Mitochondrial ADCK3 Employs an Atypical Protein Kinase-like Fold to Enable Coenzyme Q Biosynthesis

Stefely, Jonathan A.; Reidenbach, Andrew G.; Ulbrich, Arne; Oruganty, Krishnadev; Floyd, Brendan J.; Jochem, Adam; Saunders, Jaclyn M.; Johnson, Isabel E.; Minogue, Catherine E.; Wrobel, Russell L.; Barber, Grant E.; Lee, David E.; Li, Sheng; Kannan, Natarajan; Coon, Joshua J.; Bingman, C.A.; Pagliarini, David J.

doi:10.1016/j.molcel.2014.11.002

Cited by 108 publications

(171 citation statements)

References 57 publications

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“…Finally, a recent study showed that a mutated form of ADCK3, a human Coq8 ortholog, possessed autophosphorylation activity (79), a finding corroborated by another recent study showing that a purified MBP-ADCK3 fusion exhibited ATPase activity in vitro (80). The authors suggested that ADCK3 may act in concert with Coq9, a hypothesis made particularly compelling by their observation that a fusion of COQ9 and ADCK3 is present in the protozoan Tetrahymena thermophila (79).…”

Section: Discussionmentioning

confidence: 79%

Identification of Coq11, a New Coenzyme Q Biosynthetic Protein in the CoQ-Synthome in Saccharomyces cerevisiae

Allan¹,

Awad²,

Johnson³

et al. 2015

Journal of Biological Chemistry

131

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Background: Yeast synthesizes coenzyme Q via a macromolecular protein complex. Results: The Q biosynthetic complex includes Coq8 and the uncharacterized protein YLR290C; the ylr290c⌬ mutant exhibits impaired Q synthesis. Conclusion: YLR290C (Coq11) is a novel protein required for efficient yeast Q biosynthesis. Significance: Discovery and characterization of yeast Coq biosynthetic proteins leads to an improved understanding of coenzyme Q biosynthesis and regulation.

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Section: Discussionmentioning

confidence: 79%

Identification of Coq11, a New Coenzyme Q Biosynthetic Protein in the CoQ-Synthome in Saccharomyces cerevisiae

Allan¹,

Awad²,

Johnson³

et al. 2015

Journal of Biological Chemistry

131

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“…59) The structure of human ADCK3 has been solved. 60) There are five Coq8-like kinases (ADCK1-5) in humans; ADCK3 is involved in CoQ synthesis, and mutations in the ADCK4 gene are related to human CoQ10 deficiency. 61) In fact, mutations in the ADCK3 and ADCK4 genes have been linked with a number of human genetic diseases (Table 2); 62) however, it is unclear whether the other ADCK proteins are also involved in CoQ biosynthesis.…”

Section: Genes Responsible For Coq Biosynthesismentioning

confidence: 99%

“…60) These inhibitory regions include an N-terminal domain that occupies the typical substrate-binding pocket, and a unique A-rich loop that limits ATP binding. 60) This structure would explain why in vitro kinase activity was not detected for UbiB. H. sapiens COQ9 displays a striking structural homology to members of the TetR family of regulators and contains a lipid-binding pocket.…”

Section: Three-dimensional Structures Of Proteins Involved In Coq Synmentioning

confidence: 99%

Biosynthesis of coenzyme Q in eukaryotes

Kawamukai

2016

Bioscience, Biotechnology, and Biochemistry

105

128

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Coenzyme Q (CoQ) is a component of the electron transport chain that participates in aerobic cellular respiration to produce ATP. In addition, CoQ acts as an electron acceptor in several enzymatic reactions involving oxidation-reduction. Biosynthesis of CoQ has been investigated mainly in Escherichia coli and Saccharomyces cerevisiae, and the findings have been extended to various higher organisms, including plants and humans. Analyses in yeast have contributed greatly to current understanding of human diseases related to CoQ biosynthesis. To date, human genetic disorders related to mutations in eight COQ biosynthetic genes have been reported. In addition, the crystal structures of a number of proteins involved in CoQ synthesis have been solved, including those of IspB, UbiA, UbiD, UbiX, UbiI, Alr8543 (Coq4 homolog), Coq5, ADCK3, and COQ9. Over the last decade, knowledge of CoQ biosynthesis has accumulated, and striking advances in related human genetic disorders and the crystal structure of proteins required for CoQ synthesis have been made. This review focuses on the biosynthesis of CoQ in eukaryotes, with some comparisons to the process in prokaryotes.

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“…These studies suggest that Coq8 over-expression might stabilize the complex by phosphorylation. Recent work identified auto-phosphorylation and ATPase activity in ADCK3, a human ortholog of yeast Coq8 [13, 14]. …”

Section: Introductionmentioning

confidence: 99%

Yeast Coq9 controls deamination of coenzyme Q intermediates that derive from para-aminobenzoic acid

Black

Nguyen

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Coq9 is a polypeptide subunit in a mitochondrial multi-subunit complex, termed the CoQ-synthome, required for biosynthesis of coenzyme Q (ubiquinone or Q). Deletion of COQ9 results in dissociation of the CoQ-synthome, but over-expression of Coq8 putative kinase stabilizes the CoQ-synthome in the coq9 null mutant and leads to the accumulation of two nitrogen containing Q-intermediates, imino-demethoxy-Q6 (IDMQ6) and 3-hexaprenyl-4-aminophenol (4-AP) when para-aminobenzoic acid (pABA) is provided as a ring precursor. To investigate whether Coq9 is responsible for deamination steps in Q biosynthesis, we utilized the yeast coq5-5 point mutant. The yeast coq5-5 point mutant is defective in the C-methyltransferase step of Q biosynthesis, but retains normal steady-state levels of the Coq5 polypeptide. Here we show that when high amounts of 13C6-pABA are provided, the coq5-5 mutant accumulates both 13C6-imino-demethyl-demethoxy-Q6 (13C6-IDDMQ6) and demethyl-demethoxy-Q6 (13C6-DDMQ6). Deletion of COQ9 in the yeast coq5-5 mutant along with Coq8 over-expression and 13C6-pABA labeling leads to the absence of 13C6-DDMQ6, and the nitrogen-containing intermediates 13C6-4-AP and 13C6-IDDMQ6 persist. We describe a coq9 temperature sensitive mutant and show that at the non-permissive temperature, steady state polypeptide levels of Coq9-ts19 increased, while Coq4, Coq5, Coq6, and Coq7 decreased. The coq9-ts19 mutant had decreased Q6 content and increased levels of nitrogen-containing intermediates. These findings identify Coq9 as a multi-functional protein that is required for the function of Coq6 and Coq7 hydroxylases, for removal of the nitrogen substituent from pABA-derived Q-intermediates, and is an essential component of the CoQ synthome.

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Mitochondrial ADCK3 Employs an Atypical Protein Kinase-like Fold to Enable Coenzyme Q Biosynthesis

Cited by 108 publications

References 57 publications

Identification of Coq11, a New Coenzyme Q Biosynthetic Protein in the CoQ-Synthome in Saccharomyces cerevisiae

Identification of Coq11, a New Coenzyme Q Biosynthetic Protein in the CoQ-Synthome in Saccharomyces cerevisiae

Biosynthesis of coenzyme Q in eukaryotes

Yeast Coq9 controls deamination of coenzyme Q intermediates that derive from para-aminobenzoic acid

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