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

The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.

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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Crossref · 10.1038/nature03887

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Metadata

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
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
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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