The β-oxidation pathway accomplishes the complete degradation of saturated fatty acids having an even number of carbon atoms. Most fatty acids have such structures because of their mode of synthesis (Chapter 28). However, not all fatty acids are so simple. The oxidation of fatty acids containing double bonds requires additional steps. Likewise, fatty acids containing an odd number of carbon atoms require additional enzyme reactions to yield a metabolically useful molecule.

Many unsaturated fatty acids are available in our diet. Indeed, we are encouraged to eat foods that are rich in certain types of polyunsaturated fatty acids, such as the ω-3 fatty acid linolenic acid, which is prominent in safflower and corn oils. Polyunsaturated fatty acids are important for a number of reasons, not the least of which is that they offer some protection from heart attacks. How are excess amounts of these fatty acids oxidized?

Consider the oxidation of palmitoleate. This C₁₆ unsaturated fatty acid, which has one double bond between C-9 and C-10, is activated to palmitoleoyl CoA and transported across the inner mitochondrial membrane in the same way as saturated fatty acids. Palmitoleoyl CoA then undergoes three cycles of degradation, which are carried out by the same enzymes as those in the oxidation of saturated fatty acids. However, the cis-Δ³-enoyl CoA formed in the third round is not a substrate for acyl CoA dehydrogenase. The presence of a double bond between C-3 and C-4 prevents the formation of another double bond between C-2 and C-3. This impasse is resolved by a new reaction that shifts the position and configuration of the cis-Δ³ double bond. cis-Δ³-Enoyl CoA isomerase converts this double bond into a trans-Δ² double bond (Figure 27.7). The subsequent reactions are those of the saturated fatty acid oxidation pathway, in which the trans-Δ²-enoyl CoA is a regular substrate.

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Human beings require polyunsaturated fatty acids, which have multiple double bonds, as important precursors of signal molecules, but excess polyunsaturated fatty acids are degraded by β oxidation. However, when these fats are subjected to β oxidation, molecules result that cannot themselves be degraded by β oxidation. To prevent a wasteful buildup of these molecules, the initial degradation products of the polyunsaturated fatty acids must first be modified. Consider linoleate, a C₁₈ polyunsaturated fatty acid with cis-Δ⁹ and cis-Δ¹² double bonds (Figure 27.8). The cis-Δ³ double bond formed after three rounds of β oxidation is converted into a trans-Δ² double bond by the aforementioned isomerase. The acyl CoA produced by another round of β oxidation contains a cis-Δ⁴ double bond. The dehydrogenation of this species by acyl CoA dehydrogenase yields a 2,4-dienoyl intermediate, which is not a substrate for the next enzyme in the β-oxidation pathway. This impasse is circumvented by 2,4-dienoyl CoA reductase, an enzyme that uses NADPH to reduce the 2,4-dienoyl intermediate to trans-Δ³-enoyl CoA. cis-Δ³-Enoyl CoA isomerase then converts trans-Δ³-enoyl CoA into the trans-Δ² form, a normal intermediate in the β-oxidation pathway. These catalytic strategies are elegant and economical. Only two extra enzymes are needed for the oxidation of any polyunsaturated fatty acid. In polyunsaturated fatty acids, odd-numbered double bonds are handled by the isomerase alone, and even-numbered ones are handled by the reductase and the isomerase.

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Fatty acids having an odd number of carbon atoms are a minor class found in small amounts in vegetables. They are oxidized in the same way as fatty acids having an even number of carbon atoms, except that propionyl CoA and acetyl CoA, rather than two molecules of acetyl CoA, are produced in the final round of degradation. The activated three-carbon unit in propionyl CoA is converted into succinyl CoA, at which point it enters the citric acid cycle.

The pathway from propionyl CoA to succinyl CoA is especially interesting because it entails a rearrangement that requires vitamin B₁₂ (also known as cobalamin). Propionyl CoA is carboxylated by propionyl CoA carboxylase (a biotin enzyme) at the expense of the hydrolysis of a molecule of ATP to yield the d isomer of methylmalonyl CoA (Figure 27.9). The d isomer of methylmalonyl CoA is converted into the l isomer, the substrate for a mutase that converts it into succinyl CoA by an intramolecular rearrangement. The —CO—S—CoA group migrates from C-2 to the methyl group in exchange for a hydrogen atom. This very unusual isomerization is catalyzed by methylmalonyl CoA mutase, which contains vitamin B₁₂ as its coenzyme.