The promiscuous enzyme medium-chain 3-keto-acyl-CoA thiolase triggers a vicious cycle in fatty-acid beta-oxidation
Fig 6
Elucidating the mechanism of flux decline.
1. Upon substrate overload with cytosolic palmitoyl-CoA, MCKAT’s ketoacyl-CoA substrates start to accumulate. 2. The unfavourable equilibrium constant of the preceding enzyme, medium/short-chain hydroxyacyl-CoA dehydrogenase, works as an amplifier, leading to the accumulation of upstream CoA esters, including acyl-CoA esters. 3. These acyl-CoA esters are at the same time products of MCKAT and inhibit its already low activity further. 4. Finally, the accumulation of CoA esters leads to a sequestration of free CoA. CoA being a cofactor for MCKAT, its sequestration limited the MCKAT activity even further, thus completing the vicious cycle. 5. Since CoA is also a substrate for distant enzymes (such as MTP), it efficiently communicates the ‘traffic jam’ at MCKAT to the entire pathway.