The FET3 gene of S. cerevisiae encodes a multicopper oxidase required for ferrous iron uptake

Askwith, Candice C.; Eide, David J.; Ho, Anthony Van; Bernard, Philip S.; Li, Liangtao; Davis‐Kaplan, Sandra; Sipe, David M.; Kaplan, Jerry

doi:10.1016/0092-8674(94)90346-8

Cited by 653 publications

(618 citation statements)

References 30 publications

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“…3A). Another defect in ctr1 strain is its inability to take up iron with high affinity because of defect in copper incorporation into FET3, an iron oxidase-reductase (18,31). This highaffinity iron uptake defect is also rescued by hCTR1 expression, as shown in Fig.…”

Section: Resultsmentioning

confidence: 65%

hCTR1: A human gene for copper uptake identified by complementation in yeast

Zhou

Gitschier

1997

Proc. Natl. Acad. Sci. U.S.A.

509

336

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The molecular mechanisms responsible for the cellular uptake of copper in mammalian cells are unknown. We describe isolation of a human gene involved in this process by complementation of the yeast high-affinity copper uptake mutant, ctr1. Besides complementing ctr1 growth defect on nonfermentable media, the human gene also rescues iron transport and SOD1 defects in ctr1 yeast. Overexpression of the gene in yeast leads to vulnerability to the toxicity of copper overload. In addition, its expression in ctr1 yeast significantly increases the level of cellular copper, as demonstrated by atomic absorption. We propose this gene as a candidate for high-affinity copper uptake in humans and by analogy have named it hCTR1. The hCTR1 and yeast CTR1 predicted transmembrane proteins are 29% identical, but the human protein is substantially smaller in both the extracellular metal-binding and intracellular domains. An additional human gene similar to hCTR1, here named hCTR2, was identified in a database search. Both hCTR1 and hCTR2 are expressed in all human tissues examined, and both genes are located in 9q31͞32. These studies, together with the previously recognized functional and sequence similarity between the Menkes͞Wilson copper export proteins and CCC2 in yeast, demonstrate that similar copper homeostatic mechanisms are used in these evolutionarily divergent organisms.

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Section: Resultsmentioning

confidence: 65%

hCTR1: A human gene for copper uptake identified by complementation in yeast

Zhou

Gitschier

1997

Proc. Natl. Acad. Sci. U.S.A.

509

336

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“…Transcripts for Fre1p, Fre2p and Fet3p are not detected in the absence of a functional AFT1 gene (Yamaguchi et al, 1995). Cells grown in lowiron medium (1-10 µM) contain abundant FET3 mRNA, while cells grown in high-iron medium (1000 µM) show no detectable FET3 mRNA (Askwith et al, 1994). The high-affinity iron uptake system in S. cerevisiae requires copper.…”

Section: Introductionmentioning

confidence: 95%

“…The two steps are the reduction of Fe(III) to Fe(II) by the surface ferric reductases Fre1p and Fre2p (Dancis et al, 1994 ;Georgatsou & Alexandraki, 1994), and the transport (and oxidation ?) by a low-or highaffinity Fe(II) transport system (Dix et al, 1997 ;Askwith et al, 1994). The high-affinity system has a K m for iron of 0n15 µM .…”

Section: Introductionmentioning

confidence: 99%

A multicopper oxidase gene from Candida albicans: cloning, characterization and disruption b bThe EMBL accession number for the sequence reported in this paper is Y09329.

et al. 1999

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A multicopper oxidase gene from the human pathogenic yeast Candida albicans was isolated and characterized. An open reading frame of 1872 bp, designated CaFET3, was identified, encoding a predicted protein of 624 amino acids and a molecular mass of 70 5 kDa. The identity between the deduced amino acid sequences of CaFET3 and the Saccharomyces cerevisiae FET3 gene is 55 %. CaFET3 was localized on chromosome 6. A null mutant (fet3∆/fet3∆) was constructed by sequential gene disruption. Unlike the C. albicans SC5314 wildtype strain the fet3∆ mutant was unable to grow in low-iron medium. The lack of growth of a S. cerevisiae fet3∆ mutant in iron-limited medium was compensated by transformation with CaFET3. The null mutant strain showed no change in pathogenicity compared with the wild-type strain in the mouse model of systemic candidiasis.

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“…The Cu atoms are integral in catalyzing successive one electron transfers from the substrate to reduce molecular oxygen to water. Most MCOs oxidize organic compounds, especially phenolic compounds, however MCO's have also been shown to oxidize Fe(II) in yeast (Fet3) (Askwith et al 1994), bacteria (Huston et al 2002), and humans (ceruloplasmin) (Lindley et al 1997). In addition, fungal MCOs (laccases) (Hofer and Schlosser 1999;Schlosser and Hofer 2002) have been described that can oxidize Mn(II) to Mn (III).…”

Section: Introductionmentioning

confidence: 99%

In vitro studies indicate a quinone is involved in bacterial Mn(II) oxidation

Johnson

Tebo

2007

Arch Microbiol

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Manganese(II)-oxidizing bacteria play an integral role in the cycling of Mn as well as other metals and organics. Prior work with Mn(II)-oxidizing bacteria suggested that Mn(II) oxidation involves a multicopper oxidase, but whether this enzyme directly catalyzes Mn(II) oxidation is unknown. For a clearer understanding of Mn(II) oxidation, we have undertaken biochemical studies in the model marine α-proteobacterium, Erythrobacter sp. strain SD21. The optimum pH for Mn(II)-oxidizing activity was 8.0 with a specific activity of 2.5 nmol × min −1 × mg −1 and a K m = 204 µM. The activity was soluble suggesting a cytoplasmic or periplasmic protein. Mn(III) was an intermediate in the oxidation of Mn(II) and likely the primary product of enzymatic oxidation. The activity was stimulated by pyrroloquinoline quinone (PQQ), NAD + , and calcium but not by copper. In addition, PQQ rescued Pseudomonas putida MnB1 non Mn(II)-oxidizing mutants with insertions in the anthranilate synthase gene. The substrate and product of anthranilate synthase are intermediates in various quinone biosyntheses. Partially purified Mn(II) oxidase was enriched in quinones and had a UV/VIS absorption spectrum similar to a known quinone requiring enzyme but not to multicopper oxidases. These studies suggest that quinones may play an integral role in bacterial Mn(II) oxidation.

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The FET3 gene of S. cerevisiae encodes a multicopper oxidase required for ferrous iron uptake

Cited by 653 publications

References 30 publications

hCTR1: A human gene for copper uptake identified by complementation in yeast

hCTR1: A human gene for copper uptake identified by complementation in yeast

A multicopper oxidase gene from Candida albicans: cloning, characterization and disruption b bThe EMBL accession number for the sequence reported in this paper is Y09329.

In vitro studies indicate a quinone is involved in bacterial Mn(II) oxidation

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