In the pathway for the oxidation of fatty acids (Figure 1), two carbons at a time are cleaved from acyl-CoA molecules, starting at the carboxyl end. The chain is broken between the α(2)- and β(3)-carbon atoms—hence the process is termed β-oxidation. The two-carbon units formed are acetyl-CoA; thus, palmitoyl(C16)-CoA forms eight acetyl-CoA molecules.

Fig1. Overview of β-oxidation of fatty acids.

The β-Oxidation Cycle Generates FADH2 & NADH

Several enzymes found in the mitochondrial matrix or inner membrane adjacent to the respiratory chain catalyze the oxidation of acyl-CoA to acetyl-CoA via the β-oxidation pathway. The system proceeds in cyclic fashion which results in the degradation of long fatty acids to acetyl-CoA. In the process, large quantities of the reducing equivalents FADH2 and NADH are generated and are used to form ATP by oxidative phosphorylation (Figure 2).

Fig2. β-Oxidation of fatty acids. Long-chain acyl CoA is cycled through reactions 2 to 5 , acetyl-CoA being split off, each cycle, by thiolase (reaction 5 ). When the acyl radical is only four carbon atoms in length, two acetyl-CoA molecules are formed in reaction 5 .

The first step is the removal of two hydrogen atoms from the 2(α)- and 3(β)-carbon atoms, catalyzed by acyl-CoA dehydrogenase and requiring flavin adenine dinucleotide (FAD). This results in the formation of Δ2-trans-enoyl-CoA and FADH2 . Next, water is added to saturate the double bond and form 3-hydroxyacyl-CoA, catalyzed by Δ2-enoyl-CoA hydratase. The 3-hydroxy derivative undergoes further dehydrogenation on the 3-carbon catalyzed by l-3-hyroxyacyl-CoA dehydrogenase to form the corresponding 3-ketoacyl-CoA compound. In this case, NAD+ is the coenzyme involved. Finally, 3-ketoacyl CoA is split at the 2,3-position by thiolase (3-ketoacyl-CoA thiolase), forming acetyl-CoA and a new acyl-CoA two carbons shorter than the original acyl-CoA molecule. The shorter acyl-CoA formed in the cleavage reaction reenters the oxidative pathway at reaction 2 (see Figure 2). In this way, a long-chain fatty acid with an even number of carbons may be degraded completely to acetyl-CoA (C2 units). For example, after seven cycles, the C16 fatty acid, palmitate, would be con verted to eight acetyl-CoA molecules. Since acetyl-CoA can be oxidized to CO2 and water via the citric acid cycle (which is also found within the mitochondria), the complete oxidation of fatty acids is achieved.

Fatty acids with an odd number of carbon atoms are oxidized by the pathway of β-oxidation described earlier, producing acetyl-CoA until a three-carbon (propionyl-CoA) residue remains. This compound is converted to succinyl-CoA, a constituent of the citric acid cycle. Hence, the propionyl residue from an odd-chain fatty acid is the only part of a fatty acid that is glucogenic.

Oxidation of Fatty Acids Produces a Large Quantity of ATP

Each cycle of β-oxidation generates one molecule of FADH2 and one of NADH. The breakdown of 1 mol of the C16 fatty acid, palmitate, requires seven cycles and produces 8 mol of acetyl CoA. Oxidation of the reducing equivalents via the respiratory chain leads to the synthesis of 28 mol of ATP (Table 1 ) and oxidation of acetyl-CoA via the citric acid cycle produces 80 mol of ATP (see Table 1). The breakdown of 1 mol of palmitate, therefore, yields a gross total of 108 mol of ATP. However, two high-energy phosphates are used in the initial activation step (see Figure 2), thus there is a net gain of 106 mol of ATP per mole of palmitate used (see Table 1), or 106 × 30.5* = 3233 kJ. This represents 33% of the free energy of combustion of palmitic acid.

Table1. Generation of ATP From the Complete Oxidation of a C16 Fatty Acid

Peroxisomes Oxidize Very-Long-Chain Fatty Acids

A modified form of β-oxidation is found in peroxisomes and leads to the breakdown of very-long-chain fatty acids (eg, C20, C22) with the formation of acetyl-CoA and H2 O2 , which is broken down by catalase (see Chapter 12). This system, however, is not linked directly to phosphorylation and the generation of ATP. The peroxisomal enzymes are induced by high-fat diets and in some species by hypolipidemic drugs such as clofibrate.

Another role of peroxisomal β-oxidation is to shorten the side chain of cholesterol in bile acid formation. Peroxisomes also take part in the synthesis of ether glycerolipids , cholesterol, and dolichol .

Oxidation of Unsaturated Fatty Acids Occurs by a Modified β-Oxidation Pathway

 The CoA esters of unsaturated fatty acids are degraded by the enzymes normally responsible for β-oxidation until there is a cis double bond in the Δ3 or Δ4 position (Figure 3). A Δ3 cis compound is isomerized (Δ3cis → Δ2-trans-enoyl-CoA isomerase) to the corresponding Δ2-trans-CoA stage of β-oxidation for subsequent hydration and oxidation. Any Δ4-cis-acyl-CoA either remaining, as in the case of linoleic acid (shown in Figure 3), or entering the pathway at this point after conversion by acyl-CoA dehydrogenase to Δ2 trans-Δ4-cis-dienoyl-CoA, is then metabolized as indicated in Figure 3.

Fig3. Sequence of reactions in the oxidation of unsaturated fatty acids, for example, linoleic acid. β-Oxidation proceeds as for saturated fatty acids until there is a cis double bond in the Δ3 position. This is then isomerized to the corresponding Δ2-trans compound allowing one cycle of β-oxidation to proceed, producing the Δ2- trans- Δ4-cis derivative. Δ4-cis-fatty acids or fatty acids forming Δ4-cis-enoyl-CoA enter the pathway here. A reduction step forming Δ3-trans-enoyl-CoA followed by an isomerization to the Δ2-trans form is required to enable β-oxidation to then go to completion. NADPH for the dienoyl-CoA reductase step is supplied by intramitochondrial sources such as glutamate dehydrogenase, isocitrate dehydrogenase, and NAD(P)H transhydrogenase.

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