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Gene Review

ERG1  -  Erg1p

Saccharomyces cerevisiae S288c

 
 
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Disease relevance of ERG1

  • Recombinant SPF produced in Escherichia coli enhances microsomal squalene epoxidase activity and promotes intermembrane transfer of squalene in vitro [1].
  • On the basis of functional homologies to p-hydroxybenzoate hydroxylase (PHBH) from Pseudomonas fluorescens, the Erg1 protein contains two flavin adenine dinucleotide (FAD) domains and one nucleotide binding (NB) site [2].
 

High impact information on ERG1

  • Squalene epoxidase, a membrane-associated enzyme that converts squalene to squalene 2,3-oxide, plays an important role in the maintenance of cholesterol homeostasis [1].
  • Introduction of the erg26 mutation into an erg1 (squalene epoxidase) strain also was viable in ergosterol-supplemented media [3].
  • Thus, ETS1 and ETS2 are allelic to ERG1 and ERG7, respectively [4].
  • The quadruple mutant, however, was more sensitive to terbinafine, an inhibitor of Erg1p, than the are1are2 strain suggesting that the presence of TAG and/or intact lipid particles has an additional protective effect [5].
  • Most interestingly, the amount of the squalene epoxidase Erg1p, which is dually located in lipid particles and endoplasmic reticulum of wild type, is decreased in the quadruple mutant, whereas amounts of other lipid particle proteins tested were not reduced [5].
 

Biological context of ERG1

 

Anatomical context of ERG1

 

Associations of ERG1 with chemical compounds

  • Squalene epoxidase, encoded by the ERG1 gene in yeast, is a key enzyme of sterol biosynthesis [9].
  • Chromosomal integration of ERG1 ERG7 at their loci in erg26-1ts ets1-1 and erg26-1ts and ets2-1 mutants, respectively, results in the loss of accumulation of squalene and squalene epoxide, re-accumulation of 4-carboxysterols and cell inviability at high temperature [4].
  • Inhibition of ergosterol biosynthesis with terbinafine increases the expression of ERG1 in a concentration-dependent manner to a maximum of sevenfold [7].
  • The ERG1 gene of Saccharomyces cerevisiae encodes squalene epoxidase, a key enzyme in the ergosterol pathway [6].
  • Inhibition of later steps in the ergosterol-biosynthetic pathway by ketoconazole, an inhibitor of the lanosterol-14alpha-demethylase, and U18666A, an inhibitor of the squalene-2,3-epoxide-lanosterol cyclase, also induce expression of ERG1, suggesting that ERG1 expression is positively regulated by diminished intracellular ergosterol levels [7].
 

Regulatory relationships of ERG1

 

Other interactions of ERG1

  • In the yeast Saccharomyces cerevisiae, three enzymes of the sterol biosynthetic pathway, namely Erg1p, Erg6p and Erg7p, are located in lipid particles [12].
  • Both antifungals induced to various levels the expression of ERG1, ERG11, CDR1, and CDR2; addition of TSA reduced this upregulation 50 to 100% [13].
  • A comparison between planktonic and biofilm populations of transcript abundance for genes coding for enzymes in the ergosterol (ERG1, -3, -5, -6, -9, -11, and -25) and beta-1,6-glucan (SKN and KRE1, -5, -6, and -9) pathways was performed by quantitative RT-PCR [14].
  • As de novo lipid synthesis may be involved in ethanol tolerance, we studied the effect of oxygen addition on sterol and UFA auxotrophs (erg1 and ole1 mutants, respectively) [15].
  • Squalene synthetase (EC 2.5.1.21) and squalene epoxidase (EC 1.14 99.7) activities have been measured in cell-free extracts of wild type yeast grown in aerobic and semi-anaerobic conditions as well as in sterol-auxotrophic mutant strains grown aerobically [16].
 

Analytical, diagnostic and therapeutic context of ERG1

References

  1. Supernatant protein factor, which stimulates the conversion of squalene to lanosterol, is a cytosolic squalene transfer protein and enhances cholesterol biosynthesis. Shibata, N., Arita, M., Misaki, Y., Dohmae, N., Takio, K., Ono, T., Inoue, K., Arai, H. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  2. Characterization of Squalene Epoxidase of Saccharomyces cerevisiae by Applying Terbinafine-Sensitive Variants. Ruckenstuhl, C., Lang, S., Poschenel, A., Eidenberger, A., Baral, P.K., Koh??t, P., Hapala, I., Gruber, K., Turnowsky, F. Antimicrob. Agents Chemother. (2007) [Pubmed]
  3. Characterization of the Saccharomyces cerevisiae ERG26 gene encoding the C-3 sterol dehydrogenase (C-4 decarboxylase) involved in sterol biosynthesis. Gachotte, D., Barbuch, R., Gaylor, J., Nickel, E., Bard, M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  4. Characterizing sterol defect suppressors uncovers a novel transcriptional signaling pathway regulating zymosterol biosynthesis. Germann, M., Gallo, C., Donahue, T., Shirzadi, R., Stukey, J., Lang, S., Ruckenstuhl, C., Oliaro-Bosso, S., McDonough, V., Turnowsky, F., Balliano, G., Nickels, J.T. J. Biol. Chem. (2005) [Pubmed]
  5. A yeast strain lacking lipid particles bears a defect in ergosterol formation. Sorger, D., Athenstaedt, K., Hrastnik, C., Daum, G. J. Biol. Chem. (2004) [Pubmed]
  6. ERG1, encoding squalene epoxidase, is located on the right arm of chromosome VII of Saccharomyces cerevisiae. Landl, K.M., Klösch, B., Turnowsky, F. Yeast (1996) [Pubmed]
  7. A novel sequence element is involved in the transcriptional regulation of expression of the ERG1 (squalene epoxidase) gene in Saccharomyces cerevisiae. Leber, R., Zenz, R., Schröttner, K., Fuchsbichler, S., Pühringer, B., Turnowsky, F. Eur. J. Biochem. (2001) [Pubmed]
  8. Single amino acid exchanges in FAD-binding domains of squalene epoxidase of Saccharomyces cerevisiae lead to either loss of functionality or terbinafine sensitivity. Ruckenstuhl, C., Eidenberger, A., Lang, S., Turnowsky, F. Biochem. Soc. Trans. (2005) [Pubmed]
  9. Dual localization of squalene epoxidase, Erg1p, in yeast reflects a relationship between the endoplasmic reticulum and lipid particles. Leber, R., Landl, K., Zinser, E., Ahorn, H., Spök, A., Kohlwein, S.D., Turnowsky, F., Daum, G. Mol. Biol. Cell (1998) [Pubmed]
  10. Terbinafine: a review of its use in onychomycosis in adults. Darkes, M.J., Scott, L.J., Goa, K.L. American journal of clinical dermatology. (2003) [Pubmed]
  11. Effect of detergents on sterol synthesis in a cell-free system of yeast. Hata, S., Nishino, T., Ariga, N., Katsuki, H. J. Lipid Res. (1982) [Pubmed]
  12. Targeting of proteins involved in sterol biosynthesis to lipid particles of the yeast Saccharomyces cerevisiae. Müllner, H., Zweytick, D., Leber, R., Turnowsky, F., Daum, G. Biochim. Biophys. Acta (2004) [Pubmed]
  13. Histone deacetylase inhibitors enhance Candida albicans sensitivity to azoles and related antifungals: correlation with reduction in CDR and ERG upregulation. Smith, W.L., Edlind, T.D. Antimicrob. Agents Chemother. (2002) [Pubmed]
  14. A Small Subpopulation of Blastospores in Candida albicans Biofilms Exhibit Resistance to Amphotericin B Associated with Differential Regulation of Ergosterol and {beta}-1,6-Glucan Pathway Genes. Khot, P.D., Suci, P.A., Miller, R.L., Nelson, R.D., Tyler, B.J. Antimicrob. Agents Chemother. (2006) [Pubmed]
  15. Oxygen consumption by anaerobic Saccharomyces cerevisiae under enological conditions: effect on fermentation kinetics. Rosenfeld, E., Beauvoit, B., Blondin, B., Salmon, J.M. Appl. Environ. Microbiol. (2003) [Pubmed]
  16. Regulation of squalene synthetase and squalene epoxidase activities in Saccharomyces cerevisiae. M'Baya, B., Fegueur, M., Servouse, M., Karst, F. Lipids (1989) [Pubmed]
  17. An oxysterol-derived positive signal for 3-hydroxy- 3-methylglutaryl-CoA reductase degradation in yeast. Gardner, R.G., Shan, H., Matsuda, S.P., Hampton, R.Y. J. Biol. Chem. (2001) [Pubmed]
  18. Cloning and expression of squalene epoxidase from the pathogenic yeast Candida albicans. Favre, B., Ryder, N.S. Gene (1997) [Pubmed]
 
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