Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae

In the paper

“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].”

What the sources say

• Not checked yetcites [44] Zweytick, 2000, Contribution of Are1p and Are2p to steryl ester synthesis in the yeast Saccharomyces cerevisiae, Eur. J. Biochem. source
• Not checked yetcites [48] Sorger, 2004, A yeast strain lacking lipid particles bears a defect in ergosterol formation, J. Biol. Chem. source

In the paper

“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].”

What the sources say

• Not checked yetcites [8] Liu, 2019, Outline of the biosynthesis and regulation of ergosterol in yeast, World J. Microbiol. Biotechnol. source
• Not checked yetcites [9] Protchenko, 2010, Metabolic response to iron deficiency in Saccharomyces cerevisiae, J. Biol. Chem. source

In the paper

“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].”

What the sources say

• Not checked yetcites [13] Ward, 2018, Altered sterol metabolism in budding yeast affects mitochondrial iron-sulfur (Fe-S) cluster synthesis, J. Biol. Chem. source
• Not checked yetcites [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
• Not checked yetcites [43] Giusiano, 2006, Antifungal agents: Mode of action in yeast cells, Rev. Esp. Quimioter.

In the paper

“Thus, oxygen and iron depletion are associated with reduced activity of these enzymes and changes in sterol production.”

In the paper

“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].”

What the sources say

• Not checked yetcites [48] Sorger, 2004, A yeast strain lacking lipid particles bears a defect in ergosterol formation, J. Biol. Chem. source
• Not checked yetcites [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
• Not checked yetcites [50] Ploier, 2015, Regulatory link between steryl ester formation and hydrolysis in the yeast Saccharomyces cerevisiae, Biochim. Biophys. Acta source

In the paper

“Erg1 displays a dual localization at the ER and LPs, being enzymatically inactive in the latter [57].”

What the sources say

• Not checked yetcites [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

In the paper

“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]).”

What the sources say

• Not checked yetcites [6] Hu, 2017, Recent Advances in Ergosterol Biosynthesis and Regulation Mechanisms in Saccharomyces cerevisiae, Indian J. Microbiol. source

In the paper

“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.”

In the paper

“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]).”

What the sources say

• Not checked yetcites [6] Hu, 2017, Recent Advances in Ergosterol Biosynthesis and Regulation Mechanisms in Saccharomyces cerevisiae, Indian J. Microbiol. source
• Not checked yetcites [18] Sokolov, 2019, Ergosterol Turnover in Yeast: An Interplay between Biosynthesis and Transport, Biochemistry (Mosc) source

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [28] Lorenz, 1987, Regulation of ergosterol biosynthesis and sterol uptake in a sterol-auxotrophic yeast, J. Bacteriol. source

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [75] Davies, 2006, A role for sterol levels in oxygen sensing in Saccharomyces cerevisiae, Genetics source
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [71] Yang, 2015, Structural mechanism of ergosterol regulation by fungal sterol transcription factor Upc2, Nat. Commun. source

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [75] Davies, 2006, A role for sterol levels in oxygen sensing in Saccharomyces cerevisiae, Genetics source

In the paper

“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].”

What the sources say

• Not checked yetcites [68] Vik, 2001, Upc2p and Ecm22p, dual regulators of sterol biosynthesis in Saccharomyces cerevisiae, Mol. Cell Biol. source
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [58] Mukherjee, 2002, The mammalian exosome mediates the efficient degradation of mRNAs that contain AU-rich elements, EMBO J. source
• Not checked yetcites [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

In the paper

“Upon a block in mitochondrial respiration, Erg27 migrates rapidly from LPs to the ER, although this does not imply the relocation of Erg7 [4].”

What the sources say

• Not checked yetcites [4] Cirigliano, 2019, Ergosterol reduction impairs mitochondrial DNA maintenance in S. cerevisiae, Biochim. Biophys. Acta Mol. Cell Biol. Lipids source

In the paper

“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].”

What the sources say

• Not checked yetcites [75] Davies, 2006, A role for sterol levels in oxygen sensing in Saccharomyces cerevisiae, Genetics source

In the paper

“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].”

What the sources say

• Not checked yetcites [9] Protchenko, 2010, Metabolic response to iron deficiency in Saccharomyces cerevisiae, J. Biol. Chem. source

In the paper

“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].”

What the sources say

• Not checked yetcites [78] Donigan, 2013, The yeast anaerobic response element AR1b regulates aerobic antifungal drug-dependent sterol gene expression, J. Biol. Chem. source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [60] Mo, 2003, In yeast sterol biosynthesis the 3-keto reductase protein (Erg27p) is required for oxidosqualene cyclase (Erg7p) activity, Biochim. Biophys. Acta source

In the paper

“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”

What the sources say

• Not checked yetcites [68] Vik, 2001, Upc2p and Ecm22p, dual regulators of sterol biosynthesis in Saccharomyces cerevisiae, Mol. Cell Biol. source
• Not checked yetcites [71] Yang, 2015, Structural mechanism of ergosterol regulation by fungal sterol transcription factor Upc2, Nat. Commun. source
• Not checked yetcites [72] Marie, 2008, Cytoplasmic localization of sterol transcription factors Upc2p and Ecm22p in S. cerevisiae, Fungal Genet Biol. source
• Not checked yetcites [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 yetcites [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 yetcites [75] Davies, 2006, A role for sterol levels in oxygen sensing in Saccharomyces cerevisiae, Genetics source

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [103] Lai, 2006, Metabolic-state-dependent remodeling of the transcriptome in response to anoxia and subsequent reoxygenation in Saccharomyces cerevisiae, Eukaryot Cell source

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [114] Li, 1996, Characterization of yeast methyl sterol oxidase (ERG25) and identification of a human homologue, J. Biol. Chem. source
• Not checked yetcites [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

In the paper

“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).”

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [9] Protchenko, 2010, Metabolic response to iron deficiency in Saccharomyces cerevisiae, J. Biol. Chem. source

In the paper

“In any case, under iron deprivation, the loss of Dap1 is rescued by ERG11 overexpression but not by increasing heme biosynthesis [111].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [75] Davies, 2006, A role for sterol levels in oxygen sensing in Saccharomyces cerevisiae, Genetics source
• Not checked yetcites [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 yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [96] Hickman, 2011, The Hog1 mitogen-activated protein kinase mediates a hypoxic response in Saccharomyces cerevisiae, Genetics source
• Not checked yetcites [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 yetcites [100] Bendjilali, 2017, Time-Course Analysis of Gene Expression During the Saccharomyces cerevisiae Hypoxic Response, G3 (Bethesda) source
• Not checked yetcites [101] Becerra, 2002, The yeast transcriptome in aerobic and hypoxic conditions: Effects of hap1, rox1, rox3 and srb10 deletions, Mol. Microbiol. source
• Not checked yetcites [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 yetcites [103] Lai, 2006, Metabolic-state-dependent remodeling of the transcriptome in response to anoxia and subsequent reoxygenation in Saccharomyces cerevisiae, Eukaryot Cell source

In the paper

“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].”

What the sources say

• Not checked yetcites [116] Puig, 2005, Coordinated remodeling of cellular metabolism during iron deficiency through targeted mRNA degradation, Cell source
• Not checked yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [13] Ward, 2018, Altered sterol metabolism in budding yeast affects mitochondrial iron-sulfur (Fe-S) cluster synthesis, J. Biol. Chem. source

In the paper

“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].”

What the sources say

• Not checked yetcites [9] Protchenko, 2010, Metabolic response to iron deficiency in Saccharomyces cerevisiae, J. Biol. Chem. source

In the paper

“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]).”

What the sources say

• Not checked yetcites [122] Singh, 2017, Budding Yeast: An Ideal Backdrop for In vivo Lipid Biochemistry, Front Cell Dev. Biol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [121] Romero, 2019, A genome-Wide transcriptional study reveals that iron deficiency inhibits the yeast TORC1 pathway, Biochim. Biophys. Acta Gene Regul. Mech. source

In the paper

“Nevertheless, the currently available drugs have been related to emerging resistance by fungal pathogens, significant side effects and toxicity (reviewed in [123]).”

What the sources say

• Not checked yetcites [123] Sanglard, 2016, Emerging Threats in Antifungal-Resistant Fungal Pathogens, Front Med (Lausanne)

In the paper

“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.”

In the paper

“As a consequence, erg29 mutants exhibit defects in iron-sulfur cluster assembly and mitochondrial iron accumulation [13,115].”

What the sources say

• Not checked yetcites [13] Ward, 2018, Altered sterol metabolism in budding yeast affects mitochondrial iron-sulfur (Fe-S) cluster synthesis, J. Biol. Chem. source
• Not checked yetcites [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