrix, fatty acids undergo activation involving CoA in an ATP-dependent reaction catalyzed by acetate thiokinase (Fig. 9.1). Next, the acyl-CoA derivative is oxidized with the participation of acyl-CoA dehydrogenase. Cells contain several different acyl-CoA dehydrogenases specific to fatty acid CoA derivatives of varying hydrocarbon chain lengths. All of these enzymes utilize FAD as a prosthetic group. The FADH₂ generated within the acyl-CoA dehydrogenase is oxidized by another flavoprotein that transfers electrons to the respiratory chain embedded in the mitochondrial membrane.

The oxidation product, enoyl-CoA, is hydrated by the action of enoyl-CoA hydratase to form ß-hydroxyacyl-CoA (Fig. 9.1). Enoyl-CoA hydratases exist that are specific to both the cis- and trans-forms of fatty acid enoyl-CoA derivatives. Specifically, trans-enoyl-CoA is stereospecifically hydrated to L-ß-hydroxyacyl-CoA, whereas cis-isomers are converted to D-stereoisomers of ß-hydroxyacyl-CoA esters.

The final stage of the ß-oxidation reactions involves the dehydrogenation of L-ß-hydroxyacyl-CoA (Fig. 9.1). Because the ß-carbon atom of the molecule undergoes oxidation, the entire process is named ß-oxidation. The reaction is catalyzed by ß-hydroxyacyl-CoA dehydrogenase, which is specific exclusively to the L-forms of ß-hydroxyacyl-CoA. This enzyme utilizes NAD as a coenzyme. The dehydrogenation of D-isomers of ß-hydroxyacyl-CoA occurs following an additional isomerization step that converts them into L-ß-hydroxyacyl-CoA (via the enzyme ß-hydroxyacyl-CoA epimerase). The product of this reaction step is ß-ketoacyl-CoA, which is readily cleaved by thiolase into two derivatives: an acyl-CoA molecule that is shorter than the initial activated substrate by two carbon atoms, and acetyl-CoA—a two-carbon unit cleaved from the fatty acid chain (Fig. 9.1). The acyl-CoA derivative enters the next cycle of ß-oxidation reactions, while the acetyl-CoA can enter The Tricarboxylic Acid Cycle for further oxidation.

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Fig. 9.1. The process of ß-oxidation of fatty acids. R represents the hydrocarbon moiety of the fatty acid molecule.

Thus, each cycle of fatty acid ß-oxidation is accompanied by the Cleavage of a two-carbon fragment (acetyl-CoA) from the substrate, along with two pairs of hydrogen atoms that reduce 1 molecule of NAD⁺ and one molecule of FAD. The process continues until the fatty acid chain is completely degraded. If the fatty acid contains an odd number of carbon atoms, ß-oxidation concludes with The formation of propionyl-CoA, which is converted into succinyl-CoA through a series of reactions and can subsequently enter the TCA cycle.

The majority of fatty acids found in animal, plant, and microbial cells possess unbranched hydrocarbon chains. At the same time, the lipids of certain microorganisms and plant Waxes contain fatty acids whose hydrocarbon radicals feature branch points (typically in the form of methyl groups). If branching is sparse and all branch points occur at even positions (at carbon atoms 2, 4, etc.), ß-oxidation proceeds via the standard pathway, yielding acetyl-CoA and propionyl-CoA. However, if methyl groups are located at odd carbon atoms, ß-oxidation is blocked at the Hydration stage. This must be taken into account in the manufacture of synthetic detergents: to ensure their rapid and complete biodegradation in the environment, only variants with unbranched hydrocarbon chains should be approved for mass consumption.

Oxidation of Unsaturated fatty acids. This process proceeds in compliance with all the regularities of ß-oxidation. However, most naturally occurring Unsaturated fatty acids contain double bonds at positions in the hydrocarbon chain such that the sequential removal of two-carbon fragments from the carboxyl end yields an acyl-CoA derivative with a double bond at the 3–4 position. Furthermore, the double bonds of natural fatty acids possess a cis-configuration. For the dehydrogenation step catalyzed by ß-hydroxyacyl-CoA dehydrogenase (which is specific to L-forms of ß-hydroxyacyl-CoA) to take place, an additional enzymatic isomerization step is required. During this step, the double bond in the fatty acid CoA derivative shifts from the 3–4 position to the 2–3 position, and its configuration changes from cis to trans. This metabolite serves as a substrate for enoyl-CoA hydratase, which converts trans-enoyl-CoA into L-ß-hydroxyacyl-CoA.

In cases where the shifting and isomerization of the double bond are impossible, the double bond is reduced with the participation of NADPH. Subsequent degradation of the fatty acid then proceeds via the standard ß-oxidation mechanism.

Minor pathways of fatty acid oxidation. ß-Oxidation represents the principal, but not the only, pathway of fatty acid Catabolism. For instance, an a-oxidation process has been discovered in plant cells for fatty acids containing 15 to 18 carbon atoms. This pathway involves the initial attack of the fatty acid by a peroxidase in the presence of hydrogen peroxide, resulting in the release of the carboxyl carbon as CO₂ and The oxidation of the a-carbon atom to an aldehyde group. Subsequently, the aldehyde is oxidized by a dehydrogenase to yield a higher fatty acid, and the process repeats (Fig. 9.2). However, this pathway cannot achieve complete oxidation. It is utilized merely for shortening fatty acid chains and serves as a bypass route when ß-oxidation is blocked due to the presence of side-chain methyl groups. The process does not require CoA and is not accompanied by ATP synthesis.

Certain fatty acids may also undergo oxidation at the ω-carbon atom (ω-oxidation). In this case, the CH₃ group undergoes hydroxylation mediated by a monooxygenase, yielding an ω-hydroxy acid that is subsequently oxidized to a dicarboxylic acid. The dicarboxylic acid can then be shortened from either end via ß-oxidation reactions.

Fig. 9.2. The process of a-oxidation of fatty acids

In a similar manner, saturated hydrocarbons are degraded in the cells of microorganisms and certain animal Tissues. In The First stage, molecular oxygen mediates the hydroxylation of the molecule to form an alcohol, which is sequentially oxidized to an aldehyde and a carboxylic acid, activated by the attachment of CoA, and enters the ß-oxidation pathway.