Identification of zyklopen, a new member of the vertebrate multicopper ferroxidase family, and characterization in rodents and human cells
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We previously detected a membrane-bound, copper-containing oxidase that may be involved in iron efflux in BeWo cells, a human placental cell line. We have now identified a gene encoding a predicted multicopper ferroxidase (MCF) with a putative C-terminal membrane-spanning sequence and high sequence identity to hephaestin (Heph) and ceruloplasmin (Cp), the other known vertebrate MCF. Molecular modeling revealed conservation of all type I, II, and III copper-binding sites as well as a putative iron-binding site. Protein expression was observed in multiple diverse mouse tissues, including placenta and mammary gland, and the expression pattern was distinct from that of Cp and Heph. The protein possessed ferroxidase activity, and protein levels decreased in cellular copper deficiency. Knockdown with small interfering RNA in BeWo cells indicates that this gene represents the previously detected oxidase. We propose calling this new member of the MCF family "zyklopen."
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At the outer cell membrane, iron is oxidized to Fe3+ by ceruloplasmin, hephaestin, and zyklopen.
“At the outer cell membrane iron is oxidized to its ferric (Fe3+) form by three iron oxidases each displaying distinct expression patterns—ceruloplasmin (CP) (Miller and Cohen, 2001), hephaestin (HEPH) (Vulpe et al., 1999), and zyklopen (HEPHL1) (Chen et al., 2010; Figure 1).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Chen et al., 2010
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- Authors
- Chen, H., Attieh, Z. K., Syed, B. A., Kuo, Y.-M., Stevens, V., Fuqua, B. K., Andersen, H. S., Naylor, C. E., Evans, R. W., Gambling, L., Danzeisen, R., Bacouri-Haidar, M., Usta, J., Vulpe, C. D., & McArdle, H. J.
- Affiliations
- Nanjing University (CN)
- American University of Science and Technology (LB)
- University of California, Berkeley (US)
- University of California, San Francisco (US)
- University of Aberdeen (GB)
- Birkbeck, University of London (GB)
- Brunel University of London (GB)
- Lebanese University (LB)
- American University of Beirut (LB)
- Corresponding author
- Vulpe, Chris D.
- ORCID
- Venue
- The Journal of Nutrition
- Publisher
- Elsevier BV
- Published
- 2010-10
- Volume
- 140
- Issue
- 10
- Pages
- 1728-1735
- ISSN
- 0022-3166 (ISSN-L)
- PMC
- PMC2937573
- OpenAlex
- W2155736361
- Cited by
- 122
- References
- 45
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 3 · 2023: 4 · 2022: 6 · 2021: 12 · 2020: 6 · 2019: 9 · 2018: 14 · 2017: 7 · 2016: 9 · 2015: 7 · 2014: 7 · 2013: 5 · 2012: 11
- FWCI
- 8.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Nutrition (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- Université Libanaise
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK056376)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- iron efflux, ferroxidase activity, copper binding site, hephaestin, ceruloplasmin, placenta, mammary gland, copper deficiency, gene knockdown, BeWo cells, tissue expression
- MeSH terms
- Oxidoreductases Acting on CH-NH Group Donors, Amino Acid Sequence, Animals, Base Sequence, Binding Sites, Cell Line, Ceruloplasmin, Copper, Female, Humans, Iron, Mammary Glands, Animal, Membrane Proteins, Mice, Inbred C57BL, Mice, Inbred ICR, Models, Molecular, Organ Specificity, Peptide Fragments, Placenta, Pregnancy, Gene Expression, Sequence Homology, Caco-2 Cells, RNA, Small Interfering, Cell Line, Tumor, Mice, Rats
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