Genes and lipids that impact uptake and assimilation of exogenous coenzyme Q in Saccharomyces cerevisiae

Fernández-del-Rio, Lucía; Kelly, Miranda E.; Contreras, Jaime; Bradley, Michelle C.; James, Andrew M.; Murphy, Michael P.; Payne, Grégory S.; Clarke, Catherine F.

doi:10.1016/j.freeradbiomed.2020.04.029

Cited by 14 publications

(22 citation statements)

References 108 publications

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“…Decreased content of CoQ in patients can be caused by direct alteration of the proteins involved in CoQ biosynthesis (primary deficiencies) or by defects not directly linked with CoQ biosynthesis (secondary deficiencies) [46]. Secondary deficiencies can have a genetic origin but they can also result from non-genetic conditions including, clinical treatments (e.g., hypercholesterolemia treatment with statins), environmental toxins, fibromyalgia, metabolic disorders, aging, and agerelated diseases [3,[46][47][48][49]. Primary deficiencies are very rare and affect the central and peripheral nervous system; sensory organs; and heart, muscle, and renal systems [5,46].…”

Section: Figure 1 Current Model Of Coq Biosynthesis (A)mentioning

confidence: 99%

Coenzyme Q Biosynthesis: An Update on the Origins of the Benzenoid Ring and Discovery of New Ring Precursors

Fernández-del-Rio

Clarke

2021

Metabolites

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Coenzyme Q (ubiquinone or CoQ) is a conserved polyprenylated lipid essential for mitochondrial respiration. CoQ is composed of a redox-active benzoquinone ring and a long polyisoprenyl tail that serves as a membrane anchor. A classic pathway leading to CoQ biosynthesis employs 4-hydroxybenzoic acid (4HB). Recent studies with stable isotopes in E. coli, yeast, and plant and animal cells have identified CoQ intermediates and new metabolic pathways that produce 4HB. Stable isotope labeling has identified para-aminobenzoic acid as an alternate ring precursor of yeast CoQ biosynthesis, as well as other natural products, such as kaempferol, that provide ring precursors for CoQ biosynthesis in plants and mammals. In this review, we highlight how stable isotopes can be used to delineate the biosynthetic pathways leading to CoQ.

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Section: Figure 1 Current Model Of Coq Biosynthesis (A)mentioning

confidence: 99%

Coenzyme Q Biosynthesis: An Update on the Origins of the Benzenoid Ring and Discovery of New Ring Precursors

Fernández-del-Rio

Clarke

2021

Metabolites

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“…However, the biosynthesis of these hydrophobic quinones presents known biochemical challenges at the aqueous/membrane interface 61 . Enzymes involved in this biosynthesis require simultaneous access to water-soluble cofactors and lipid-soluble substrates and need to avoid the release of immature precursors into the membrane that may lead to toxic interactions with the quinonedependent enzymes 62 . In the CoQ pathway, prenylation occurs at a very early step 4 , thereby creating a scenario whereby all subsequent intermediates are poised to partition into the membrane.…”

Section: Discussionmentioning

confidence: 99%

Structure and functionality of a multimeric human COQ7:COQ9 complex

Manicki

Aydin

Abriata

et al. 2021

Preprint

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Coenzyme Q (CoQ, ubiquinone) is a redox-active lipid essential for core metabolic pathways and antioxidant defense. CoQ is synthesized upon the mitochondrial inner membrane by an ill-defined ‘complex Q’ metabolon. Here we present a structure and functional analyses of a substrate- and NADH-bound oligomeric complex comprised of two complex Q subunits: the hydroxylase COQ7, which performs the penultimate step in CoQ biosynthesis, and the prenyl lipid-binding protein COQ9. We reveal that COQ7 adopts a modified ferritin-like fold with an extended hydrophobic access channel whose substrate binding capacity is enhanced by COQ9. Using molecular dynamics simulations, we further show that two COQ7:COQ9 heterodimers form a curved tetramer that deforms the membrane, potentially opening a pathway for CoQ intermediates to translocate from within the bilayer to the proteins’ lipid-binding sites. Two such tetramers assemble into a soluble octamer, closed like a capsid, with lipids captured within. Together, these observations indicate that COQ7 and COQ9 cooperate to access hydrophobic precursors and coordinate subsequent synthesis steps toward producing mature CoQ.

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“…CoQ 8 , CoQ 9 , and CoQ 10 present in Drosophila samples were separated and quantified with a standard curve generated with commercial CoQ 10 . Standard curves were generated at each round of analysis by injecting on the HPLC-ECD system various volumes of a stock solution of CoQ 10 (12.4 µM, as determined from 275 nm absorbance using an extinction coefficient of 15200 M −1 cm −1 as described 73 ), representing quantities of 10-200 pmoles CoQ 10 . The repeatability and the linearity of the calibration curve were excellent.…”

Section: Determination Of Quinone Content In Yeast and Drosophilamentioning

confidence: 99%

Manganese-driven CoQ deficiency

et al. 2022

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Overexposure to manganese disrupts cellular energy metabolism across species, but the molecular mechanism underlying manganese toxicity remains enigmatic. Here, we report that excess cellular manganese selectively disrupts coenzyme Q (CoQ) biosynthesis, resulting in failure of mitochondrial bioenergetics. While respiratory chain complexes remain intact, the lack of CoQ as lipophilic electron carrier precludes oxidative phosphorylation and leads to premature cell and organismal death. At a molecular level, manganese overload causes mismetallation and proteolytic degradation of Coq7, a diiron hydroxylase that catalyzes the penultimate step in CoQ biosynthesis. Coq7 overexpression or supplementation with a CoQ headgroup analog that bypasses Coq7 function fully corrects electron transport, thus restoring respiration and viability. We uncover a unique sensitivity of a diiron enzyme to mismetallation and define the molecular mechanism for manganese-induced bioenergetic failure that is conserved across species.

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Genes and lipids that impact uptake and assimilation of exogenous coenzyme Q in Saccharomyces cerevisiae

Cited by 14 publications

References 108 publications

Coenzyme Q Biosynthesis: An Update on the Origins of the Benzenoid Ring and Discovery of New Ring Precursors

Coenzyme Q Biosynthesis: An Update on the Origins of the Benzenoid Ring and Discovery of New Ring Precursors

Structure and functionality of a multimeric human COQ7:COQ9 complex

Manganese-driven CoQ deficiency

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