FRE2/YKL220C Summary Help

Standard Name FRE2
Systematic Name YKL220C
Feature Type ORF, Verified
Description Ferric reductase and cupric reductase; reduces siderophore-bound iron and oxidized copper prior to uptake by transporters; expression induced by low iron levels but not by low copper levels (1, 2, 3 and see Summary Paragraph)
Name Description Ferric REductase
Chromosomal Location
ChrXI:11226 to 9091 | ORF Map | GBrowse
Note: this feature is encoded on the Crick strand.
Gene Ontology Annotations All FRE2 GO evidence and references
  View Computational GO annotations for FRE2
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
Regulators 3 genes
Classical genetics
Large-scale survey
8 total interaction(s) for 6 unique genes/features.
Physical Interactions
  • PCA: 2

Genetic Interactions
  • Dosage Rescue: 1
  • Negative Genetic: 1
  • Phenotypic Enhancement: 2
  • Synthetic Growth Defect: 2

Expression Summary
Length (a.a.) 711
Molecular Weight (Da) 80,072
Isoelectric Point (pI) 9.82
Phosphorylation PhosphoGRID | PhosphoPep Database
sequence information
ChrXI:11226 to 9091 | ORF Map | GBrowse
Note: this feature is encoded on the Crick strand.
Last Update Coordinates: 2011-02-03 | Sequence: 1996-07-31
Subfeature details
Most Recent Updates
Coordinates Sequence
CDS 1..2136 11226..9091 2011-02-03 1996-07-31
Retrieve sequences
Analyze Sequence
S288C only
S288C vs. other species
S288C vs. other strains
External Links All Associated Seq | E.C. | Entrez Gene | Entrez RefSeq Protein | MIPS | Search all NCBI (Entrez) | TCDB | UniProtKB
Primary SGDIDS000001703

High-affinity (Fet3p/Ftr1p) and low-affinity (Fet4p) iron uptake involve the binding and import of Fe(II) ions from the surrounding medium. Fe(III) ions can be reduced to Fe(II) by cell-surface iron reductases such as Fre1p to become physiologically usable.

Fre1p and Fre2p are the major cell-surface iron reductases and together account for 90-98% of cell-surface reductase activity (4, 5, 6). This activity is directed against both free Fe(III) and Fe(III) bound in siderophores, bacterially-secreted compounds that chelate Fe(III) for direct uptake. Fre1p is responsible for most of the reductase activity for the first 3-4 hours of growth, and Fre2p is responsible for most of the activity after 12 hours (6, 7). In some cases, deletion of FRE1 abolishes iron reduction and/or uptake (4, 5), but, in others, deletion of FRE1 reduces activity and slows growth, while deletion of both FRE1 and FRE2 abolishes growth in low iron (6, 8). Fre1p and Fre2p are also copper reductases, converting Cu(II) to usable Cu(I) (9, 10, 1). Overexpression of FRE1 causes copper sensitivity (11).

Fre1p and Fre2p are homologous to the human gp91phox protein (OMIM), the large subunit of human cytochrome b558 (6, 8, 12), which reduces oxygen to bactericidal superoxide (O2-) on the surface of phagocytic leukocytes. Deficiency of gp91phox causes X-linked chronic granulomatous disease (OMIM). Fre1p activity requires NADPH, FMN, and heme (5, 12, 13, 14).

FRE1 and FRE2 are part of a family of nine homologous genes that can be roughly grouped into three classes based on sequence similarity and transcriptional regulation (2, 15). FRE1 and FRE7 (16) are induced during copper depletion. FRE2 through FRE6 are induced during iron depletion, with FRE2 and FRE3 being strongly induced and FRE4, FRE5, and FRE6 being moderately induced. (FRE1, but not FRE7, is induced during iron depletion.) FRE8 and YGL160W transcription is not affected by either iron or copper (2). Fre3p and Fre4p can reduce Fe(III) bound to specific siderophores (3). Genome-scale experiments have localized Fre5p to mitochondria (17) and Fre6p to the vacuole (18). Deletion of FRE6 (19) or FRE7 (20) confers no apparent phenotype. Mutants lacking FRE8 are unable to grow in low iron and are respiration deficient (21).

Aft1p regulates transcription of FRE1 through FRE6 in response to iron levels (2, 15, 22, 23, 24, 25). FRE1 is also induced by Aft2p (24). Ssn6p and either Nhp6ap or Nhp6bp are required for induction of FRE2 by Aft1p in response to iron depletion (26).

Mac1p induces transcription of FRE1 (2, 9, 21, 27, 28) and FRE7 (2, 15, 28) in response to low iron or copper levels. FRE2 is repressed by Mac1p, and it has been proposed that Mac1p is responsible for the temporal regulation of FRE1 and FRE2 (2, 1, 21).

FRE1 is also repressed in anaerobic conditions (29) and induced by Rap1p (8), overexpression of SUB2 (with FRE2 and FRE5) (30) and at pH 8 (31). Fre1p is inhibited by menadione (5), platinum(II) (10) and nitric oxide (32). In end1 mutants, which lack vacuoles, FRE1 becomes iron-insensitive and is constitutively expressed (13). Reduced transcription of FRE1, FRE2, or FRE4 increases resistance to the drug itraconazole, which may be a mechanism of acquired resistance in Candida albicans (33).

Last updated: 2005-08-17 Contact SGD

References cited on this page View Complete Literature Guide for FRE2
1) Georgatsou E, et al.  (1997) The yeast Fre1p/Fre2p cupric reductases facilitate copper uptake and are regulated by the copper-modulated Mac1p activator. J Biol Chem 272(21):13786-92
2) Georgatsou E and Alexandraki D  (1999) Regulated expression of the Saccharomyces cerevisiae Fre1p/Fre2p Fe/Cu reductase related genes. Yeast 15(7):573-84
3) Yun CW, et al.  (2001) The role of the FRE family of plasma membrane reductases in the uptake of siderophore-iron in Saccharomyces cerevisiae. J Biol Chem 276(13):10218-23
4) Dancis A, et al.  (1990) Genetic evidence that ferric reductase is required for iron uptake in Saccharomyces cerevisiae. Mol Cell Biol 10(5):2294-301
5) Anderson GJ, et al.  (1992) Ferric iron reduction and iron assimilation in Saccharomyces cerevisiae. J Inorg Biochem 47(3-4):249-55
6) Georgatsou E and Alexandraki D  (1994) Two distinctly regulated genes are required for ferric reduction, the first step of iron uptake in Saccharomyces cerevisiae. Mol Cell Biol 14(5):3065-73
7) Casas C, et al.  (1997) The AFT1 transcriptional factor is differentially required for expression of high-affinity iron uptake genes in Saccharomyces cerevisiae. Yeast 13(7):621-37
8) Dancis A, et al.  (1992) Ferric reductase of Saccharomyces cerevisiae: molecular characterization, role in iron uptake, and transcriptional control by iron. Proc Natl Acad Sci U S A 89(9):3869-73
9) Jungmann J, et al.  (1993) MAC1, a nuclear regulatory protein related to Cu-dependent transcription factors is involved in Cu/Fe utilization and stress resistance in yeast. EMBO J 12(13):5051-6
10) Hassett R and Kosman DJ  (1995) Evidence for Cu(II) reduction as a component of copper uptake by Saccharomyces cerevisiae. J Biol Chem 270(1):128-34
11) Shi X, et al.  (2003) Fre1p Cu2+ reduction and Fet3p Cu1+ oxidation modulate copper toxicity in Saccharomyces cerevisiae. J Biol Chem 278(50):50309-15
12) Shatwell KP, et al.  (1996) The FRE1 ferric reductase of Saccharomyces cerevisiae is a cytochrome b similar to that of NADPH oxidase. J Biol Chem 271(24):14240-4
13) Amillet JM, et al.  (1996) Effect of heme and vacuole deficiency on FRE1 gene expression and ferrireductase activity in Saccharomyces cerevisiae. FEMS Microbiol Lett 137(1):25-9
14) Lesuisse E, et al.  (1996) Evidence for the Saccharomyces cerevisiae ferrireductase system being a multicomponent electron transport chain. J Biol Chem 271(23):13578-83
15) Martins LJ, et al.  (1998) Metalloregulation of FRE1 and FRE2 homologs in Saccharomyces cerevisiae. J Biol Chem 273(37):23716-21
16) Casamayor A, et al.  (1995) DNA sequence analysis of a 13 kbp fragment of the left arm of yeast chromosome XV containing seven new open reading frames. Yeast 11(13):1281-8
17) Sickmann A, et al.  (2003) The proteome of Saccharomyces cerevisiae mitochondria. Proc Natl Acad Sci U S A 100(23):13207-12
18) Huh WK, et al.  (2003) Global analysis of protein localization in budding yeast. Nature 425(6959):686-91
19) Ahmed Khan S, et al.  (2000) Functional analysis of eight open reading frames on chromosomes XII and XIV of Saccharomyces cerevisiae. Yeast 16(16):1457-68
20) Hajji K, et al.  (1999) Disruption and phenotypic analysis of seven ORFs from the left arm of chromosome XV of Saccharomyces cerevisiae. Yeast 15(5):435-41
21) De Freitas JM, et al.  (2004) Exploratory and confirmatory gene expression profiling of mac1Delta. J Biol Chem 279(6):4450-8
22) Yamaguchi-Iwai Y, et al.  (1995) AFT1: a mediator of iron regulated transcriptional control in Saccharomyces cerevisiae. EMBO J 14(6):1231-9
23) Yamaguchi-Iwai Y, et al.  (1996) Iron-regulated DNA binding by the AFT1 protein controls the iron regulon in yeast. EMBO J 15(13):3377-84
24) Rutherford JC, et al.  (2003) Aft1p and Aft2p mediate iron-responsive gene expression in yeast through related promoter elements. J Biol Chem 278(30):27636-43
25) Shakoury-Elizeh M, et al.  (2004) Transcriptional remodeling in response to iron deprivation in Saccharomyces cerevisiae. Mol Biol Cell 15(3):1233-43
26) Fragiadakis GS, et al.  (2004) Nhp6 facilitates Aft1 binding and Ssn6 recruitment, both essential for FRE2 transcriptional activation. EMBO J 23(2):333-42
27) Yamaguchi-Iwai Y, et al.  (1997) Homeostatic regulation of copper uptake in yeast via direct binding of MAC1 protein to upstream regulatory sequences of FRE1 and CTR1. J Biol Chem 272(28):17711-8
28) Gross C, et al.  (2000) Identification of the copper regulon in Saccharomyces cerevisiae by DNA microarrays. J Biol Chem 275(41):32310-6
29) Hassett RF, et al.  (1998) Regulation of high affinity iron uptake in the yeast Saccharomyces cerevisiae. Role of dioxygen and Fe. J Biol Chem 273(13):7628-36
30) Lahue E, et al.  (2005) The Saccharomyces cerevisiae Sub2 protein suppresses heterochromatic silencing at telomeres and subtelomeric genes. Yeast 22(7):537-51
31) Lamb TM, et al.  (2001) Alkaline response genes of Saccharomyces cerevisiae and their relationship to the RIM101 pathway. J Biol Chem 276(3):1850-6
32) Shinyashiki M, et al.  (2004) Inhibition of the yeast metal reductase heme protein fre1 by nitric oxide (NO): a model for inhibition of NADPH oxidase by NO. Free Radic Biol Med 37(5):713-23
33) Barker KS, et al.  (2003) Identification of genes differentially expressed in association with reduced azole susceptibility in Saccharomyces cerevisiae. J Antimicrob Chemother 51(5):1131-40