FRE4/YNR060W Summary Help

Standard Name FRE4
Systematic Name YNR060W
Feature Type ORF, Verified
Description Ferric reductase; reduces a specific subset of siderophore-bound iron prior to uptake by transporters; expression induced by low iron levels (1, 2, 3 and see Summary Paragraph)
Name Description Ferric REductase
Chromosomal Location
ChrXIV:739951 to 742110 | ORF Map | GBrowse
Gene Ontology Annotations All FRE4 GO evidence and references
  View Computational GO annotations for FRE4
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
Regulators 9 genes
Classical genetics
Large-scale survey
10 total interaction(s) for 10 unique genes/features.
Physical Interactions
  • Affinity Capture-RNA: 1
  • PCA: 2

Genetic Interactions
  • Negative Genetic: 4
  • Phenotypic Suppression: 1
  • Positive Genetic: 1
  • Synthetic Growth Defect: 1

Expression Summary
Length (a.a.) 719
Molecular Weight (Da) 82,015
Isoelectric Point (pI) 9.96
Phosphorylation PhosphoGRID | PhosphoPep Database
sequence information
ChrXIV:739951 to 742110 | ORF Map | GBrowse
Last Update Coordinates: 2011-02-03 | Sequence: 1997-01-28
Subfeature details
Most Recent Updates
Coordinates Sequence
CDS 1..2160 739951..742110 2011-02-03 1997-01-28
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 SGDIDS000005343

FRE4 is part of a family of nine homologous genes involved or predicted to be involved in iron uptake that can be roughly grouped into three classes based on sequence similarity and transcriptional regulation: FRE1 and FRE7; FRE2 through FRE6; and FRE8 and YGL160W (1, 2). FRE2 through FRE6 are induced during iron depletion, with FRE2 and FRE3 being strongly induced and FRE4, FRE5, and FRE6 being moderately induced. Aft1p regulates transcription of FRE1 through FRE6 in response to iron levels (1, 2, 4, 5, 6, 7).

Fre1p and Fre2p are the major cell-surface iron reductases and together account for 90-98% of cell-surface reductase activity (8, 9, 10). 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 and Fre2p are homologous to the human gp91phox protein (OMIM), the large subunit of human cytochrome b558 (10, 11, 12), which reduces oxygen to bactericidal superoxide (O2-) on the surface of phagocytic leukocytes. Deficiency of gp91phox causes X-linked chronic granulomatous disease (OMIM).

Fre3p and Fre4p can reduce Fe(III) bound to specific siderophores (3). In an fre1 fre2 background, deletion of FRE3 ablates 73% of the residual ferrioxamine B-iron reductase activity. Fre3p, which is a plasma membrane protein, can also reduce iron bound to ferrichrome, triacetylfusarinine C, or rhodotorulic acid, but not enterobactin. Fre1p and Fre2p can reduce enterobactin-iron. Fre4p can reduce rhodotorulic acid-iron at high concentrations.

Reduced transcription of FRE1, FRE2, or FRE4 increases resistance to the drug itraconazole, which may be a mechanism of acquired resistance in Candida albicans (13).

Last updated: 2005-08-17 Contact SGD

References cited on this page View Complete Literature Guide for FRE4
1) Martins LJ, et al.  (1998) Metalloregulation of FRE1 and FRE2 homologs in Saccharomyces cerevisiae. J Biol Chem 273(37):23716-21
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) Yamaguchi-Iwai Y, et al.  (1995) AFT1: a mediator of iron regulated transcriptional control in Saccharomyces cerevisiae. EMBO J 14(6):1231-9
5) 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
6) 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
7) Shakoury-Elizeh M, et al.  (2004) Transcriptional remodeling in response to iron deprivation in Saccharomyces cerevisiae. Mol Biol Cell 15(3):1233-43
8) 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
9) Anderson GJ, et al.  (1992) Ferric iron reduction and iron assimilation in Saccharomyces cerevisiae. J Inorg Biochem 47(3-4):249-55
10) 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
11) 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
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) 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