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An Iron-Regulated Ferric Reductase Associated with the Absorption of Dietary Iron
Abstract
The ability of intestinal mucosa to absorb dietary ferric iron is attributed to the presence of a brush-border membrane reductase activity that displays adaptive responses to iron status. We have isolated a complementary DNA, Dcytb (for duodenal cytochrome b), which encoded a putative plasma membrane di-heme protein in mouse duodenal mucosa. Dcytb shared between 45 and 50% similarity to the cytochrome b561 family of plasma membrane reductases, was highly expressed in the brush-border membrane of duodenal enterocytes, and induced ferric reductase activity when expressed in Xenopus oocytes and cultured cells. Duodenal expression levels of Dcytb messenger RNA and protein were regulated by changes in physiological modulators of iron absorption. Thus, Dcytb provides an important element in the iron absorption pathway.
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In the citing paper
“Iron homeostasis and bioavailability to either the host or invading pathogens is tightly regulated through coordination of hepcidin, iron binding proteins and several enzymes involved in iron metabolism (McKie et al., 2001; Nemeth et al., 2004).”
From Iron at the Centre of Candida albicans Interactions (2018) · cites this paper as McKie et al., 2001
In the citing paper
“The uptake of ionic NHI in contrast, is a sequential process that is well characterized: Following the reduction of ferric iron by DCYTB (for duodenal cytochrome B) at the luminal surface of enterocytes (ENT), it is DMT1 (for divalent metal transporter-1) that imports iron into the cytoplasm (Gunshin et al., 1997;McKie et al., 2001).”
From Iron in infection and immunity (2020) · cites this paper as McKie et al., 2001
In the citing paper
“When systemic iron levels in the blood stream are low, expression of DMT1 (divalent metal transporter 1, also called NRAMP2 as well as SLC11A2) and DcytB (duodenal membrane associated cytochrome-b) ferrireductase increases on the surface of intestinal enterocytes on the luminal side enabling the reduction of Fe3+ into its ferrous form (Fe2+) which can then be taken up by DMT1 (McKie et al., 2001).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as McKie et al., 2001
In the citing paper
“At either location, Dmt1 only accepts ferrous iron along with other divalent cations, such as copper or manganese, and co-localizes with an iron reductase [152, 177].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [152]
In the citing paper
“To overcome the low availability of Fe2+, duodenal cytochrome b (DCYTB) enzymes that are present within the apical membrane of enterocytes are able to reduce any soluble Fe3+ to Fe2+ before DMT1‐mediated Fe2+ import. 14 , 15”
From The battle for iron in enteric infections (2020) · cites this paper as [14]
In the citing paper
“However, inorganic iron uptake from the gastrointestinal lumen by enterocytes depends upon the divalent metal transporter protein 1 (DMT1 or NRAMP2), which is not able to import Fe3+. 12 , 13 , 14”
From The battle for iron in enteric infections (2020) · cites this paper as [14]
In the citing paper
“Mammals acquire ferrous (Fe2+) from the diet via a mechanism assisted by the divalent metal transporter ion transporter 1 (DMT1) expressed by duodenum enterocytes (12, 13).”
From Innate Nutritional Immunity (2018) · cites this paper as [13]
In the citing paper
“It must be reduced to ferrous (Fe 2ϩ ) iron, either chemically or through the action of a brush border ferrireductase such as duodenal cytochrome B (CYBRD1, also known as DCYTB), a cytochrome B561 homolog that may use ascorbic acid as a cofactor.53”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [53]
In the citing paper
“CYBRD1 was one of 2 iron transport-related molecules discovered by McKie through a very productive RNA subtraction approach.53,54”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [53]
In the citing paper
“IRP1-knockout mice survived with insignificant effects on iron homeostasis in kidney and brown fat that highly express IRP1 (55, 200).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [200]
In the citing paper
“IRP2-knockout mice showed abnormal induction of ferritin expression, resulting in iron misregulation in intestinal mucosa and the CNS (55, 200).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [200]
In the citing paper
“IRP2 was also sensitive to iron levels, whereas IRP1 was not, suggesting that IRP2 is the predominant posttranscriptional regulator of key genes involved iron homeostasis (200).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [200]
In the citing paper
“IRP2 was also sensitive to iron levels, whereas IRP1 was not, suggesting that IRP2 is the predominant posttranscriptional regulator of key genes involved iron homeostasis (200).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [200]
In the citing paper
“IRP1-knockout mice misregulate iron in specific tissues, namely in brown fat and kidney, whereas IRP2-knockout mice exhibit aberrant management of iron in multiple tissues.”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [200]
Citations
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Cloning and characterization of a mammalian proton-coupled metal-ion transporter
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Self-citationMcKie, A. T., Marciani, P., Rolfs, A., Brennan, K., Wehr, K., Barrow, D., Miret, S., Bomford, A., Peters, T. J., Farzaneh, F., et al. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)80425-6 · Cited by 1,422
Self-citationA ferric-chelate reductase for iron uptake from soils
Robinson, N. J., Procter, C. M., Connolly, E. L., & Guerinot, M. L. (1999) · Nature · doi:10.1038/17800 · Cited by 1,271
Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene
Fleming, M. D., Trenor, C. C., Su, M. A., Foernzler, D., Beier, D. R., Dietrich, W. F., & Andrews, N. C. (1997) · Nature Genetics · doi:10.1038/ng0897-383 · Cited by 1,159
Dancis, A., Roman, D. G., Anderson, G. J., Hinnebusch, A. G., & Klausner, R. D. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.9.3869 · Cited by 358
Identification and characterization of a second mouse Nramp gene
Gruenheid, S., Cellier, M. F., Vidal, S. M., & Gros, P. (1995) · Genomics · doi:10.1016/0888-7543(95)80053-o · Cited by 287
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Trinder, D., Oates, P. S., Thomas, C., Sadleir, J., & Morgan, E. H. (2000) · Gut · doi:10.1136/gut.46.2.270 · Cited by 231
Crystal, R. G. (1997) · Nature Medicine · doi:10.1038/nm0497-383 · Cited by 204
Research works printed but not linked: 5
- Male mice (6 to 9 weeks old) of the CD-1 strain were used for experimental manipulations of iron status. Hypoxia iron deficiency and iron loading were carried out as described previously (10). Hypotransferrinemic mice were bred and maintained as described previously (16). Animal procedures were approved by the U.K. Home Office. Total RNA was extracted from tissues and Northern blotting was carried out as previously described (10). The above-described 114-bp fragment of Dcytb was used as the probe. We carried out reverse transcription on 10 μg of total RNA from each tissue using 100 U of Superscript II (Gibco) and 100 nM random hexamers (Pharmacia) and following the manufacturer's instructions. PCR was performed in a PTC 200 thermal cycler (MJ Research Waltham MA) with 0.5 U of Taq polymerase (Supertaq HT Biotechnology Cambridge) 200 μM deoxynucleoside triphosphate (Fermentas Hanover MD) and gene-specific primers (sequences available on request) at a concentration of 10 μM. Products were compared after 20 25 and 30 cycles. The products shown in Fig. 2D are after 20 [GAPDH (glyceraldehyde phosphate dehydrogenase) and Dcytb] and 30 cycles (gp91- phox ). The data shown were reproducible in independent experiments on individual mice from each group. In situ hybridizations were carried out as previously described (10).
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Metadata
- Authors
- McKie, A. T., Barrow, D., Latunde-Dada, G. O., Rolfs, A., Sager, G., Mudaly, E., Mudaly, M., Richardson, C., Barlow, D., Bomford, A., Peters, T. J., Raja, K. B., Shirali, S., Hediger, M. A., Farzaneh, F., & Simpson, R. J.
- Affiliations
- King's College London (GB)
- Brigham and Women's Hospital (US)
- Department of Clinical Biochemistry,
- Corresponding author
- McKie, Andrew T.
- ORCID
- Venue
- Science
- Published
- 2001-03-02
- Volume
- 291
- Issue
- 5509
- Pages
- 1755-1759
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2105749655
- Cited by
- 1,101
- References
- 26
- Citations by year
- 2026: 25 · 2025: 41 · 2024: 44 · 2023: 30 · 2022: 45 · 2021: 43 · 2020: 55 · 2019: 40 · 2018: 50 · 2017: 33 · 2016: 22 · 2015: 28 · 2014: 48 · 2013: 44 · 2012: 47
- FWCI
- 28.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Micronutrient Interactions and Effects
- Keywords
- ferric reductase, dietary iron absorption, duodenal cytochrome b, Dcytb, cytochrome b561, brush border membrane, duodenal enterocytes, Xenopus oocyte expression
- MeSH terms
- Amino Acid Sequence, Anemia, Animals, Hypoxia, Cell Line, Cloning, Molecular, Cytochrome b Group, Duodenum, Enzyme Induction, Ferric Compounds, Intestinal Absorption, Intestinal Mucosa, Male, Microvilli, Molecular Sequence Data, Nitroblue Tetrazolium, Oocytes, Oxidation-Reduction, Oxidoreductases, RNA, Messenger, Tetrazolium Salts, Thiazoles, Transfection, Xenopus, Up-Regulation, DNA, Complementary, Iron, Dietary, Enterocytes, Mice
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