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• W2126096987 abstract "Most of the Coq proteins involved in coenzyme Q (ubiquinone or Q) biosynthesis are interdependent within a multiprotein complex in the yeast Saccharomyces cerevisiae. Lack of only one Coq polypeptide, as in Δcoq strains, results in the degradation of several Coq proteins. Consequently, Δcoq strains accumulate the same early intermediate of the Q6 biosynthetic pathway; this intermediate is therefore not informative about the deficient biosynthetic step in a particular Δcoq strain. In this work, we report that the overexpression of the protein Coq8 in Δcoq strains restores steady state levels of the unstable Coq proteins. Coq8 has been proposed to be a kinase, and we provide evidence that the kinase activity is essential for the stabilizing effect of Coq8 in the Δcoq strains. This stabilization results in the accumulation of several novel Q6 biosynthetic intermediates. These Q intermediates identify chemical steps impaired in cells lacking Coq4 and Coq9 polypeptides, for which no function has been established to date. Several of the new intermediates contain a C4-amine and provide information on the deamination reaction that takes place when para-aminobenzoic acid is used as a ring precursor of Q6. Finally, we used synthetic analogues of 4-hydroxybenzoic acid to bypass deficient biosynthetic steps, and we show here that 2,4-dihydroxybenzoic acid is able to restore Q6 biosynthesis and respiratory growth in a Δcoq7 strain overexpressing Coq8. The overexpression of Coq8 and the use of 4-hydroxybenzoic acid analogues represent innovative tools to elucidate the Q biosynthetic pathway.Background: Several steps of eukaryotic coenzyme Q biosynthesis are still in question.Results: Yeast coq null mutants overexpressing the Coq8 kinase have stable Coq polypeptides and accumulate new Q intermediates that help diagnose the blocked step.Conclusion: New functions for Coq polypeptides are proposed.Significance: Identification of the blocked step allows for the use of alternate ring precursors that rescue Q biosynthesis in some mutants. Most of the Coq proteins involved in coenzyme Q (ubiquinone or Q) biosynthesis are interdependent within a multiprotein complex in the yeast Saccharomyces cerevisiae. Lack of only one Coq polypeptide, as in Δcoq strains, results in the degradation of several Coq proteins. Consequently, Δcoq strains accumulate the same early intermediate of the Q6 biosynthetic pathway; this intermediate is therefore not informative about the deficient biosynthetic step in a particular Δcoq strain. In this work, we report that the overexpression of the protein Coq8 in Δcoq strains restores steady state levels of the unstable Coq proteins. Coq8 has been proposed to be a kinase, and we provide evidence that the kinase activity is essential for the stabilizing effect of Coq8 in the Δcoq strains. This stabilization results in the accumulation of several novel Q6 biosynthetic intermediates. These Q intermediates identify chemical steps impaired in cells lacking Coq4 and Coq9 polypeptides, for which no function has been established to date. Several of the new intermediates contain a C4-amine and provide information on the deamination reaction that takes place when para-aminobenzoic acid is used as a ring precursor of Q6. Finally, we used synthetic analogues of 4-hydroxybenzoic acid to bypass deficient biosynthetic steps, and we show here that 2,4-dihydroxybenzoic acid is able to restore Q6 biosynthesis and respiratory growth in a Δcoq7 strain overexpressing Coq8. The overexpression of Coq8 and the use of 4-hydroxybenzoic acid analogues represent innovative tools to elucidate the Q biosynthetic pathway. Background: Several steps of eukaryotic coenzyme Q biosynthesis are still in question. Results: Yeast coq null mutants overexpressing the Coq8 kinase have stable Coq polypeptides and accumulate new Q intermediates that help diagnose the blocked step. Conclusion: New functions for Coq polypeptides are proposed. Significance: Identification of the blocked step allows for the use of alternate ring precursors that rescue Q biosynthesis in some mutants. Coenzyme Q (ubiquinone or Q) 5The abbreviations used are: Qubiquinone or coenzyme Q4-AP3-hexaprenyl-4-aminophenolDDMQ6oxidized form of demethyl-demethoxy-Q6H2DHHB3-hexaprenyl-4,5-dihydroxybenzoic acid2,4-diHB2,4-dihydroxybenzoic acidDMQ6demethoxy-Q6ECDelectrochemical detection4-HB4-hydroxybenzoic acidHAB3-hexaprenyl-4-aminobenzoic acidHHAB3-hexaprenyl-4-amino-5-hydroxybenzoic acidHHB3-hexaprenyl-4-hydroxybenzoic acidHMAB3-hexaprenyl-4-amino-5-methoxybenzoic acid4-HP3-hexaprenyl-4-hydroxyphenolIDMQ64-imino-demethoxy-Q6MRMmultiple reaction monitoringOEoverexpressionpABApara-aminobenzoic acidRP-HPLC-MS/MSreverse phase-HPLC-MS/MSVAvanillic acid (4-hydroxy-3-methoxybenzoic acid)DOGALDrop Out Galactose medium. is a redox-active lipid essential for electron and proton transport in the mitochondrial respiratory chain. Q is also important in the mitochondrial inner membrane because it serves as an antioxidant, modulates the function of the mitochondrial membrane transition pore, and is a cofactor of uncoupling proteins (1Bentinger M. Tekle M. Dallner G. Coenzyme Q-biosynthesis and functions.Biochem. Biophys. Res. Commun. 2010; 396: 74-79Crossref PubMed Scopus (321) Google Scholar). Q is composed of a fully substituted benzoquinone ring that is attached to a polyisoprenyl tail of various lengths (6 isoprenyl units in Saccharomyces cerevisiae hence Q6 and 10 units in humans, hence Q10). The eukaryotic Q biosynthetic pathway has been studied most thoroughly in S. cerevisiae where it implicates at least 11 proteins, Coq1–Coq9, Arh1, and Yah1 (2Tran U.C. Clarke C.F. Endogenous synthesis of coenzyme Q in eukaryotes.Mitochondrion. 2007; 7: S62-S71Crossref PubMed Scopus (215) Google Scholar, 3Pierrel F. Hamelin O. Douki T. Kieffer-Jaquinod S. Mühlenhoff U. Ozeir M. Lill R. Fontecave M. Involvement of mitochondrial ferredoxin and para-aminobenzoic acid in yeast coenzyme Q biosynthesis.Chem. Biol. 2010; 17: 449-459Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). ubiquinone or coenzyme Q 3-hexaprenyl-4-aminophenol oxidized form of demethyl-demethoxy-Q6H2 3-hexaprenyl-4,5-dihydroxybenzoic acid 2,4-dihydroxybenzoic acid demethoxy-Q6 electrochemical detection 4-hydroxybenzoic acid 3-hexaprenyl-4-aminobenzoic acid 3-hexaprenyl-4-amino-5-hydroxybenzoic acid 3-hexaprenyl-4-hydroxybenzoic acid 3-hexaprenyl-4-amino-5-methoxybenzoic acid 3-hexaprenyl-4-hydroxyphenol 4-imino-demethoxy-Q6 multiple reaction monitoring overexpression para-aminobenzoic acid reverse phase-HPLC-MS/MS vanillic acid (4-hydroxy-3-methoxybenzoic acid) Drop Out Galactose medium. Genetic and biochemical studies have shown that most Coq proteins are present in a high molecular mass, multisubunit Q6 biosynthetic complex in S. cerevisiae (4Marbois B. Gin P. Faull K.F. Poon W.W. Lee P.T. Strahan J. Shepherd J.N. Clarke C.F. Coq3 and Coq4 define a polypeptide complex in yeast mitochondria for the biosynthesis of coenzyme Q.J. Biol. Chem. 2005; 280: 20231-20238Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 5Marbois B. Gin P. Gulmezian M. Clarke C.F. The yeast Coq4 polypeptide organizes a mitochondrial protein complex essential for coenzyme Q biosynthesis.Biochim. Biophys. Acta. 2009; 1791: 69-75Crossref PubMed Scopus (61) Google Scholar). The absence of a single Coq polypeptide from the complex causes a drastic diminution of the steady state levels of some Coq proteins. For example, the steady state levels of Coq4, Coq6, Coq7, and Coq9 are decreased in each of the Δcoq1–Δcoq9 null strains (6Hsieh E.J. Gin P. Gulmezian M. Tran U.C. Saiki R. Marbois B.N. Clarke C.F. Saccharomyces cerevisiae Coq9 polypeptide is a subunit of the mitochondrial coenzyme Q biosynthetic complex.Arch. Biochem. Biophys. 2007; 463: 19-26Crossref PubMed Scopus (73) Google Scholar). As a result, the same early intermediate 3-hexaprenyl-4-hydroxybenzoic acid (HHB; Fig. 1, path 1) accumulates in each of the Δcoq3–Δcoq9 strains. Certain point mutations resulting in amino acid substitutions seem to have less impact on the integrity of the Q biosynthetic complex than a null mutation; expression of the inactive Coq7-E194K polypeptide in a Δcoq7 strain caused accumulation of the expected intermediate demethoxy-Q6 (DMQ6, Fig. 1) (7Padilla S. Jonassen T. Jiménez-Hidalgo M.A. Fernández-Ayala D.J. López-Lluch G. Marbois B. Navas P. Clarke C.F. Santos-Ocaña C. Demethoxy-Q, an intermediate of coenzyme Q biosynthesis, fails to support respiration in Saccharomyces cerevisiae and lacks antioxidant activity.J. Biol. Chem. 2004; 279: 25995-26004Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 8Tran U.C. Marbois B. Gin P. Gulmezian M. Jonassen T. Clarke C.F. Complementation of Saccharomyces cerevisiae coq7 mutants by mitochondrial targeting of the Escherichia coli UbiF polypeptide. Two functions of yeast Coq7 polypeptide in coenzyme Q biosynthesis.J. Biol. Chem. 2006; 281: 16401-16409Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). Apart from this example, the absence of accumulation of biosynthetic intermediates downstream of HHB in Δcoq strains has hindered our understanding of the Q biosynthetic pathway. Therefore, the precise order of certain biosynthetic steps is still elusive, and the function of Coq4 and Coq9 is not defined. The yeast COQ8 gene was formerly called ABC1 and was thought to be essential for complex III function (9Bousquet I. Dujardin G. Slonimski P.P. ABC1, a novel yeast nuclear gene has a dual function in mitochondria. It suppresses a cytochrome b messenger-RNA translation defect and is essential for the electron transfer in the bc1 complex.EMBO J. 1991; 10: 2023-2031Crossref PubMed Scopus (95) Google Scholar, 10Brasseur G. Tron G. Dujardin G. Slonimski P.P. Brivet-Chevillotte P. The nuclear ABC1 gene is essential for the correct conformation and functioning of the cytochrome bc1 complex and the neighboring complexes II and IV in the mitochondrial respiratory chain.Eur. J. Biochem. 1997; 246: 103-111Crossref PubMed Scopus (57) Google Scholar). However, it was later shown that COQ8 was required for Q6 biosynthesis, and as such, its deletion only affected complex III activity indirectly (11Do T.Q. Hsu A.Y. Jonassen T. Lee P.T. Clarke C.F. A defect in coenzyme Q biosynthesis is responsible for the respiratory deficiency in Saccharomyces cerevisiae abc1 mutants.J. Biol. Chem. 2001; 276: 18161-18168Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar). Coq8 is a matrix protein peripherally associated with the mitochondrial inner membrane (12Xie L.X. Hsieh E.J. Watanabe S. Allan C.M. Chen J.Y. Tran U.C. Clarke C.F. Expression of the human atypical kinase ADCK3 rescues coenzyme Q biosynthesis and phosphorylation of Coq polypeptides in yeast coq8 mutants.Biochim. Biophys. Acta. 2011; 1811: 348-360Crossref PubMed Scopus (86) Google Scholar) and belongs to the “atypical kinases” subgroup of the protein-kinase-like superfamily (13Lagier-Tourenne C. Tazir M. López L.C. Quinzii C.M. Assoum M. Drouot N. Busso C. Makri S. Ali-Pacha L. Benhassine T. Anheim M. Lynch D.R. Thibault C. Plewniak F. Bianchetti L. Tranchant C. Poch O. DiMauro S. Mandel J.L. Barros M.H. Hirano M. Koenig M. ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency.Am. J. Hum. Genet. 2008; 82: 661-672Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar). Mutations in ADCK3, the human orthologue of COQ8, were shown to cause Q10 deficiency and cerebellar ataxia (13Lagier-Tourenne C. Tazir M. López L.C. Quinzii C.M. Assoum M. Drouot N. Busso C. Makri S. Ali-Pacha L. Benhassine T. Anheim M. Lynch D.R. Thibault C. Plewniak F. Bianchetti L. Tranchant C. Poch O. DiMauro S. Mandel J.L. Barros M.H. Hirano M. Koenig M. ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency.Am. J. Hum. Genet. 2008; 82: 661-672Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar, 14Mollet J. Delahodde A. Serre V. Chretien D. Schlemmer D. Lombes A. Boddaert N. Desguerre I. de Lonlay P. de Baulny H.O. Munnich A. Rötig A. CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures.Am. J. Hum. Genet. 2008; 82: 623-630Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar). In yeast, Coq8 is essential for phosphorylation of Coq3 and for its association with the Q biosynthetic complex (12Xie L.X. Hsieh E.J. Watanabe S. Allan C.M. Chen J.Y. Tran U.C. Clarke C.F. Expression of the human atypical kinase ADCK3 rescues coenzyme Q biosynthesis and phosphorylation of Coq polypeptides in yeast coq8 mutants.Biochim. Biophys. Acta. 2011; 1811: 348-360Crossref PubMed Scopus (86) Google Scholar, 15Tauche A. Krause-Buchholz U. Rödel G. Ubiquinone biosynthesis in Saccharomyces cerevisiae. The molecular organization of O-methylase Coq3p depends on Abc1p/Coq8p.FEMS Yeast Res. 2008; 8: 1263-1275Crossref PubMed Scopus (67) Google Scholar). In addition, several phosphorylated forms of Coq5 and Coq7 disappear in a yeast strain expressing the G130D mutant form of Coq8 (12Xie L.X. Hsieh E.J. Watanabe S. Allan C.M. Chen J.Y. Tran U.C. Clarke C.F. Expression of the human atypical kinase ADCK3 rescues coenzyme Q biosynthesis and phosphorylation of Coq polypeptides in yeast coq8 mutants.Biochim. Biophys. Acta. 2011; 1811: 348-360Crossref PubMed Scopus (86) Google Scholar), which mimics the pathogenic G272D mutation found in ADCK3 (14Mollet J. Delahodde A. Serre V. Chretien D. Schlemmer D. Lombes A. Boddaert N. Desguerre I. de Lonlay P. de Baulny H.O. Munnich A. Rötig A. CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures.Am. J. Hum. Genet. 2008; 82: 623-630Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar). Therefore, Coq8 appears to be a kinase essential for the phosphorylation of several conserved Coq polypeptides and some of these phosphorylated forms likely play a role in the assembly or maintenance of the Q6 biosynthetic complex. Recent studies indicate that overexpression of COQ8 can have profound effects on Q6 biosynthesis. Indeed, the overexpression of Coq8 (from now on referred to as Coq8 OE) in a Δcoq7 strain promoted the accumulation of DMQ6 (16Padilla S. Tran U.C. Jiménez-Hidalgo M. López-Martín J.M. Martín-Montalvo A. Clarke C.F. Navas P. Santos-Ocaña C. Hydroxylation of demethoxy-Q6 constitutes a control point in yeast coenzyme Q6 biosynthesis.Cell. Mol. Life Sci. 2009; 66: 173-186Crossref PubMed Scopus (41) Google Scholar), implying that all Coq proteins acting upstream of Coq7 in the biosynthetic pathway were stable and active. The effect of Coq8 OE is likely post-transcriptional because COQ4 mRNA levels in the Δcoq7 strain were not dependent on the level of Coq8 OE (16Padilla S. Tran U.C. Jiménez-Hidalgo M. López-Martín J.M. Martín-Montalvo A. Clarke C.F. Navas P. Santos-Ocaña C. Hydroxylation of demethoxy-Q6 constitutes a control point in yeast coenzyme Q6 biosynthesis.Cell. Mol. Life Sci. 2009; 66: 173-186Crossref PubMed Scopus (41) Google Scholar). Recently, the low steady state level of Coq4 encountered in Δcoq2, Δcoq3, Δcoq5, and Δcoq7 strains was shown to be restored to wild-type levels by Coq8 OE (17Zampol M.A. Busso C. Gomes F. Ferreira-Junior J.R. Tzagoloff A. Barros M.H. Overexpression of COQ10 in Saccharomyces cerevisiae inhibits mitochondrial respiration.Biochem. Biophys. Res. Commun. 2010; 402: 82-87Crossref PubMed Scopus (24) Google Scholar). In the case of a Δcoq6 strain, Coq8 OE allowed the specific accumulation of 3-hexaprenyl-4-hydroxyphenol (4-HP) (Fig. 1), which led us to identify Coq6 as the monooxygenase responsible for the C5-hydroxylation step (18Ozeir M. Mühlenhoff U. Webert H. Lill R. Fontecave M. Pierrel F. Coenzyme Q biosynthesis. Coq6 is required for the C5-hydroxylation reaction and substrate analogues rescue Coq6 deficiency.Chem. Biol. 2011; 18: 1134-1142Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). This example demonstrates that the accumulation of Q6 biosynthetic intermediates in Δcoq strains and the identification of their chemical structure are important for understanding the function of Coq proteins. In addition to the classic Q biosynthetic pathway emanating from 4-hydroxybenzoic acid (4-HB), S. cerevisiae also makes use of para-aminobenzoic acid (pABA) as a ring precursor for Q6 biosynthesis (Fig. 1, path 2) (3Pierrel F. Hamelin O. Douki T. Kieffer-Jaquinod S. Mühlenhoff U. Ozeir M. Lill R. Fontecave M. Involvement of mitochondrial ferredoxin and para-aminobenzoic acid in yeast coenzyme Q biosynthesis.Chem. Biol. 2010; 17: 449-459Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 19Marbois B. Xie L.X. Choi S. Hirano K. Hyman K. Clarke C.F. para-Aminobenzoic acid is a precursor in coenzyme Q6 biosynthesis in Saccharomyces cerevisiae.J. Biol. Chem. 2010; 285: 27827-27838Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). Coq2 is able to catalyze the prenylation of 4-HB to yield HHB, as well as the prenylation of pABA to yield 3-hexaprenyl-4-aminobenzoic acid (HAB). We have hypothesized that Coq3–Coq9 enzymes modify both HAB and HHB and that the C4-amino group must be removed from the HAB-derived intermediates to produce Q6 (3Pierrel F. Hamelin O. Douki T. Kieffer-Jaquinod S. Mühlenhoff U. Ozeir M. Lill R. Fontecave M. Involvement of mitochondrial ferredoxin and para-aminobenzoic acid in yeast coenzyme Q biosynthesis.Chem. Biol. 2010; 17: 449-459Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 19Marbois B. Xie L.X. Choi S. Hirano K. Hyman K. Clarke C.F. para-Aminobenzoic acid is a precursor in coenzyme Q6 biosynthesis in Saccharomyces cerevisiae.J. Biol. Chem. 2010; 285: 27827-27838Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). The deamination reaction likely occurs before the C6-hydroxylation step catalyzed by Coq7 because 4-imino-DMQ6 (IDMQ6) was proposed to be a precursor of DMQ6 (19Marbois B. Xie L.X. Choi S. Hirano K. Hyman K. Clarke C.F. para-Aminobenzoic acid is a precursor in coenzyme Q6 biosynthesis in Saccharomyces cerevisiae.J. Biol. Chem. 2010; 285: 27827-27838Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). Ring precursors other than 4-HB and pABA can also be used in vivo by S. cerevisiae to synthesize Q6. Indeed, 3,4-dihydroxybenzoic acid and vanillic acid bypass a deficiency in the Coq6-mediated C5-hydroxylation reaction and restore Q6 biosynthesis in coq6 or yah1 mutant strains (18Ozeir M. Mühlenhoff U. Webert H. Lill R. Fontecave M. Pierrel F. Coenzyme Q biosynthesis. Coq6 is required for the C5-hydroxylation reaction and substrate analogues rescue Coq6 deficiency.Chem. Biol. 2011; 18: 1134-1142Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). In this study, we show that Coq8 OE restores the steady state levels of the Coq proteins in most Δcoq strains. The stabilization of the Coq polypeptides leads to the accumulation of Q6 biosynthetic intermediates that allow the diagnosis of the impaired step. We have used this property to demonstrate that several biosynthetic steps are impaired in the Δcoq4 and Δcoq9 strains and to gain insights into the deamination reaction. Finally, the use of alternate ring precursors promoted the restoration of Q6 biosynthesis and respiratory growth for a Δcoq7 strain. S. cerevisiae strains used in this study are listed in Table 1. S. cerevisiae strains were transformed with lithium acetate as described (20Elble R. A simple and efficient procedure for transformation of yeasts.BioTechniques. 1992; 13: 18-20PubMed Google Scholar, 21Burke D. Dawson D. Stearns T. Methods in Yeast Genetics. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2000Google Scholar). YNB without pABA and folate (−pABA−folate) was purchased from MP Biomedicals. Rich YP medium was prepared as described (22Sherman F. Getting started with yeast.Methods Enzymol. 2002; 350: 3-41Crossref PubMed Scopus (976) Google Scholar). Dextrose or lactate-glycerol was used at 2%. In preparation for analyses by HPLC-ECD, yeast cells were cultured as described (3Pierrel F. Hamelin O. Douki T. Kieffer-Jaquinod S. Mühlenhoff U. Ozeir M. Lill R. Fontecave M. Involvement of mitochondrial ferredoxin and para-aminobenzoic acid in yeast coenzyme Q biosynthesis.Chem. Biol. 2010; 17: 449-459Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar) and grown for 18 h at 30 °C. Stock solutions of 4-HB analogues at 100 mm were prepared by slowly titrating NaOH (care was taken not to exceed pH 9) until complete dissolution. The solutions were then filter-sterilized, and aliquots were kept at −20 °C for several months. The 4-HB analogues were added to −pABA−folate growth medium at the indicated concentrations. Alternatively, in preparation for analyses by HPLC-MS/MS, yeast cells were cultured in Drop Out Galactose medium (DOGAL) (19Marbois B. Xie L.X. Choi S. Hirano K. Hyman K. Clarke C.F. para-Aminobenzoic acid is a precursor in coenzyme Q6 biosynthesis in Saccharomyces cerevisiae.J. Biol. Chem. 2010; 285: 27827-27838Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar) and labeled as described. Briefly, 100 A600 cells were collected from overnight culture and transferred to fresh medium in the presence of various aromatic ring precursors for 2–4 h at 30 °C. Cells were then collected by centrifugation and subject to LC-MS/MS analysis.TABLE 1Genotype and source of yeast strainsStrainGenotypeSourceW303-1AMAT a ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1R. RothsteinaDr. Rodney Rothstein, Dept. of Human Genetics, Columbia University.W303Δcoq1MAT a ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 coq1::LEU223Gin P. Clarke C.F. Genetic evidence for a multisubunit complex in coenzyme Q biosynthesis in yeast and the role of the Coq1 hexaprenyl diphosphate synthase.J. Biol. Chem. 2005; 280: 2676-2681Abstract Full Text Full Text PDF PubMed Scopus (66) Google ScholarW303Δcoq2MAT a ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 coq2::HIS331Ashby M.N. Kutsunai S.Y. Ackerman S. Tzagoloff A. Edwards P.A. COQ2 is a candidate for the structural gene encoding para-hydroxybenzoate:polyprenyltransferase.J. Biol. Chem. 1992; 267: 4128-4136Abstract Full Text PDF PubMed Google ScholarCC303MAT α ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 coq3::LEU232Do T.Q. Schultz J.R. Clarke C.F. Enhanced sensitivity of ubiquinone-deficient mutants of Saccharomyces cerevisiae to products of autoxidized polyunsaturated fatty acids.Proc. Natl. Acad. Sci. U.S.A. 1996; 93: 7534-7539Crossref PubMed Scopus (142) Google ScholarW303Δcoq4MAT a ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 coq4::TRP133Hsu A.Y. Do T.Q. Lee P.T. Clarke C.F. Genetic evidence for a multisubunit complex in the O-methyltransferase steps of coenzyme Q biosynthesis.Biochim. Biophys. Acta. 2000; 1484: 287-297Crossref PubMed Scopus (67) Google ScholarW303Δcoq5MAT a ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 coq5::HIS334Barkovich R.J. Shtanko A. Shepherd J.A. Lee P.T. Myles D.C. Tzagoloff A. Clarke C.F. Characterization of the COQ5 gene from Saccharomyces cerevisiae. Evidence for a C-methyltransferase in ubiquinone biosynthesis.J. Biol. Chem. 1997; 272: 9182-9188Abstract Full Text Full Text PDF PubMed Scopus (78) Google ScholarW303Δcoq6MAT a ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 coq6::LEU235Gin P. Hsu A.Y. Rothman S.C. Jonassen T. Lee P.T. Tzagoloff A. Clarke C.F. The Saccharomyces cerevisiae COQ6 gene encodes a mitochondrial flavin-dependent monooxygenase required for coenzyme Q biosynthesis.J. Biol. Chem. 2003; 278: 25308-25316Abstract Full Text Full Text PDF PubMed Scopus (60) Google ScholarW303Δcoq7MAT α ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 coq7::LEU236Marbois B.N. Clarke C.F. The COQ7 gene encodes a protein in Saccharomyces cerevisiae necessary for ubiquinone biosynthesis.J. Biol. Chem. 1996; 271: 2995-3004Abstract Full Text Full Text PDF PubMed Scopus (153) Google ScholarW303Δcoq8MAT a ade2-1 his3-1,15 leu2-3,112 trp1-1 ura3-1 abc1/coq8::HIS333Hsu A.Y. Do T.Q. Lee P.T. Clarke C.F. Genetic evidence for a multisubunit complex in the O-methyltransferase steps of coenzyme Q biosynthesis.Biochim. Biophys. Acta. 2000; 1484: 287-297Crossref PubMed Scopus (67) Google ScholarBY4741MAT a his3Δ1 leu2Δ0 met15Δ0 ura3Δ037Brachmann C.B. Davies A. Cost G.J. Caputo E. Li J. Hieter P. Boeke J.D. Designer deletion strains derived from Saccharomyces cerevisiae S288C. A useful set of strains and plasmids for PCR-mediated gene disruption and other applications.Yeast. 1998; 14: 115-132Crossref PubMed Scopus (2613) Google ScholarBY4741Δcoq9MAT a coq9Δ::kanMX4 his3Δ1 leu2Δ0 met15Δ0 ura3Δ038Winzeler E.A. Shoemaker D.D. Astromoff A. Liang H. Anderson K. Andre B. Bangham R. Benito R. Boeke J.D. Bussey H. Chu A.M. Connelly C. Davis K. Dietrich F. Dow S.W. El Bakkoury M. Foury F. Friend S.H. Gentalen E. Giaever G. Hegemann J.H. Jones T. Laub M. Liao H. Liebundguth N. Lockhart D.J. Lucau-Danila A. Lussier M. M'Rabet N. Menard P. Mittmann M. Pai C. Rebischung C. Revuelta J.L. Riles L. Roberts C.J. Ross-MacDonald P. Scherens B. Snyder M. Sookhai-Mahadeo S. Storms R.K. Véronneau S. Voet M. Volckaert G. Ward T.R. Wysocki R. Yen G.S. Yu K. Zimmermann K. Philippsen P. Johnston M. Davis R.W. Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis.Science. 1999; 285: 901-906Crossref PubMed Scopus (3183) Google Scholar, bEuropean S. cerevisiae Archive for Functional Analysis (EUROSCARF), available on-line.C9-E1MAT a ade2-1, coq4-1, trp1-1, ura3-139Belogrudov G.I. Lee P.T. Jonassen T. Hsu A.Y. Gin P. Clarke C.F. Yeast COQ4 encodes a mitochondrial protein required for coenzyme Q synthesis.Arch. Biochem. Biophys. 2001; 392: 48-58Crossref PubMed Scopus (55) Google ScholarBY4741Δcoq3MAT a coq3Δ::kanMX4 his3Δ1 leu2Δ0 met15Δ0 ura3Δ038Winzeler E.A. Shoemaker D.D. Astromoff A. Liang H. Anderson K. Andre B. Bangham R. Benito R. Boeke J.D. Bussey H. Chu A.M. Connelly C. Davis K. Dietrich F. Dow S.W. El Bakkoury M. Foury F. Friend S.H. Gentalen E. Giaever G. Hegemann J.H. Jones T. Laub M. Liao H. Liebundguth N. Lockhart D.J. Lucau-Danila A. Lussier M. M'Rabet N. Menard P. Mittmann M. Pai C. Rebischung C. Revuelta J.L. Riles L. Roberts C.J. Ross-MacDonald P. Scherens B. Snyder M. Sookhai-Mahadeo S. Storms R.K. Véronneau S. Voet M. Volckaert G. Ward T.R. Wysocki R. Yen G.S. Yu K. Zimmermann K. Philippsen P. Johnston M. Davis R.W. Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis.Science. 1999; 285: 901-906Crossref PubMed Scopus (3183) Google Scholar, bEuropean S. cerevisiae Archive for Functional Analysis (EUROSCARF), available on-line.BY4742Δcoq4MAT α coq4Δ::kanMX4 his3Δ1 leu2Δ0 lys2Δ0 ura3Δ038Winzeler E.A. Shoemaker D.D. Astromoff A. Liang H. Anderson K. Andre B. Bangham R. Benito R. Boeke J.D. Bussey H. Chu A.M. Connelly C. Davis K. Dietrich F. Dow S.W. El Bakkoury M. Foury F. Friend S.H. Gentalen E. Giaever G. Hegemann J.H. Jones T. Laub M. Liao H. Liebundguth N. Lockhart D.J. Lucau-Danila A. Lussier M. M'Rabet N. Menard P. Mittmann M. Pai C. Rebischung C. Revuelta J.L. Riles L. Roberts C.J. Ross-MacDonald P. Scherens B. Snyder M. Sookhai-Mahadeo S. Storms R.K. Véronneau S. 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