SIGNIFICANCE OF THE REDUCTASE-DEPENDENT PATHWAY FOR THE BETA-OXIDATION OF UNSATURATED FATTY-ACIDS WITH ODD-NUMBERED DOUBLE-BONDS - MITOCHONDRIAL METABOLISM OF 2-TRANS-5-CIS-OCTADIENOYL-COA

The beta-oxidation of unsaturated fatty acids with odd-numbered double bonds proceeds by reduction of the double bond (reductase-dependent p athway) in addition to the well established isomerization of the doubl e bond (isomerase-dependent pathway). The metabolic significance of th e reductase-dependent pathway was assessed with 2-trans-5-cis-octadien oyl-CoA (2,5-octadienoyl-CoA) and its products, all of which are metab olites of alpha-linolenic acid, A kinetic evaluation of beta-oxidation enzymes revealed that the presence of a 5-cis double bond in the subs trate most adversely affected the activity of 3-ketoacyl-CoA thiolase although not enough to become rate-limiting, Concentration dependent a nd time-dependent measurements indicated that most (80%) of 2,5-octadi enoyl-CoA is metabolized via the isomerase-dependent pathway, The reas on for the greater flux through the isomerase-dependent pathway is the higher activity of L-3-hydroxyacyl-CoA dehydrogenase as compared with Delta(3),Delta(2)-enoyl-CoA isomerase. These two enzymes catalyze the rate-limiting steps in the isomerase-dependent and reductase-dependen t pathways, respectively, Once 2,5-octadienoyl-CoA is converted to 3,5 -octadienoyl-CoA (perhaps fortuitously because of the presence of Delt a(3),Delta(2)-enoyl-CoA isomerase), the only effective route for its d egradation is via the reductase-dependent pathway, It is concluded tha t the reductase-dependent pathway assures the degradation of 3,5-dieno yl-CoA intermediates, thereby preventing the depletion of free coenzym e A and a likely impairment of mitochondrial oxidative function.