Non-canonical coenzyme A biosynthesis
Non-canonical coenzyme A biosynthesis
Every living cell depends on a molecule called coenzyme A (CoA) to survive. CoA is essential for producing energy and for countless other vital chemical processes. Because cells cannot absorb CoA directly from their environment, they must manufacture it themselves, starting from vitamin B5 (pantothenate). When the genes responsible for this production process are faulty, serious diseases can result, including rare brain conditions (PKAN and CoPAN) and heart muscle disease (cardiomyopathy). Currently, no treatments exist for these disorders.
This thesis of Jouke Wedman explores whether cells can acquire CoA through an alternative, "non-canonical" route, bypassing the steps that are blocked by disease. One promising approach involves supplying cells with pantethine, a molecule that sits further along the CoA production pathway and can circumvent the faulty steps.
Using fruit flies as a disease model, we showed that CoA and its building blocks can be passed from mother to offspring, sustaining early development. We also demonstrated that adding pantethine to the diet significantly extended the survival of flies lacking a key CoA-producing enzyme, but only when certain gut bacteria were present. These bacteria could convert pantethine into 4′-phosphopantetheine, the form the fly's cells could use to continue CoA production.
In yeast cells, we identified the first-ever transporter protein capable of importing the CoA precursor (4′-phospho)pantetheine directly into the cell. This discovery opens new possibilities for understanding how cells might be supplied with these molecules therapeutically.
Together, these findings lay important groundwork for developing future treatments for CoA-related diseases affecting the brain and heart.