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Gene Review

FRE2  -  Fre2p

Saccharomyces cerevisiae S288c

Synonyms: Ferric-chelate reductase 2, Ferric/cupric reductase transmembrane component 2, YKL220C
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Disease relevance of FRE2


High impact information on FRE2

  • We have shown that Nhp6 interacts directly with the Aft1 N-half, including the DNA-binding region, to facilitate Aft1 binding at FRE2 UAS [2].
  • We found Nhp6a/b yeast HMG-box chromatin-associated architectural factors and Ssn6 (Cyc8) corepressor to be crucial transcriptional coactivators of FRE2 gene [2].
  • This Nhp6/Ssn6 role in Aft1-mediated transcription is FRE2 promoter context specific, and both regulators are required for activation-dependent chromatin remodeling [2].
  • Nhp6 facilitates Aft1 binding and Ssn6 recruitment, both essential for FRE2 transcriptional activation [2].
  • FRE1 and FRE2 encode plasma membrane ferric reductases, obligatory for ferric iron assimilation, and FET3 encodes a copper-dependent membrane-associated oxidase required for ferrous iron uptake [3].

Biological context of FRE2

  • The yeast genome contains five additional FRE1 and FRE2 homologues, four of which are regulated by iron and the major iron-dependent transcription factor, Aft1p, but whose function remains unknown [4].
  • The Saccharomyces cerevisiae genome contains nine open reading frames (ORFs)--YLR214w (FRE1), YKL220c (FRE2), YOR381w, YNR060w, YOR384w, YLL051c, YOL152w, YGL160w and YLR047c--which, based on amino acid sequence similarity, fall in the category of iron/copper reductase-related genes [5].

Anatomical context of FRE2

  • Reduction of iron (III) outside the cell is accomplished by means of reductases encoded by FRE1 and FRE2, homologues of the gp91-phox component of the oxygen reductase of human granulocytes [6].
  • Fre1p and Fre2p are ferric reductases which account for the total plasma membrane associated activity, a prerequisite for iron uptake, in Saccharomyces cerevisiae [7].

Associations of FRE2 with chemical compounds

  • FRE1 and FRE2 encode cell surface metalloreductases that are required for reduction and uptake of free ferric iron [4].
  • The high affinity uptake systems for iron and copper ions in Saccharomyces cerevisiae involve metal-specific permeases and two known cell surface Cu(II) and Fe(III) metalloreductases, Fre1 and Fre2 [8].
  • Cell-surface reductases, FRE1 and FRE2, provide ferrous iron for both systems [9].
  • Elevated Fe(III) reduction was also observed in all FRE2 and some FRE1 lines [1].

Regulatory relationships of FRE2

  • The yeast Fre1p/Fre2p cupric reductases facilitate copper uptake and are regulated by the copper-modulated Mac1p activator [7].

Other interactions of FRE2

  • In contrast, cells that overexpressed FRE2 had maximal ferrireductase activity when NCP1 was repressed [10].
  • Aft1 protein is required for maintaining detectable non-induced level of FET3 expression and for induction of FRE2 in iron starvation conditions [11].

Analytical, diagnostic and therapeutic context of FRE2

  • Northern-blot analyses revealed mRNA of two different sizes in FRE1 lines, whereas all FRE2 lines had mRNA only of the expected length [1].


  1. Expression of the yeast FRE genes in transgenic tobacco. Samuelsen, A.I., Martin, R.C., Mok, D.W., Mok, M.C. Plant Physiol. (1998) [Pubmed]
  2. Nhp6 facilitates Aft1 binding and Ssn6 recruitment, both essential for FRE2 transcriptional activation. Fragiadakis, G.S., Tzamarias, D., Alexandraki, D. EMBO J. (2004) [Pubmed]
  3. AFT1: a mediator of iron regulated transcriptional control in Saccharomyces cerevisiae. Yamaguchi-Iwai, Y., Dancis, A., Klausner, R.D. EMBO J. (1995) [Pubmed]
  4. The role of the FRE family of plasma membrane reductases in the uptake of siderophore-iron in Saccharomyces cerevisiae. Yun, C.W., Bauler, M., Moore, R.E., Klebba, P.E., Philpott, C.C. J. Biol. Chem. (2001) [Pubmed]
  5. Regulated expression of the Saccharomyces cerevisiae Fre1p/Fre2p Fe/Cu reductase related genes. Georgatsou, E., Alexandraki, D. Yeast (1999) [Pubmed]
  6. A genetic approach to elucidating eukaryotic iron metabolism. Klausner, R.D., Dancis, A. FEBS Lett. (1994) [Pubmed]
  7. The yeast Fre1p/Fre2p cupric reductases facilitate copper uptake and are regulated by the copper-modulated Mac1p activator. Georgatsou, E., Mavrogiannis, L.A., Fragiadakis, G.S., Alexandraki, D. J. Biol. Chem. (1997) [Pubmed]
  8. Metalloregulation of FRE1 and FRE2 homologs in Saccharomyces cerevisiae. Martins, L.J., Jensen, L.T., Simon, J.R., Keller, G.L., Winge, D.R., Simons, J.R. J. Biol. Chem. (1998) [Pubmed]
  9. Molecular biology of iron acquisition in Saccharomyces cerevisiae. Askwith, C.C., de Silva, D., Kaplan, J. Mol. Microbiol. (1996) [Pubmed]
  10. Cytochrome P-450 reductase is responsible for the ferrireductase activity associated with isolated plasma membranes of Saccharomyces cerevisiae. Lesuisse, E., Casteras-Simon, M., Labbe, P. FEMS Microbiol. Lett. (1997) [Pubmed]
  11. The AFT1 transcriptional factor is differentially required for expression of high-affinity iron uptake genes in Saccharomyces cerevisiae. Casas, C., Aldea, M., Espinet, C., Gallego, C., Gil, R., Herrero, E. Yeast (1997) [Pubmed]
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