Plasma membrane ascorbate-dependent reductase CYBRD1 (CYBRD1)
The protein contains 286 amino acids for an estimated molecular weight of 31641 Da.
Plasma membrane reductase that uses cytoplasmic ascorbate as an electron donor to reduce extracellular Fe(3+) into Fe(2+) (PubMed:30272000). Probably functions in dietary iron absorption at the brush border of duodenal enterocytes by producing Fe(2+), the divalent form of iron that can be transported into enterocytes (PubMed:30272000). It is also able to reduce extracellular monodehydro-L-ascorbate and may be involved in extracellular ascorbate regeneration by erythrocytes in blood (PubMed:17068337). May also act as a ferrireductase in airway epithelial cells (Probable). May also function as a cupric transmembrane reductase (By similarity). (updated: June 2, 2021)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt, is predicted to be membranous by TOPCONS.
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| Variant | Description |
|---|---|
| dbSNP:rs16859487 | |
| some patients with hereditary hemochromatosis | |
| dbSNP:rs10455 |
Biological Process
Ascorbate homeostasis
Cellular iron ion homeostasis
Iron ion homeostasis
Reductive iron assimilation
Response to iron ion
Transmembrane transport
The reference OMIM entry for this protein is 605745
Cytochrome b reductase 1; cybrd1
Duodenal cytochrome b; dcytb
CLONING
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. McKie et al. (2001) isolated a cDNA, which they called Dcytb for 'duodenal cytochrome b,' that encodes a putative plasma membrane di-heme protein in mouse duodenal mucosa. By searching EST databases, the authors also found a fully sequenced cDNA clone from a human small intestine library containing the full-length human DCYTB cDNA (GenBank GENBANK AK027115). DCYTB encodes a protein with 6 predicted transmembrane domains and 4 conserved histidine residues which are proposed heme ligands. DCYTB shares 45 to 50% similarity with the cytochrome b561 (600019) family of plasma membrane reductases, is highly expressed in the brush-border membrane of duodenal enterocytes, and induces ferric reductase activity when expressed in Xenopus oocytes and cultured cells. Duodenal expression levels of DCYTB mRNA and protein were regulated by changes in physiologic modulators of iron absorption, including chronic anemia, iron deficiency, and hypoxia. Three major transcripts of 1, 4, and greater than 5 kb were detectable by Northern blot analysis, indicative of alternative splicing or the presence of unprocessed pre-mRNA species. DCYTB appears to lack any conventional NADH-, NADPH-, or flavin-binding motifs that would allow these cofactors to act as intracellular electron donors. Cytochrome b561 receives an electron from ascorbate and does not appear to require other components. McKie et al. (2001) speculated that DCYTB may also use ascorbate or, like gp91-phox (300481), associate with several other proteins to form an active complex.GENE FUNCTION
Zoller et al. (2003) studied the mRNA and protein expression and activity of DCYTB in duodenal biopsies of patients with iron deficiency anemia, hereditary hemochromatosis (235200), and controls. They found that DCYTB activity in iron deficiency is stimulated via enhanced protein expression, whereas in hemochromatosis due to mutations in the HFE gene (613609) it is upregulated posttranslationally. Hemochromatosis patients with no mutations in HFE did not have increased DCYTB activity. Zoller et al. (2003) concluded that there are different kinetics of intestinal iron uptake between iron deficiency and hemochromatosis due to mutations in HFE, and that duodenal iron accumulation in hereditary hemochromatosis due to mutations in HFE and hereditary hemochromatosis due to mutations in other genes is pathophysiologically different.MAPPING
The International Radiation Hybrid Mapping Consortium mapped the CYBRD1 gene to chromosome 2 (TMAP RH46529). ... More on the omim web site
July 1, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.
April 10, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 605745 was added.