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Cited by 489Fungal and yeast genetics researchAntifungal resistance and susceptibilityLipid metabolism and biosynthesis

Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae

Open access
Jordá, Tania, Puig, Sergi·2020·Genes
DOI 10.3390/genes11070795PMC PMC7397035
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Abstract

Ergosterol is an essential component of fungal cell membranes that determines the fluidity, permeability and activity of membrane-associated proteins. Ergosterol biosynthesis is a complex and highly energy-consuming pathway that involves the participation of many enzymes. Deficiencies in sterol biosynthesis cause pleiotropic defects that limit cellular proliferation and adaptation to stress. Thereby, fungal ergosterol levels are tightly controlled by the bioavailability of particular metabolites (e.g., sterols, oxygen and iron) and environmental conditions. The regulation of ergosterol synthesis is achieved by overlapping mechanisms that include transcriptional expression, feedback inhibition of enzymes and changes in their subcellular localization. In the budding yeast Saccharomyces cerevisiae, the sterol regulatory element (SRE)-binding proteins Upc2 and Ecm22, the heme-binding protein Hap1 and the repressor factors Rox1 and Mot3 coordinate ergosterol biosynthesis (ERG) gene expression. Here, we summarize the sterol biosynthesis, transport and detoxification systems of S. cerevisiae, as well as its adaptive response to sterol depletion, low oxygen, hyperosmotic stress and iron deficiency. Because of the large number of ERG genes and the crosstalk between different environmental signals and pathways, many aspects of ergosterol regulation are still unknown. The study of sterol metabolism and its regulation is highly relevant due to its wide applications in antifungal treatments, as well as in food and pharmaceutical industries.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes ergosterol biosynthesis, transport, detoxification, and regulation in *Saccharomyces cerevisiae*, emphasizing control by sterols, oxygen, osmotic stress, and iron. It highlights Upc2/Ecm22, Hap1, Rox1, Mot3, and other factors, while noting that many regulatory mechanisms remain unresolved.

Key findings

  • Ergosterol biosynthesis is highly energy-consuming, requiring 24 molecules of ATP and 16 molecules of NADPH per ergosterol, and depends on oxygen and iron at multiple enzymatic steps.
  • Regulation occurs through overlapping mechanisms: feedback degradation of Hmg2 via ERAD and Erg1 via Doa10, subcellular localization of Erg enzymes including the ergosome, and transcriptional control by Upc2/Ecm22, Hap1, Rox1, and Mot3.
  • Under sterol depletion, Upc2’s carboxy-terminal domain senses ergosterol; ligand dissociation promotes nuclear translocation and activation of ERG genes, sterol uptake genes (*AUS1*, *PDR11*), *DAN/TIR*, and *PAU* genes.
  • The late ergosterol pathway is a major antifungal target: azoles inhibit Erg11, allylamines inhibit Erg1, morpholines inhibit Erg2/Erg24, and polyenes bind cell-surface ergosterol; *ERG6* deletion or overexpression causes especially compromised phenotypes.

Methods

  • Narrative review synthesizing published literature on *S. cerevisiae* sterol biosynthesis, transport, detoxification, and regulation; no primary experiments, datasets, or systematic search criteria are described.
  • Discusses adaptive responses to sterol depletion, low oxygen, hyperosmotic stress, and iron deficiency, citing genome-wide expression studies but performing no new analysis.

Limitations

  • The authors state that many aspects of ergosterol regulation remain unknown because of the large number of ERG genes and crosstalk between environmental signals and pathways.
  • The authors note conflicting results for Hap1 effects on ERG gene expression under anaerobic conditions, possibly due to strain or media differences, and propose hypotheses that require further study.
  • Evident from the text: as a narrative review, it lacks systematic methodology, quantitative synthesis, and new experimental validation; conclusions rely on cited studies.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/genes11070795

Cites

124 of 124 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 137 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    When Erg11 is inhibited, an alternate pathway catalyzed by Erg6, Erg25-Erg26-Erg27 and Erg3 is activated leading to the formation of the fungistatic 14α methylergosta 8-24 (28) dienol.

    “When Erg11 is inhibited, an alternate pathway catalyzed by Erg6, Erg25-Erg26-Erg27 and Erg3 is activated leading to the formation of the fungistatic 14α methylergosta 8-24 (28) dienol [19,22].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Bhattacharya, S., Esquivel, B.D., and White, T.C. (2018). Overexpression or Deletion of Ergosterol Biosynthesis Genes Alters Doubling Time, Response to Stress Agents, and Drug Susceptibility in Saccharomyces cerevisiae. mBio, 9. source

      Not checked in the free run.

    • cites [22] Kelly, 1997, Resistance to fluconazole and cross-resistance to amphotericin B in Candida albicans from AIDS patients caused by defective sterol delta5,6-desaturation, FEBS Lett. source

      Not checked in the free run.

  • Premisecitation

    The single deletion of the majority of ERG genes within the late pathway is lethal under standard growth conditions without the addition of ergosterol.

    “The single deletion of the majority of ergosterol biosynthetic (ERG) genes within the late pathway is lethal under standard growth conditions without the addition of ergosterol.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Johnston, 2020, The wide-Ranging phenotypes of ergosterol biosynthesis mutants, and implications for microbial cell factories, Yeast source

      Not checked in the free run.

  • Premisecitation

    S. cerevisiae cells do not import significant amounts of extracellular sterols in the presence of oxygen, a phenomenon referred to as "aerobic sterol exclusion".

    “Despite this, S. cerevisiae cells do not import significant amounts of extracellular sterols in the presence of oxygen, a phenomenon referred to as “aerobic sterol exclusion” [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Lorenz, 1987, Regulation of ergosterol biosynthesis and sterol uptake in a sterol-auxotrophic yeast, J. Bacteriol. source

      Not checked in the free run.

  • Premisecitation

    Sterol esterification is essential for efficient sterol uptake.

    “Sterol esterification is essential for efficient sterol uptake [32].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Li, 2004, ATP-Binding cassette (ABC) transporters mediate nonvesicular, raft-Modulated sterol movement from the plasma membrane to the endoplasmic reticulum, J. Biol. Chem. source

      Not checked in the free run.

  • Interpretationnone given

    In S. cerevisiae, the SRE-binding proteins Upc2 and Ecm22, the heme-binding protein Hap1 and the repressor factors Rox1 and Mot3 coordinate ERG gene expression.

    “In the budding yeast Saccharomyces cerevisiae, the sterol regulatory element (SRE)-binding proteins Upc2 and Ecm22, the heme-binding protein Hap1 and the repressor factors Rox1 and Mot3 coordinate ergosterol biosynthesis (ERG) gene expression.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 39
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Premisecitation

    The double mutant are1∆are2∆ does not display any altered growth under normal conditions, despite overall sterol biosynthesis drops and the level of free sterols increases.

    “Interestingly, the double mutant are1∆are2∆ does not display any altered growth under normal conditions, despite overall sterol biosynthesis drops and the level of free sterols increases [44,48].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Zweytick, 2000, Contribution of Are1p and Are2p to steryl ester synthesis in the yeast Saccharomyces cerevisiae, Eur. J. Biochem. source

      Not checked in the free run.

    • cites [48] Sorger, 2004, A yeast strain lacking lipid particles bears a defect in ergosterol formation, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ergosterol levels are important for the hypoxic and iron deficiency responses in S. cerevisiae, conditions in which the rate of ergosterol biosynthesis is limited by defects in specific enzymes that depend on oxygen and/or iron as an essential substrate or cofactor.

    “Ergosterol levels are also important for the hypoxic and iron deficiency responses in S. cerevisiae, conditions in which the rate of ergosterol biosynthesis is limited by defects in specific enzymes that depend on oxygen and/or iron as an essential substrate or cofactor [8,9].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Liu, 2019, Outline of the biosynthesis and regulation of ergosterol in yeast, World J. Microbiol. Biotechnol. source

      Not checked in the free run.

    • cites [9] Protchenko, 2010, Metabolic response to iron deficiency in Saccharomyces cerevisiae, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The accumulation of excess free sterol intermediates may become toxic for cells since it alters mitochondrial respiration, resulting in the generation of toxic methyl sterol intermediates, which raise mitochondrial oxidants and decrease the ability to synthesize iron-sulfur (Fe-S) clusters.

    “However, the accumulation of excess free sterol intermediates may become toxic for cells since it alters mitochondrial respiration, resulting in the generation of toxic methyl sterol intermediates, which raise mitochondrial oxidants and decrease the ability to synthesize iron–sulfur (Fe-S) clusters [13,42,43].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Ward, 2018, Altered sterol metabolism in budding yeast affects mitochondrial iron-sulfur (Fe-S) cluster synthesis, J. Biol. Chem. source

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    • cites [42] Demuyser, L., Swinnen, E., Fiori, A., Herrera-Malaver, B., Vestrepen, K., and Van Dijck, P. (2017). Mitochondrial Cochaperone Mge1 Is Involved in Regulating Susceptibility to Fluconazole in Saccharomyces cerevisiae and Candida Species. mBio, 8. source

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    • cites [43] Giusiano, 2006, Antifungal agents: Mode of action in yeast cells, Rev. Esp. Quimioter.

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Oxygen and iron depletion are associated with reduced activity of these enzymes and changes in sterol production.

    “Thus, oxygen and iron depletion are associated with reduced activity of these enzymes and changes in sterol production.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The expression of ERG3 is down-regulated and Erg1 protein is destabilized in the are1∆are2∆ double mutant.

    “In fact, it has been reported that the expression of ERG3 is down-regulated and Erg1 protein is destabilized in the are1∆are2∆ double mutant [48,49,50].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [48] Sorger, 2004, A yeast strain lacking lipid particles bears a defect in ergosterol formation, J. Biol. Chem. source

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    • cites [49] Crowell, 1996, Positive and negative regulation of a sterol biosynthetic gene (ERG3) in the post-squalene portion of the yeast ergosterol pathway, FEBS Lett. source

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    • cites [50] Ploier, 2015, Regulatory link between steryl ester formation and hydrolysis in the yeast Saccharomyces cerevisiae, Biochim. Biophys. Acta source

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    Premisecitation

    Erg1 displays a dual localization at the ER and LPs, being enzymatically inactive in the latter.

    “Erg1 displays a dual localization at the ER and LPs, being enzymatically inactive in the latter [57].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Leber, 1998, Dual localization of squalene epoxidase, Erg1p, in yeast reflects a relationship between the endoplasmic reticulum and lipid particles, Mol. Biol. Cell source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Ergosterol biosynthesis is a highly energy-consuming process that requires 24 molecules of ATP and 16 molecules of NADPH to obtain a single ergosterol compound.

    “Ergosterol biosynthesis is a highly energy-consuming process that requires 24 molecules of ATP and 16 molecules of NADPH to obtain a single ergosterol compound (reviewed in [6]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Hu, 2017, Recent Advances in Ergosterol Biosynthesis and Regulation Mechanisms in Saccharomyces cerevisiae, Indian J. Microbiol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    The ergosterol biosynthetic pathway represents the main target for the development of many antifungal agents because it is essential for fungal growth and viability, and its synthesis differs in particular steps from the major sterol-producing pathway in humans.

    “Remarkably, the ergosterol biosynthetic pathway represents the main target for the development of many antifungal agents because it is essential for fungal growth and viability, and its synthesis differs in particular steps from the major sterol-producing pathway in humans.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Sterols cannot be degraded, but are either stored in the form of steryl esters (SE) in LPs or secreted into the medium as sterol acetates.

    “Sterols cannot be degraded, but are either stored in the form of steryl esters (SE) in LPs or secreted into the medium as sterol acetates (reviewed in [6,18]).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Hu, 2017, Recent Advances in Ergosterol Biosynthesis and Regulation Mechanisms in Saccharomyces cerevisiae, Indian J. Microbiol. source

      Not checked in the free run.

    • cites [18] Sokolov, 2019, Ergosterol Turnover in Yeast: An Interplay between Biosynthesis and Transport, Biochemistry (Mosc) source

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  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Fungal ergosterol levels are tightly controlled by the bioavailability of particular metabolites (e.g., sterols, oxygen and iron) and environmental conditions.

    “Thereby, fungal ergosterol levels are tightly controlled by the bioavailability of particular metabolites (e.g., sterols, oxygen and iron) and environmental conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Under aerobic conditions, yeast cells do not incorporate exogenous sterols; instead, they satisfy their sterol requirements by synthesizing their own ergosterol.

    “Under aerobic conditions, yeast cells do not incorporate exogenous sterols. Instead, they satisfy their sterol requirements by synthesizing their own ergosterol.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Lorenz, 1987, Regulation of ergosterol biosynthesis and sterol uptake in a sterol-auxotrophic yeast, J. Bacteriol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The maintenance of suitable ergosterol concentrations is achieved by feedback mechanisms at the transcriptional and post-translational levels.

    “The maintenance of suitable ergosterol concentrations is achieved by feedback mechanisms at the transcriptional and post-translational levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The deletion of both UPC2 and ECM22 is synthetically lethal in the S288C yeast genetic background due to a Ty1 insertion mutation into HAP1 coding sequence that partially compromises its function, while it is viable in the W303 background with a wild-type HAP1 gene.

    “In fact, the deletion of both UPC2 and ECM22 is synthetically lethal in the S288C yeast genetic background due to a Ty1 insertion mutation into HAP1 coding sequence that partially compromises its function, while it is viable in the W303 background with a wild-type HAP1 gene [75,83].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [75] Davies, 2006, A role for sterol levels in oxygen sensing in Saccharomyces cerevisiae, Genetics source

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    • cites [83] Valachovic, 2006, Cumulative mutations affecting sterol biosynthesis in the yeast Saccharomyces cerevisiae result in synthetic lethality that is suppressed by alterations in sphingolipid profiles, Genetics source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The carboxy-terminal domain (CTD) of yeast Upc2 displays a novel α-helical fold and serves as an ergosterol-binding and sensing domain.

    “The recent elucidation of the structure of the carboxy-terminal domain (CTD) of yeast Upc2, which displays a novel α-helical fold, has demonstrated that it serves as an ergosterol-binding and sensing domain (Figure 2A) [71].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Yang, 2015, Structural mechanism of ergosterol regulation by fungal sterol transcription factor Upc2, Nat. Commun. source

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  • May combine two claims.

    Interpretationnone given

    During aerobic growth, heme is properly synthesized and available for binding to Hap1 protein.

    “During aerobic growth, heme is properly synthesized and available for binding to Hap1 protein.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Upon low sterol levels, the abundance of Ecm22 protein, and consequently its binding to ERG promoters, decreases in a process that involves its direct physical interaction with the repressor Mot3.

    “Upon low sterol levels, the abundance of Ecm22 protein, and consequently its binding to ERG promoters, decreases in a process that involves its direct physical interaction with the repressor Mot3 (Figure 3B) [74,75].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [74] Davies, 2005, Dual activators of the sterol biosynthetic pathway of Saccharomyces cerevisiae: Similar activation/regulatory domains but different response mechanisms, Mol. Cell Biol. source

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    • cites [75] Davies, 2006, A role for sterol levels in oxygen sensing in Saccharomyces cerevisiae, Genetics source

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  • May combine two claims.

    Premisecitation

    At the same time, the levels of Upc2, and their association to ERG promoters, strongly increase, which finally results in the transcriptional induction of ERG genes.

    “At the same time, the levels of Upc2, and their association to ERG promoters, strongly increase, which finally results in the transcriptional induction of ERG genes [68,74].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [68] Vik, 2001, Upc2p and Ecm22p, dual regulators of sterol biosynthesis in Saccharomyces cerevisiae, Mol. Cell Biol. source

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    • cites [74] Davies, 2005, Dual activators of the sterol biosynthetic pathway of Saccharomyces cerevisiae: Similar activation/regulatory domains but different response mechanisms, Mol. Cell Biol. source

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  • May combine two claims.

    Premisecitation

    A fusion between Erg7 and the ER-resident protein Erg28 restores ergosterol biosynthesis to erg27 mutants, suggesting that the retention of Erg7 in the ER increases its activity.

    “Interestingly, a fusion between Erg7 and the ER-resident protein Erg28 restores ergosterol biosynthesis to erg27 mutants, suggesting that the retention of Erg7 in the ER increases its activity [61].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Layer, 2013, Characterization of a mutation that results in independence of oxidosqualene cyclase (Erg7) activity from the downstream 3-ketoreductase (Erg27) in the yeast ergosterol biosynthetic pathway, Biochim. Biophys. Acta source

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  • May combine two claims.

    Premisecitation

    Erg28 functions as a scaffold of the C-4 demethylation enzyme complex Erg25-Erg26-Erg27 tethering it to the ER, and acting as a bridge to the Erg6 enzyme required for the next biosynthetic step.

    “Erg28 functions as a scaffold of the C-4 demethylation enzyme complex Erg25–Erg26–Erg27 tethering it to the ER, and acting as a bridge to the Erg6 enzyme required for the next biosynthetic step [58,59].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [58] Mukherjee, 2002, The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements, EMBO J. source

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    • cites [59] Mo, 2004, The ERG28-Encoded protein, Erg28p, interacts with both the sterol C-4 demethylation enzyme complex as well as the late biosynthetic protein, the C-24 sterol methyltransferase (Erg6p), Biochim. Biophys. Acta source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upon a block in mitochondrial respiration, Erg27 migrates rapidly from LPs to the ER, although this does not imply the relocation of Erg7.

    “Upon a block in mitochondrial respiration, Erg27 migrates rapidly from LPs to the ER, although this does not imply the relocation of Erg7 [4].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Cirigliano, 2019, Ergosterol reduction impairs mitochondrial DNA maintenance in S. cerevisiae, Biochim. Biophys. Acta Mol. Cell Biol. Lipids source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Genetic data suggest that Hap1 is required for the basal expression of some ERG genes and for their Ecm22-dependent activation by sterol depletion.

    “Genetic data suggest that Hap1 is required for the basal expression of some ERG genes and for their Ecm22-dependent activation by sterol depletion [75].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Davies, 2006, A role for sterol levels in oxygen sensing in Saccharomyces cerevisiae, Genetics source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When ergosterol synthesis decreases due to iron deficiency, Erg1 exclusively localizes to the ER, where it is active, probably to enhance the iron-limited production of ergosterol.

    “When ergosterol synthesis decreases due to iron deficiency, Erg1 exclusively localizes to the ER, where it is active, probably to enhance the iron-limited production of ergosterol [9].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Protchenko, 2010, Metabolic response to iron deficiency in Saccharomyces cerevisiae, J. Biol. Chem. source

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  • May combine two claims.

    Premisecitation

    An auto-induction of UPC2 transcription, exclusively mediated by the direct binding of Upc2 to two TAAACGA anaerobic response (AR1b) elements within its own promoter, is required not only for the increase in Upc2 protein abundance, but also for the global activation of ERG genes and the resistance to antifungal drug treatments.

    “Interestingly, an auto-induction of UPC2 transcription, exclusively mediated by the direct binding of Upc2 to two TAAACGA anaerobic response (AR1b) elements within its own promoter, is required not only for the increase in Upc2 protein abundance, but also for the global activation of ERG genes and the resistance to antifungal drug treatments (Figure 3B) [78].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Donigan, 2013, The yeast anaerobic response element AR1b regulates aerobic antifungal drug-dependent sterol gene expression, J. Biol. Chem. source

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  • May combine two claims.

    Interpretationnone given

    Multiple gain-of-function mutations in C. albicans Upc2 CTD result in the constitutive activation of the ergosterol synthesis pathway and sterol uptake, which diminishes the strain susceptibility to azole drugs.

    “Multiple gain-of-function mutations in C. albicans Upc2 CTD result in the constitutive activation of the ergosterol synthesis pathway and sterol uptake, which diminishes the strain susceptibility to azole drugs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Erg27 can also localize to LPs, where it physically binds to Erg7, promoting its association with LPs and preventing its degradation.

    “As indicated above, Erg27 can also localize to LPs, where it physically binds to Erg7, promoting its association with LPs and preventing its degradation [60].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Mo, 2003, In yeast sterol biosynthesis the 3-keto reductase protein (Erg27p) is required for oxidosqualene cyclase (Erg7p) activity, Biochim. Biophys. Acta source

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  • May combine two claims.

    Premisecitation

    Upon ergosterol depletion, the dissociation of the sterol ligand causes a conformational change that exposes Upc2 NLS, causing its translocation to the nucleus, where it activates the transcription of SRE/AR1c-containing genes including most ERG genes, sterol uptake genes (AUS1, PDR11), the DAN/TIR genes, and members of the PAU gene family.

    “Upon ergosterol depletion, the dissociation of the sterol ligand causes a conformational change that exposes Upc2 NLS, causing its translocation to the nucleus, where it activates the transcription of SRE/AR1c-containing genes including most ERG genes, sterol uptake genes (AUS1, PDR11), the DAN/TIR genes, which encode nine cell wall mannoproteins, and members of the seripauperin (PAU) gene family”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [68] Vik, 2001, Upc2p and Ecm22p, dual regulators of sterol biosynthesis in Saccharomyces cerevisiae, Mol. Cell Biol. source

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    • cites [71] Yang, 2015, Structural mechanism of ergosterol regulation by fungal sterol transcription factor Upc2, Nat. Commun. source

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    • cites [72] Marie, 2008, Cytoplasmic localization of sterol transcription factors Upc2p and Ecm22p in S. cerevisiae, Fungal Genet Biol. source

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    • cites [73] Wilcox, 2002, Transcriptional profiling identifies two members of the ATP-Binding cassette transporter superfamily required for sterol uptake in yeast, J. Biol. Chem. source

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    • cites [74] Davies, 2005, Dual activators of the sterol biosynthetic pathway of Saccharomyces cerevisiae: Similar activation/regulatory domains but different response mechanisms, Mol. Cell Biol. source

      Not checked in the free run.

    • cites [75] Davies, 2006, A role for sterol levels in oxygen sensing in Saccharomyces cerevisiae, Genetics source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The number of ERG genes with altered expression increases with the severity of oxygen restriction, and genes encoding for oxygen-dependent enzymes are up-regulated (e.g., ERG1, ERG11 and ERG3) upon acute oxygen starvation conditions.

    “As expected, the number of ERG genes with altered expression increases with the severity of oxygen restriction, and genes encoding for oxygen-dependent enzymes are up-regulated (e.g., ERG1, ERG11 and ERG3) upon acute oxygen starvation conditions [94,102,103].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [94] Kwast, 1999, Oxygen sensing in yeast: Evidence for the involvement of the respiratory chain in regulating the transcription of a subset of hypoxic genes, Proc. Natl. Acad. Sci. USA source

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    • cites [102] Lai, 2005, Dynamical remodeling of the transcriptome during short-term anaerobiosis in Saccharomyces cerevisiae: Differential response and role of Msn2 and/or Msn4 and other factors in galactose and glucose media, Mol. Cell Biol. source

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    • cites [103] Lai, 2006, Metabolic-state-dependent remodeling of the transcriptome in response to anoxia and subsequent reoxygenation in Saccharomyces cerevisiae, Eukaryot Cell source

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  • May combine two claims.

    Premisecitation

    The transcription factor Sut1, which is up-regulated under anaerobiosis due to loss of Rox1 repression, stimulates the expression of AUS1 and DAN1, but not PDR11.

    “Additionally, the transcription factor Sut1, which is up-regulated under anaerobiosis due to loss of Rox1 repression [94], stimulates the expression of AUS1 and DAN1, but not PDR11 (Figure 3C) [105].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [94] Kwast, 1999, Oxygen sensing in yeast: Evidence for the involvement of the respiratory chain in regulating the transcription of a subset of hypoxic genes, Proc. Natl. Acad. Sci. USA source

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    • cites [105] Alimardani, 2004, SUT1-promoted sterol uptake involves the ABC transporter Aus1 and the mannoprotein Dan1 whose synergistic action is sufficient for this process, Biochem. J. source

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    Premisecitation

    Mutants in essential genes ERG25 and ERG29 lead to growth defects in low iron and respiratory conditions, respectively, due to impaired ergosterol production.

    “In addition to Dap1, mutants in other components of ergosterol biosynthesis, such as in the essential genes ERG25 and ERG29, also lead to growth defects in low iron and respiratory conditions, respectively, due to impaired ergosterol production [114,115].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [114] Li, 1996, Characterization of yeast methyl sterol oxidase (ERG25) and identification of a human homologue, J. Biol. Chem. source

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    • cites [115] Netto, 2013, The essential gene YMR134W from Saccharomyces cerevisiae is important for appropriate mitochondrial iron utilization and the ergosterol biosynthetic pathway, FEBS Lett. source

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  • May combine two claims.

    Premisecitation

    Ergosterol biosynthesis depends on iron in four steps, catalyzed by enzymes with heme (Erg5, Erg11, Dap1) or oxo-diiron (Erg25, Erg3) cofactors.

    “As already indicated, ergosterol biosynthesis depends on iron in four steps, which are catalyzed by enzymes that contain a cofactor in the form of heme (Erg5, Erg11 and its regulator Dap1) or oxo-diiron (Erg25 and Erg3) centers (Figure 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The heme-binding domain of Dap1 is required for activity of Erg11 and for growth in iron-deficient conditions.

    “Further studies have indicated that the heme-binding domain of the cytochrome b5 related protein Dap1 is required for the activity of the cytochrome P450 enzyme Erg11 as well as for growth in iron-deficient conditions [111].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [111] Craven, 2007, Regulation of iron homeostasis mediated by the heme-binding protein Dap1 (damage resistance protein 1) via the P450 protein Erg11/Cyp51, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When the levels of oxygen are appropriate (normoxia), Mot3 represses AUS1 and PDR11 expression, whereas Upc2 allows their up-regulation upon oxygen depletion.

    “When the levels of oxygen are appropriate (normoxia), Mot3 represses AUS1 and PDR11 expression [106], whereas Upc2 allows their up-regulation upon oxygen depletion [73].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [106] Sullivan, 2009, Tritium suicide selection identifies proteins involved in the uptake and intracellular transport of sterols in Saccharomyces cerevisiae, Eukaryot Cell source

      Not checked in the free run.

    • cites [73] Wilcox, 2002, Transcriptional profiling identifies two members of the ATP-Binding cassette transporter superfamily required for sterol uptake in yeast, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Iron deficiency reduces metabolic flux through the sterol pathway, decreasing ergosterol and zymosterol levels and accumulating squalene and lanosterol.

    “Consequently, iron deficiency reduces the metabolic flux through the sterol pathway, leading to a decrease in ergosterol and zymosterol levels, and the accumulation of squalene and lanosterol [9], which are the substrates of Erg1 and Erg11, respectively.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Protchenko, 2010, Metabolic response to iron deficiency in Saccharomyces cerevisiae, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Under iron deprivation, loss of Dap1 is rescued by ERG11 overexpression but not by increasing heme biosynthesis.

    “In any case, under iron deprivation, the loss of Dap1 is rescued by ERG11 overexpression but not by increasing heme biosynthesis [111].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [111] Craven, 2007, Regulation of iron homeostasis mediated by the heme-binding protein Dap1 (damage resistance protein 1) via the P450 protein Erg11/Cyp51, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Heme depletion mainly signals the Hap1 pathway, while sterol depletion directly activates the expression of ERG and DAN/TIR/PAU genes via Upc2-Ecm22.

    “Although both pathways are interdependent, heme depletion mainly signals the Hap1 pathway, while sterol depletion directly activates the expression of ERG and DAN/TIR/PAU genes via Upc2-Ecm22 (Figure 3C) [75,86,95].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [75] Davies, 2006, A role for sterol levels in oxygen sensing in Saccharomyces cerevisiae, Genetics source

      Not checked in the free run.

    • cites [86] Abramova, 2001, Regulatory mechanisms controlling expression of the DAN/TIR mannoprotein genes during anaerobic remodeling of the cell wall in Saccharomyces cerevisiae, Genetics source

      Not checked in the free run.

    • cites [95] Cohen, 2001, Induction and repression of DAN1 and the family of anaerobic mannoprotein genes in Saccharomyces cerevisiae occurs through a complex array of regulatory sites, Nucleic Acids Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ERG genes involved in the first two modules of the ergosterol biosynthesis pathway seem to be down-regulated (e.g., ERG8, ERG13 and ERG19) or constitutively expressed (e.g., ERG10 and IDI1) when oxygen availability decreases, whereas most genes involved in the latter module are induced (e.g., NCP1, DAP1, ERG25, ERG26, ERG28) and only few of them are down-regulated (e.g., ERG5).

    “ERG genes involved in the first two modules of the ergosterol biosynthesis pathway seem to be down-regulated (e.g., ERG8, ERG13 and ERG19) or constitutively expressed (e.g., ERG10 and IDI1) when oxygen availability decreases, whereas most genes involved in the latter module are induced (e.g., NCP1, DAP1, ERG25, ERG26, ERG28) and only few of them are down-regulated (e.g., ERG5).”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [94] Kwast, 1999, Oxygen sensing in yeast: Evidence for the involvement of the respiratory chain in regulating the transcription of a subset of hypoxic genes, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

    • cites [96] Hickman, 2011, The Hog1 mitogen-activated protein kinase mediates a hypoxic response in Saccharomyces cerevisiae, Genetics source

      Not checked in the free run.

    • cites [98] Hickman, 2007, Heme levels switch the function of Hap1 of Saccharomyces cerevisiae between transcriptional activator and transcriptional repressor, Mol. Cell Biol. source

      Not checked in the free run.

    • cites [100] Bendjilali, 2017, Time-Course Analysis of Gene Expression During the Saccharomyces cerevisiae Hypoxic Response, G3 (Bethesda) source

      Not checked in the free run.

    • cites [101] Becerra, 2002, The yeast transcriptome in aerobic and hypoxic conditions: Effects of hap1, rox1, rox3 and srb10 deletions, Mol. Microbiol. source

      Not checked in the free run.

    • cites [102] Lai, 2005, Dynamical remodeling of the transcriptome during short-term anaerobiosis in Saccharomyces cerevisiae: Differential response and role of Msn2 and/or Msn4 and other factors in galactose and glucose media, Mol. Cell Biol. source

      Not checked in the free run.

    • cites [103] Lai, 2006, Metabolic-state-dependent remodeling of the transcriptome in response to anoxia and subsequent reoxygenation in Saccharomyces cerevisiae, Eukaryot Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upon iron starvation, Cth2 protein binds to multiple mRNAs containing AREs within their 3′UTR and promotes their degradation and translation inhibition.

    “Upon iron starvation, Cth2 protein binds to multiple mRNAs containing AU-rich elements (AREs) within their 3′ untranslated region (3′UTR), and promotes their degradation and translation inhibition [116,119,120].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [116] Puig, 2005, Coordinated remodeling of cellular metabolism during iron deficiency through targeted mRNA degradation, Cell source

      Not checked in the free run.

    • cites [119] Vergara, 2008, The Cth2 ARE-binding protein recruits the Dhh1 helicase to promote the decay of succinate dehydrogenase SDH4 mRNA in response to iron deficiency, J. Biol. Chem. source

      Not checked in the free run.

    • cites [120] Ramos-Alonso, L., Romero, A.M., Soler, M.A., Perea-Garcia, A., Alepuz, P., Puig, S., and Martinez-Pastor, M.T. (2018). Yeast Cth2 protein represses the translation of ARE-containing mRNAs in response to iron deficiency. PLoS Genet, 14. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The presence of multiple AREs on the 3′UTR of this subset of ERG genes suggests that Cth2 may trigger their down-regulation when iron is scarce.

    “The presence of multiple AREs on the 3′UTR of this subset of ERG genes suggests that Cth2 may trigger their down-regulation when iron is scarce.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Defects in the methyl sterol oxidase step lead to accumulation of toxic intermediates that increase mitochondrial oxidation and affect stability of Ffh1, which is implicated in mitochondrial iron metabolism.

    “Defects in this step lead to the accumulation of toxic intermediates of the methyl sterol oxidase reaction that increase mitochondrial oxidation and affect the stability of the yeast frataxin homolog Ffh1, which is implicated in mitochondrial iron metabolism [13].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Ward, 2018, Altered sterol metabolism in budding yeast affects mitochondrial iron-sulfur (Fe-S) cluster synthesis, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Abundance of other Erg proteins, such as Erg6 and Erg25, is kept roughly constant or even increases, which is the case of Erg3.

    “However, the abundance of other Erg proteins, such as Erg6 and Erg25, is kept roughly constant or even increases, which is the case of Erg3 [9].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Protchenko, 2010, Metabolic response to iron deficiency in Saccharomyces cerevisiae, J. Biol. Chem. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The yeast S. cerevisiae is used as a reliable model to study multiple aspects of lipid biology due to its well characterized genome, relative simplicity of lipid metabolism and homeostasis, and conservation of genes, routes and networks in other eukaryotes.

    “The yeast S. cerevisiae is used as a reliable model to study multiple aspects of lipid biology due to its well characterized genome, the relative simplicity of its lipid metabolism and homeostasis, and the conservation of genes, routes and networks in other eukaryotes (reviewed in [122]).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] Singh, 2017, Budding Yeast: An Ideal Backdrop for In vivo Lipid Biochemistry, Front Cell Dev. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A recent global kinetic study of gene expression during iron deficiency has shown that the pattern of expression differs among ERG genes and depends on the severity of the depletion.

    “In this sense, a recent global kinetic study of gene expression during the progress of iron deficiency has shown that the pattern of expression differs among ERG genes and depends on the severity of the depletion [121].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Romero, 2019, A genome-Wide transcriptional study reveals that iron deficiency inhibits the yeast TORC1 pathway, Biochim. Biophys. Acta Gene Regul. Mech. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Currently available antifungal drugs have been related to emerging resistance by fungal pathogens, significant side effects and toxicity.

    “Nevertheless, the currently available drugs have been related to emerging resistance by fungal pathogens, significant side effects and toxicity (reviewed in [123]).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] Sanglard, 2016, Emerging Threats in Antifungal-Resistant Fungal Pathogens, Front Med (Lausanne)

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The balanced regulation of all enzymes in the ergosterol biosynthesis pathway is an essential determinant of the efficiency of sterol synthesis and of optimal growth and adaptation to environmental cues.

    “The balanced regulation of all the enzymes in the ergosterol biosynthesis pathway is an essential determinant of the efficiency of sterol synthesis and, therefore, of optimal growth and adaptation to environmental cues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    erg29 mutants exhibit defects in iron-sulfur cluster assembly and mitochondrial iron accumulation.

    “As a consequence, erg29 mutants exhibit defects in iron-sulfur cluster assembly and mitochondrial iron accumulation [13,115].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Ward, 2018, Altered sterol metabolism in budding yeast affects mitochondrial iron-sulfur (Fe-S) cluster synthesis, J. Biol. Chem. source

      Not checked in the free run.

    • cites [115] Netto, 2013, The essential gene YMR134W from Saccharomyces cerevisiae is important for appropriate mitochondrial iron utilization and the ergosterol biosynthetic pathway, FEBS Lett. source

      Not checked in the free run.

45 of 45

  • The paper relies on this without support.

    Changes in ergosterol biosynthesis lead to pleiotropic defects that limit cellular proliferation and adaptation to stresses.

    “However, changes in ergosterol biosynthesis lead to pleiotropic defects that limit cellular proliferation and adaptation to stresses.”

  • The paper relies on this without support.

    The ergosterol biosynthetic pathway constitutes one of the main targets for antifungal agents in health and agriculture.

    “The ergosterol biosynthetic pathway constitutes one of the main targets for antifungal agents in health and agriculture.”

  • The paper relies on this without support.

    Treatment with terbinafine, which targets squalene epoxidase Erg1, results in accumulation of squalene, which can be used for synthesis of terpenes.

    “For instance, the treatment with terbinafine, which targets the squalene epoxidase Erg1, results in the accumulation of squalene, which can be used for the synthesis of terpenes.”
3 of 3

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Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • HMGR is assigned two different reactions

    Minor

    The paper first identifies HMGR as catalyzing the reduction to mevalonate, but later says it catalyzes the synthesis of HMG-CoA. These descriptions assign opposite roles to the same enzyme in the pathway.

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Authors
Jordá, T., & Puig, S.
Affiliations
Consejo Superior de Investigaciones Científicas (ES)
Corresponding author
Puig, Sergi
ORCID
Venue
Genes
Publisher
MDPI AG
Published
2020-07-15
Volume
11
Issue
7
Pages
795
ISSN
2073-4425 (ISSN-L)
DOI
10.3390/genes11070795
PMC
PMC7397035
OpenAlex
W3043173157
Semantic Scholar
3244edca7f024dcaa05434430339a4bf41198884
Cited by
489
References
124
Citations by year
2026: 70 · 2025: 103 · 2024: 112 · 2023: 75 · 2022: 74 · 2021: 48 · 2020: 6 · 2018: 1
FWCI
4.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Genes (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Ministerio de Ciencia, Innovación y Universidades (BIO2017-87828-C2-1-P)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
ergosterol biosynthesis, Saccharomyces cerevisiae, sterol regulatory element, UPC2, HAP1, roX1, product inhibition, sterol transport, sterol depletion, low oxygen stress, hyperosmotic stress, iron deficiency, fungal cell membrane, antifungal drug targets
MeSH terms
DNA-Binding Proteins, Ergosterol, Promoter Regions, Genetic, Repressor Proteins, Saccharomyces cerevisiae, Sterols, Transcription Factors, Trans-Activators, Gene Expression Regulation, Fungal, Drug Resistance, Fungal, Saccharomyces cerevisiae Proteins

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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