2-Propylphenol Allosterically Modulates COQ8A to Enhance ATPase Activity

ACS Chem Biol. 2022 Jul 29. doi: 10.1021/acschembio.2c00434. Online ahead of print.

Abstract

COQ8A is an atypical kinase-like protein that aids the biosynthesis of coenzyme Q, an essential cellular cofactor and antioxidant. COQ8A's mode of action remains unclear, in part due to the lack of small molecule tools to probe its function. Here, we blend NMR and hydrogen-deuterium exchange mass spectrometry to help determine how a small CoQ precursor mimetic, 2-propylphenol, modulates COQ8A activity. We identify a likely 2-propylphenol binding site and reveal that this compound modulates a conserved COQ8A domain to increase nucleotide affinity and ATPase activity. Our findings promise to aid further investigations into COQ8A's precise enzymatic function and the design of compounds capable of boosting endogenous CoQ production for therapeutic gain.