Cited by 370Iron Metabolism and DisordersHemoglobin structure and functionMetalloenzymes and iron-sulfur proteins

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Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis.

The Tübingen 2000 Screen Consortium, Wingert, Rebecca A., Galloway, Jenna L., Barut, Bruce, Foott, Helen, Fraenkel, Paula, Axe, Jennifer L., Weber, Gerhard J., Dooley, Kimberly, Davidson, Alan J., Schmidt, Bettina, Paw, Barry H., Shaw, George C., Kingsley, Paul, Palis, James, Schubert, Heidi, Chen, Opal, Kaplan, Jerry, Zon, Leonard I.·2005·Nature

DOI 10.1038/nature03887

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Abstract

Iron is required to produce haem and iron-sulphur (Fe-S) clusters, processes thought to occur independently. Here we show that the hypochromic anaemia in shiraz (sir) zebrafish mutants is caused by deficiency of glutaredoxin 5 (grx5), a gene required in yeast for Fe-S cluster assembly. We found that grx5 was expressed in erythroid cells of zebrafish and mice. Zebrafish grx5 rescued the assembly of grx5 yeast Fe-S, showing that the biochemical function of grx5 is evolutionarily conserved. In contrast to yeast, vertebrates use iron regulatory protein 1 (IRP1) to sense intracellular iron and regulate mRNA stability or the translation of iron metabolism genes. We found that loss of Fe-S cluster assembly in sir animals activated IRP1 and blocked haem biosynthesis catalysed by aminolaevulinate synthase 2 (ALAS2). Overexpression of ALAS2 RNA without the 5' iron response element that binds IRP1 rescued sir embryos, whereas overexpression of ALAS2 including the iron response element did not. Further, antisense knockdown of IRP1 restored sir embryo haemoglobin synthesis. These findings uncover a connection between haem biosynthesis and Fe-S clusters, indicating that haemoglobin production in the differentiating red cell is regulated through Fe-S cluster assembly.

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Authors: The Tübingen 2000 Screen Consortium, Wingert, R. A., Galloway, J. L., Barut, B., Foott, H., Fraenkel, P., Axe, J. L., Weber, G. J., Dooley, K., Davidson, A. J., Schmidt, B., Paw, B. H., Shaw, G. C., Kingsley, P., Palis, J., Schubert, H., Chen, O., Kaplan, J., & Zon, L. I.
Affiliations: Howard Hughes Medical Institute (US)
Brigham and Women's Hospital (US)
University of Rochester Medicine (US)
University of Utah (US)
Corresponding author: Zon, Leonard I.
ORCID: Wingert, Rebecca A.
Galloway, Jenna L.
Fraenkel, Paula
Davidson, Alan J.
Paw, Barry H.
Shaw, George C.
Kingsley, Paul
Palis, James
Schubert, Heidi
Chen, Opal
Zon, Leonard I.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2005-08-18
Volume: 436
Issue: 7053
Pages: 1035-1039
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature03887
OpenAlex: W1992193197
Cited by: 370
References: 33
Citations by year: 2026: 6 · 2025: 1 · 2024: 8 · 2023: 6 · 2022: 11 · 2021: 15 · 2020: 17 · 2019: 11 · 2018: 14 · 2017: 17 · 2016: 15 · 2015: 13 · 2014: 18 · 2013: 17 · 2012: 21
FWCI: 16.29
Type: journal article
Language: en
Update notices: erratum (2005-10-06)
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: Howard Hughes Medical Institute
Albert J. Ryan Foundation
Harvard University
National Institutes of Health
Topics: Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Metalloenzymes and iron-sulfur proteins
Keywords: heme biosynthesis, iron regulatory protein 1, erythroid cells, hypochromic anemia, iron-responsive element, hemoglobin synthesis, iron metabolism regulation
MeSH terms: Amino Acid Sequence, 5-Aminolevulinate Synthetase, Animals, Cloning, Molecular, Erythrocytes, Gene Expression Regulation, Heme, Homeostasis, Iron, Iron-Sulfur Proteins, Molecular Sequence Data, Oxidoreductases, Saccharomyces cerevisiae, Zebrafish, Response Elements, Iron Regulatory Protein 1, Mice, Glutaredoxins

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Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis.

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