Elucidating the mechanisms of coenzyme Q biosynthesis AND DISTRIBUTION
Coenzyme Q (CoQ) is a remarkable redox-active prenyl lipid that is among the most hydrophobic molecules in nature. It is a requisite component of the mitochondrial electron transport chain, an essential cofactor in various metabolic pathways, and a key antioxidant throughout cellular membranes. CoQ deficiency underlies a wide range of disorders that most often cannot be rectified through supplementation. Despite the discovery of CoQ in the 1950s, multiple steps in the CoQ pathway are likely fulfilled by yet-to-be-identified proteins and the biochemical roles of essential auxiliary proteins remain poorly defined. We are integrating various biochemical, genetic, and structural biology approaches to fill in these gaps, and are exploring new small molecule approaches to augment endogenous CoQ levels.
Selected Recent Publications
- ADCK3/COQ8A: The choice target of the UbiB protein kinase-like family
Asquith CRM†, Murray NH, and Pagliarini DJ†
Nature Reviews Drug Discovery, 2019 doi: 10.1038/d41573-019-00158-w - An isoprene lipid binding protein promotes eukaryotic coenzyme Q biosynthesis
Lohman DC*, Aydin D*, Von Bank H, Smith R, Linke V, Weisenhorn EM, McDevitt MT, Hutchins PD, Wilkerson EM, Wancewicz B, Russell JD, Stefely MS, Beebe ET, Jochem A, Coon JJ, Bingman CA, Dal Peraro M†, and Pagliarini DJ†
Molecular Cell, 2019 73(4): 763-774 - Conserved lipid and small molecule modulation of COQ8 reveals regulation of the ancient kinase-like UbiB family
Reidenbach AG, Kemmerer ZA, Aydin D, Jochem A, McDevitt MT, Hutchins PD, Stark JL, Stefely JA, Reddy T, Hebert AS, Wilkerson EM, JA, Johnson IE, Bingman CA, Markley JL, Coon JJ, Dal Peraro M, and Pagliarini DJ
Cell Chemical Biology, 2018 25(2):154-165
- Biochemistry of Mitochondrial Coenzyme Q Biosynthesis
Stefely JA and Pagliarini DJ
Trends in Biochemical Sciences, 2017 42(10):824-843 - Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity
Stefely JA*, Licitra F*, Laredj L, Reidenbach AG, Kemmerer ZA, Grangeray A, Jaeg-Ehret T, Minogue CE, Ulbrich A, Hutchins PD, Wilkerson EM, Ruan Z, Aydin D, Hebert AS, Guo X, Freiberger EC, Reutenauer L, Jochem A, Chergova M, Johnson IE, Lohman DC, Rush MJ, Kwiecien NW, Singh PK, Schlagowski AI, Floyd BJ, Forsman U, Sindelar PJ, Westphall MS, Pierrel F, Zoll J, Dal Peraro M, Kannan N, Bingman CA, Coon JJ, Isope P, Puccio H†, Pagliarini DJ†
Molecular Cell, 2016 Aug 18;63(4):608-2. - Mitochondrial ADCK3 Employs an Atypical Protein Kinase-like Fold to Enable Coenzyme Q Biosynthesis
Stefely JA*, Reidenbach AG*, Ulbrich A, Oruganty K, Floyd BJ, Jochem A, Saunders JM, Johnson IE, Minogue CE, Wrobel RL, Barber GE, Lee D, Li S, Kannan N, Coon JJ, Bingman CA and Pagliarini DJ
Molecular Cell, 2015, 57(1):83-94 - Mitochondrial COQ9 is a lipid binding protein that associates with COQ7 to enable coenzyme Q biosynthesis
Lohman DC*, Forouhar F*, Beebe ET, Stefeley MS, Minogue CE, Ulbrich A, Stefely JA, Sukumar S, Luna-Sánchez M, Lew S, Seetharaman J, Xiao R, Wang H, Wrobel RL, Everett JK, Mitchell JC, López LC, Coon JJ, Tong L† and Pagliarini DJ†
Proceedings of the National Academy of Sciences, 2014 111(44):E4697-705
Systems biochemistry approaches to defining mitochondrial protein function
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Regulation of mitochondrial function and biogenesis