TY - JOUR
T1 - 2-Propylphenol Allosterically Modulates COQ8A to Enhance ATPase Activity
AU - Murray, Nathan H.
AU - Lewis, Adam
AU - Rincon Pabon, Juan P.
AU - Gross, Michael L.
AU - Henzler-Wildman, Katherine
AU - Pagliarini, David J.
N1 - Funding Information:
We thank members of the Pagliarini lab for helpful discussions throughout this project. This work was supported by NIH awards R35GM131795 (D.J.P.), T32GM008505 (N.H.M.), R24GM136766 (M.L.G.), and R35GM141748 (K.H.-W.). This work was also supported by NSF DGE-1747503 (N.H.M.) and funds from the BJC Investigator Program (D.J.P.). This study made use of the National Magnetic Resonance Facility at Madison, which is supported by NIH grant R24GM141526. We thank M. Tonelli and P. Cobra for assistance with NMR data acquisition. We thank G. Hicks for graphic design assistance.
Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/8/19
Y1 - 2022/8/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85136084507&partnerID=8YFLogxK
U2 - 10.1021/acschembio.2c00434
DO - 10.1021/acschembio.2c00434
M3 - Article
C2 - 35904798
AN - SCOPUS:85136084507
SN - 1554-8929
VL - 17
SP - 2031
EP - 2038
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 8
ER -