Coq6 Is Responsible for the C4-deamination Reaction in Coenzyme Q Biosynthesis in Saccharomyces cerevisiae

Ozeir, Mohammad; Pélosi, Ludovic; Ismail, Alexandre; Mellot‐Draznieks, Caroline; Fontecave, Marc; Pierrel, Fabien

doi:10.1074/jbc.m115.675744

Cited by 40 publications

(42 citation statements)

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“…Consequently, the C4 amino group of pABA must be replaced by a C4 hydroxyl group and we recently reported that the monooxygenase Coq6 catalyzes this reaction in addition to the previously reported C5-hydroxylation (Ozeir et al, 2015). The L382E mutation in Coq6 severely impairs the C4-deamination reaction but globally maintains the C5-hydroxylation (Ozeir et al, 2015).…”

Section: Paba Advances To Different Stages Of Coq Biosynthesis Dependmentioning

confidence: 74%

Impact of Chemical Analogs of 4-Hydroxybenzoic Acid on Coenzyme Q Biosynthesis: From Inhibition to Bypass of Coenzyme Q Deficiency

Pierrel

2017

Front. Physiol.

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Coenzyme Q is a lipid that participates to important physiological functions. Coenzyme Q is synthesized in multiple steps from the precursor 4-hydroxybenzoic acid. Mutations in enzymes that participate to coenzyme Q biosynthesis result in primary coenzyme Q deficiency, a type of mitochondrial disease. Coenzyme Q10 supplementation of patients is the classical treatment but it shows limited efficacy in some cases. The molecular understanding of the coenzyme Q biosynthetic pathway allowed the design of experiments to bypass deficient biosynthetic steps with analogs of 4-hydroxybenzoic acid. These molecules provide the defective chemical group and can reactivate endogenous coenzyme Q biosynthesis as demonstrated recently in yeast, mammalian cell cultures, and mouse models of primary coenzyme Q deficiency. This mini review presents how the chemical properties of various analogs of 4-hydroxybenzoic acid dictate the effect of the molecules on CoQ biosynthesis and how the reactivation of endogenous coenzyme Q biosynthesis may achieve better results than exogenous CoQ10 supplementation.

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Section: Paba Advances To Different Stages Of Coq Biosynthesis Dependmentioning

confidence: 74%

Impact of Chemical Analogs of 4-Hydroxybenzoic Acid on Coenzyme Q Biosynthesis: From Inhibition to Bypass of Coenzyme Q Deficiency

Pierrel

2017

Front. Physiol.

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“…required for ubiquinone biosynthesis. [21][22][23][24] Ubiquinone, also known as Coenzyme Q, is an essential component of the electron transport chain, carrying electrons from Complexes I and II to Complex III in mitochondria. These proteins are required for respiratory growth and gluconeogenic gene activation.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional responses of Candida glabrata biofilm cells to fluconazole are modulated by the carbon source

Alves

Kastora

Gomes-Gonçalves

et al. 2020

npj Biofilms Microbiomes

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Candida glabrata is an important human fungal pathogen known to trigger serious infections in immune-compromised individuals. Its ability to form biofilms, which exhibit high tolerance to antifungal treatments, has been considered as an important virulence factor. However, the mechanisms involving antifungal resistance in biofilms and the impact of host niche environments on these processes are still poorly defined. In this study, we performed a whole-transcriptome analysis of C. glabrata biofilm cells exposed to different environmental conditions and constraints in order to identify the molecular pathways involved in fluconazole resistance and understand how acidic pH niches, associated with the presence of acetic acid, are able to modulate these responses. We show that fluconazole treatment induces gene expression reprogramming in a carbon source and pH-dependent manner. This is particularly relevant for a set of genes involved in DNA replication, ergosterol, and ubiquinone biosynthesis. We also provide additional evidence that the loss of mitochondrial function is associated with fluconazole resistance, independently of the growth condition. Lastly, we propose that C. glabrata Mge1, a cochaperone involved in iron metabolism and protein import into the mitochondria, is a key regulator of fluconazole susceptibility during carbon and pH adaptation by reducing the metabolic flux towards toxic sterol formation. These new findings suggest that different host microenvironments influence directly the physiology of C. glabrata, with implications on how this pathogen responds to antifungal treatment. Our analyses identify several pathways that can be targeted and will potentially prove to be useful for developing new antifungals to treat biofilm-based infections.

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“…In bacteria and in yeast, the added methyl groups and hydroxyl groups derive from S -adenosyl methionine (SAM) [62] and O 2 [63, 64], respectively, and the same is predicted to be true in mammals. The proposed order of these reactions is based on isolation of CoQ intermediates from various strains of bacteria [65–69] and yeast [52, 53, 70–72].…”

Section: The Terminal Stage Of Coq Biosynthesis – Head Group Modificamentioning

confidence: 99%

“…Coq9p interacts physically and functionally with Coq7p to enhance the C 6-hydroxylation reaction [116]. Coq9p also appears to enhance Coq6p activity and the deamination of CoQ intermediates derived from pABA [64, 140]. Our current model is that COQ9 helps extract hydrophobic CoQ intermediates from the membrane and presents them to other COQ enzymes, such as COQ7.…”

Section: Uncharacterized Proteins In Coq Biosynthesismentioning

confidence: 99%

“…The primary CoQ pathway, which is conserved from yeast to humans, is depicted. A secondary CoQ pathway in yeast uses para -aminobenzoate (pABA) as the head group precursor instead of 4-hydroxybenzoate (4-HB) [39, 40], and Coq6p and Coq9p subsequently support C 4-deamination via C 4-hydroxylation [64, 140]. ‘R’ indicates the polyisoprenoid tail (Figure 1A), which would likely be anchored in the mitochondrial inner membrane.…”

Section: Figurementioning

confidence: 99%

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Biochemistry of Mitochondrial Coenzyme Q Biosynthesis

Stefely

Pagliarini

2017

Trends in Biochemical Sciences

258

290

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Coenzyme Q (CoQ, ubiquinone) is a redox active lipid produced across all domains of life that functions in electron transport and oxidative phosphorylation and whose deficiency causes human diseases. Yet, CoQ biosynthesis has not been fully defined in any organism. Several proteins with unclear molecular functions facilitate CoQ biosynthesis through unknown means, and multiple steps in the pathway are catalyzed by currently unidentified enzymes. Here we highlight recent progress toward filling these knowledge gaps through both traditional biochemistry and cutting-edge “omics” approaches. To help fill the remaining gaps, we present questions framed by the recently discovered CoQ biosynthetic complex and by putative biophysical barriers. Mapping CoQ biosynthesis, metabolism, and transport pathways has great potential to enhance treatment of numerous human diseases.

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Coq6 Is Responsible for the C4-deamination Reaction in Coenzyme Q Biosynthesis in Saccharomyces cerevisiae

Cited by 40 publications

References 50 publications

Impact of Chemical Analogs of 4-Hydroxybenzoic Acid on Coenzyme Q Biosynthesis: From Inhibition to Bypass of Coenzyme Q Deficiency

Impact of Chemical Analogs of 4-Hydroxybenzoic Acid on Coenzyme Q Biosynthesis: From Inhibition to Bypass of Coenzyme Q Deficiency

Transcriptional responses of Candida glabrata biofilm cells to fluconazole are modulated by the carbon source

Biochemistry of Mitochondrial Coenzyme Q Biosynthesis

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