Small-molecule inhibition of the archetypal UbiB protein COQ8

Murray, Nathan H.; Asquith, Christopher R. M.; Fang, Zixiang; East, Michael P.; Ptak, Naomi; Smith, Robert W.; Vasta, James D.; Zimprich, Chad; Corona, Cesear; Robers, Matthew B.; Johnson, Gary L.; Bingman, C.A.; Pagliarini, David J.

doi:10.1038/s41589-022-01168-3

Cited by 5 publications

(3 citation statements)

References 59 publications

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“…12) which was slightly increased by certain CoQ metabolites (up to 2-fold for 1) in line with previous work (Extended Data Fig. 8a;) [43][44]47]. Critically, GC/MS analyses did not detect any phosphorylated CoQ intermediates, suggesting that the enzyme is not a small-molecule kinase.…”

Section: In Vitro Reconstruction Of Coq Biosynthesissupporting

confidence: 88%

“…COQ8 imparts the streamlining capacity of the COQ metabolon COQ8 is classi ed as an atypical kinase involved in CoQ biosynthesis [42][43][44]. It presents heightened ATPase activity in the presence of CoQ intermediates, cardiolipin and triton-X 100 and removal or inhibition of both paralogs, COQ8A and COQ8B, results in diminished CoQ production in humans [44]. To learn more about the role of COQ8, we scrutinized its function in CoQ biosynthesis.…”

Section: In Vitro Reconstruction Of Coq Biosynthesismentioning

confidence: 99%

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In vitro construction of the COQ metabolon unveils the molecular determinants of coenzyme Q biosynthesis

Mattevi,

Nicoll,

Alvigini

et al. 2023

Preprint

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Metabolons are protein assemblies that perform a series of reactions in a metabolic pathway. However, the general importance and aptitude of metabolons for enzyme catalysis remains poorly understood. In animals, biosynthesis of coenzyme Q is currently attributed to ten different proteins with COQ3, COQ4, COQ5, COQ6, COQ7, and COQ9 forming the iconic COQ metabolon. Yet several reaction steps conducted by the metabolon remain enigmatic. To elucidate the prerequisites for animal coenzyme Q biosynthesis, we sought out to construct the entire metabolon in vitro. Here we show that this approach, rooted by ancestral sequence reconstruction, reveals the enzymes responsible for the uncharacterized steps and captures the biosynthetic pathway in vitro. We demonstrate that COQ8, a kinase, increases and streamlines coenzyme Q production. Our findings provide crucial insight into how biocatalytic efficiency is regulated and enhanced by these biosynthetic engines in the context of the cell.

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Section: In Vitro Reconstruction Of Coq Biosynthesissupporting

confidence: 88%

Section: In Vitro Reconstruction Of Coq Biosynthesismentioning

confidence: 99%

In vitro construction of the COQ metabolon unveils the molecular determinants of coenzyme Q biosynthesis

Mattevi,

Nicoll,

Alvigini

et al. 2023

Preprint

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“…The key amino acid residues governing intermolecular interactions were discussed, providing guidance for further medicinal chemistry optimization to improve potency and selectivity. Although previous ADCK3 inhibitors have been reported, , this study applied a combinatorial VS strategy to rapidly identify novel chemical series of ADCK3 inhibitors without a laborious and time-consuming high-throughput screening campaign. In principle, this novel strategy can be extended to any target-based screening, and it can quickly expand the molecular diversity coverage of the potential inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Identification of Potent ADCK3 Inhibitors through Structure-Based Virtual Screening

Gao,

Tambe,

Chen

et al. 2024

J. Chem. Inf. Model.

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ADCK3 is a member of the UbiB family of atypical protein kinases in humans, with homologues in archaea, bacteria, and eukaryotes. In lieu of protein kinase activity, ADCK3 plays a role in the biosynthesis of coenzyme Q10 (CoQ10), and inactivating mutations can cause a CoQ10 deficiency and ataxia. However, the exact functions of ADCK3 are still unclear, and small-molecule inhibitors could be useful as chemical probes to elucidate its molecular mechanisms. In this study, we applied structure-based virtual screening (VS) to discover a novel chemical series of ADCK3 inhibitors. Through extensive structural analysis of the active-site residues, we developed a pharmacophore model and applied it to a largescale VS. Out of ∼170,000 compounds virtually screened, 800 top-ranking candidate compounds were selected and tested in both ADCK3 and p38 biochemical assays for hit validation. In total, 129 compounds were confirmed as ADCK3 inhibitors, and among them, 114 compounds are selective against p38, which was used as a counter-target. Molecular dynamics (MD) simulations were then conducted to predict the binding modes of the most potent compounds within the ADCK3 active site. Through metadynamics analysis, we successfully detected the key amino acid residues that govern intermolecular interactions. The findings provided in this study can serve as a promising starting point for drug development.

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Coenzyme Q biochemistry and biosynthesis

Guerra

Pagliarini

2023

Trends in Biochemical Sciences

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Small-molecule inhibition of the archetypal UbiB protein COQ8

Cited by 5 publications

References 59 publications

In vitro construction of the COQ metabolon unveils the molecular determinants of coenzyme Q biosynthesis

In vitro construction of the COQ metabolon unveils the molecular determinants of coenzyme Q biosynthesis

Identification of Potent ADCK3 Inhibitors through Structure-Based Virtual Screening

Coenzyme Q biochemistry and biosynthesis

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