SUMMARY PARAGRAPH for FRE1
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 (3, 4, 5). 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 (5, 6). In some cases, deletion of FRE1 abolishes iron reduction and/or uptake (3, 4), but, in others, deletion of FRE1 reduces activity and slows growth, while deletion of both FRE1 and FRE2 abolishes growth in low iron (5, 7). Fre1p and Fre2p are also copper reductases, converting Cu(II) to usable Cu(I) (8, 9, 10). 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 (5, 7, 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 (4, 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 (1, 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 (1). Fre3p and Fre4p can reduce Fe(III) bound to specific siderophores (2). 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 (1, 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 (1, 8, 21, 27, 28) and FRE7 (1, 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 (1, 10, 21).
FRE1 is also repressed in anaerobic conditions (29) and induced by Rap1p (7), overexpression of SUB2 (with FRE2 and FRE5) (30) and at pH 8 (31). Fre1p is inhibited by menadione (4), platinum(II) (9) 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