The mitochondrial trifunctional protein: centre of a beta-oxidation metabolon?

The trifunctional enzyme comprises three consecutive steps in the mitochond rial beta-oxidation of long-chain acyl-CoA esters: 2-enoyl-CoA hydratase, 3 -hydroxyacyl-CoA dehydrogenase and 3-ketoacyl-CoA thiolase. Deficiencies in either 3-hydroxyacyl-CoA dehydrogenase activity, or all three activities, are important causes of human disease. The dehydrogenase and thiolase have a requirement for NAD(+) and CoA respectively, whose levels are conserved w ithin the mitochondrion and thus provide possible means for control and reg ulation of beta-oxidation. Using analysis of the intact CoA ester intermedi ates produced by the complex, we have examined the sensitivity of the compl ex to NAD(+)/NADH and acetyl-CoA. We consider the evidence for channelling within the trifunctional protein and propose a model for a beta-oxidation ' metabolon'.