Disease relevance of CYBRD1

• This study confirms the genetic heterogeneity of haemochromatosis and highlights the significance of CYBRD1 mutations in relation to iron overload [1].
• RESULTS: Perl's staining showed increased iron in colorectal cancers, and there was a corresponding overexpression of components of the intracellular iron import machinery (DCYTB, DMT1, and TfR1) [2].

High impact information on CYBRD1

• 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 [3].
• Spectroscopic and kinetic characterization of the recombinant wild-type and C242S mutant of the cytochrome b reductase fragment of nitrate reductase [4].
• Spectroscopic and kinetic studies comparing the behavior of the recombinant cytochrome b reductase fragment of corn leaf nitrate reductase and a mutant in which cysteine 242 is replaced with a serine residue (C242S) have been carried out [4].
• Hephaestin and Dcytb levels were not upregulated in haemochromatosis [5].
• Structural studies on corn nitrate reductase: refined structure of the cytochrome b reductase fragment at 2.5 A, its ADP complex and an active-site mutant and modeling of the cytochrome b domain [6].

Biological context of CYBRD1

• Duodenal Dcytb and hephaestin mRNA expression are not significantly modulated by variations in body iron homeostasis [7].
• Among these is duodenal cytochrome B (DcytB), but lack of an obvious phenotype in DcytB (Cybrd1) knockout mice suggests ferrireductase redundancy [8].
• The refined crystal structures of the recombinant cytochrome b reductase fragment of corn (Zea mays) nitrate reductase, its ADP complex and the active-site mutant Cys242Ser are reported here [6].
• The presence of Dcytb in airway epithelial cells and its regulation by iron therefore may contribute to pulmonary cytoprotection [9].

Anatomical context of CYBRD1

• Dcytb expression was found in other tissues apart from the duodenum and its regulation and functions at these other sites are of interest in iron metabolism [10].
• Using Northern and Western blots, RT-PCR and confocal microscopy, we studied the expression and localisation of Dcytb in cell lines and tissues of CD1 mice [10].
• Novel genes associated with iron uptake include Dcytb, a putative iron-regulated reductase and DMT1, a Fe(II) carrier in the brush border membrane [11].
• RESULTS: Dcytb (duodenal ferric reductase) was expressed at very low levels in the large intestine, compared to the duodenum, while Ireg1 and DMT1 were expressed at significant levels in the large intestine and were increased in iron-deficient caecum, proximal and distal colon, with the most significant increases seen in the distal colon [12].
• Dcytb expression was found in respiratory epithelium in vitro and in vivo and was responsive to iron concentration [9].

Associations of CYBRD1 with chemical compounds

• Dcytb, the iron regulated ferric reductase may also utilize cytoplasmic ascorbate as electron donor for transmembrane reduction of iron [10].
• Dcytb has been identified as the mammalian transplasma ferric reductase that catalyzes the reduction of ferric to ferrous iron in the process of iron absorption [10].
• In this model, His48, an invariant residue in the cytochrome b reductase family, forms an interaction with the propionic acid group of the D-ring of the heme cofactor [6].
• Iron transport was measured in human bronchial epithelial (HBE) cells using inductively coupled plasma atomic emission spectroscopy and was demonstrated to be partially inhibited in the presence of Dcytb-blocking antibody, suggesting that Dcytb reduces Fe(3+) for cellular iron transport [9].

Other interactions of CYBRD1

• In Africans with iron overload not related to the HFE gene, the possible involvement of the SLC40A1 and CYBRD1 genes was demonstrated for the first time [1].
• Duodenal cytochrome b (Dcytb) is a haem protein similar to the cytochrome b561 protein family [13].
• CONCLUSIONS: These findings demonstrate that the duodenal ferroreductase Dcytb and ferroxidase Hp mRNA expression are not significantly altered by variations in iron homeostasis [7].

References