Biochemistry and Molecular Biology - Belyasova N.A. 2002

Metabolism. Processes leading to energy storage
Catabolic pathways
Fatty acid oxidation

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 amount of reduction equivalents that drive ATP Synthesis in the Respiratory Chain. Most aerobic Cells are capable of completely oxidizing fatty acids to carbon dioxide and Water.

Fatty acids are derived from exogenous or endogenous Lipids. The latter are most commonly triacylglycerols, which are stored in cells as a reserve source of energy and carbon. In addition, cells utilize polar Membrane Lipids, which undergo continuous metabolic turnover. Lipids are cleaved by specific Enzymes (lipases) into glycerol and free fatty acids.

b-Oxidation of Fatty acids. This primary pathway of Fatty acid oxidation takes place in the Cell/35.html">Mitochondria of eukaryotes. The transport of fatty acids across the mitochondrial membranes is facilitated by carnitine (y-trimethylamino-ß-hydroxybutyrate), which binds the fatty acid molecule in a specific manner, bringing the positive charge (on the nitrogen atom) and the negative charge (on the oxygen atom of the carboxyl group) close together so that they neutralize each other.

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

The oxidation product, enoyl-CoA, is hydrated by enoyl-hydratase to form ß-hydroxyacyl-CoA (Fig. 9.1). There are enoyl-CoA hydratases specific to 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 into D-stereoisomers of ß-hydroxyacyl-CoA esters.

The final stage of ß-oxidation reactions involves the dehydrogenation of L-ß-hydroxyacyl-CoA (Fig. 9.1). The ß-carbon atom of the molecule is subjected to oxidation, which is why the entire process is termed ß-oxidation. This reaction is catalyzed by ß-hydroxyacyl-CoA dehydrogenase, which is strictly specific to the L-forms of ß-hydroxyacyl-CoA. This enzyme uses NAD as a coenzyme. The dehydrogenation of D-isomers of ß-hydroxyacyl-CoA is preceded by an additional isomerization step converting them into L-ß-hydroxyacyl-CoA (catalyzed by 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 two carbon atoms shorter than the initial activated substrate, 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 fatty acid ß-oxidation. 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 and 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 terminates with The formation of propionyl-CoA, which is converted into succinyl-CoA through a series of reactions and can then enter the TCA cycle.

Most fatty acids found in animal, plant, and microbial cells contain unbranched hydrocarbon chains. At the same time, the lipids of certain microorganisms and plant Waxes contain fatty acids whose hydrocarbon radicals feature branch points (usually as methyl groups). If branching is sparse and restricted to even-numbered positions (carbon atoms 2, 4, etc.), ß-oxidation proceeds via the standard pathway, yielding acetyl- and propionyl-CoA. However, if methyl groups are located at odd-numbered carbon atoms, ß-oxidation is blocked at the Hydration step. This must be taken into account in The production 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 follows all the general rules of ß-oxidation. However, most natural Unsaturated fatty acids contain double bonds at positions along the hydrocarbon chain such that the successive 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 in 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 to the 2—3 position, and its configuration changes from cis to trans. This intermediate serves as the substrate for enoyl-hydratase, which converts trans-enoyl-CoA into L-ß-hydroxyacyl-CoA.

In cases where the migration and isomerization of the double bond are not feasible, the bond is reduced in the presence of NADPH. Subsequent degradation of the fatty acid then proceeds via the standard ß-oxidation mechanism.

Minor pathways of fatty acid oxidation. Although ß-oxidation is the primary pathway of fatty acid Catabolism, it is not the only one. For instance, plant cells exhibit a-oxidation of fatty acids containing 15—18 carbon atoms. This pathway involves the initial attack of the fatty acid by 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. The aldehyde is subsequently oxidized to a higher fatty acid by a dehydrogenase, and the process repeats (Fig. 9.2). However, this pathway cannot ensure complete oxidation. It serves merely to shorten fatty acid chains and acts as a bypass when ß-oxidation is blocked due to the presence of side methyl groups. The process does not require CoA and is not coupled with ATP synthesis.

Certain fatty acids can also undergo oxidation at the ω-carbon atom (ω-oxidation). In this case, the CH₃ group is hydroxylated by a monooxygenase to form a ω-hydroxy acid, which 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 fatty acid a-oxidation

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