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
- Coenzyme Q4 is a functional substitute for coenzyme Q10 and can be targeted to the mitochondria
Steenberge LH, Rogers S, Sung AY, Fan J, and Pagliarini DJ
Journal of Biological Chemistry 2024 - Hem25p is required for mitochondrial IPP transport in fungi
Tai JT, Guerra RM, Rogers SW, Fang Z, Muehlbauer KL, Shishkova E, Overmyer KA, Coon JJ, and Pagliarini DJ
Nature Cell Biology, 2023 - Structure and functionality of a multimeric human COQ7:COQ9 complex
Manicki M*, Aydin H*, Abriata LA, Overmyer KA, Guerra RM, Coon JJ, Dal Peraro M, Frost A† and Pagliarini DJ†
Molecular Cell, 2022 - Small Molecule Inhibition of the Archetypal UbiB protein COQ8
Murray NH, Asquith CR, Fang Z, Smith RW, Vasta JD, Zimprich CA, Corona CR, Robers MB, Bingman CA, and Pagliarini DJ
Nature Chemical Biology, 2022 - UbiB proteins regulate cellular CoQ distribution in Saccharomyces cerevisiae
Kemmerer ZA, Robinson KP, Schmitz JM, Manicki M, Paulson BR, Jochem A, Hutchins PD, Coon JJ, and Pagliarini DJ
Nature Communications, 2021 Aug 6;12(1):4769 - Defining intermediates and redundancies in coenzyme Q precursor biosynthesis
Robinson KP, Jochem A, Johnson SE, Reddy TR, Russell JD, Coon JJ, & Pagliarini DJ
Journal of Biological Chemistry, 2021 DOI:https://doi.org/10.1016/j.jbc.2021.100643 - 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