Significance of the reductase-dependent pathway for the β-oxidation of unsaturated fatty acids with odd-numbered double bonds

Abstract

The β-oxidation of unsaturated fatty acids with odd-numbered double bonds proceeds by reduction of the double bond (reductase-dependent pathway) in addition to the well established isomerization of the double bond (isomerase-dependent pathway). The metabolic significance of the reductase- dependent pathway was assessed with 2-trans-5-cis-octadienoyl-CoA (2,5- octadienoyl-CoA) and its products, all of which are metabolites of α- linolenic acid. A kinetic evaluation of β-oxidation enzymes revealed that the presence of a 5-cis double bond in the substrate most adversely affected the activity of 3-ketoacyl-CoA thiolase although not enough to become rate- limiting. Concentration-dependent and time-dependent measurements indicated that most (80%) of 2,5-octadienoyl-CoA is metabolized via the isomerase- dependent pathway. The reason for the greater flux through the isomerase- dependent pathway is the higher activity of L-3-hydroxyacyl-CoA dehydrogenase as compared with Δ3, Δ2-enoyl-CoA isomerase. These two enzymes catalyze the rate-limiting steps in the isomerase-dependent and reductase-dependent pathways, respectively. Once 2,5-octadienoyl-CoA is converted to 3,5- octadienoyl-CoA (perhaps fortuitously because of the presence of Δ3, Δ2- enoyl-CoA isomerase), the only effective route for its degradation is via the reductase-dependent pathway. It is concluded that the reductase-dependent pathway assures the degradation of 3,5-dienoyl-CoA intermediates, thereby preventing the depletion of free coenzyme A and a likely impairment of mitochondrial oxidative function.