Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The intracellular iron transfer process is not well understood, and the identity of the iron transporter responsible for iron delivery to the secretory compartments remains elusive. In this study, we show Drosophila ZIP13 (Slc39a13), a presumed zinc importer, fulfills the iron effluxing role. Interfering with dZIP13 expression causes iron-rescuable iron absorption defect, simultaneous iron increase in the cytosol and decrease in the secretory compartments, failure of ferritin iron loading, and abnormal collagen secretion. dZIP13 expression in E. coli confers upon the host iron-dependent growth and iron resistance. Importantly, time-coursed transport assays using an iron isotope indicated a potent iron exporting activity of dZIP13. The identification of dZIP13 as an iron transporter suggests that the spondylocheiro dysplastic form of Ehlers-Danlos syndrome, in which hZIP13 is defective, is likely due to a failure of iron delivery to the secretory compartments. Our results also broaden our knowledge of the scope of defects from iron dyshomeostasis.
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PMID:The metal transporter ZIP13 supplies iron into the secretory pathway in Drosophila melanogaster. 2512 12

Multicopper oxidases (MCOs) are a specific group of enzymes that contain multiple copper centers through which different substrates are oxidized. Main members of MCO family include ferroxidases, ascorbate oxidases, and laccases. MCO type of ferroxidases is key to iron transport across the plasma membrane. In Drosophila, there are four potential multicopper oxidases, MCO1-4. No convincing evidence has been presented so far to indicate any of these, or even any insect multicopper oxidase, to be a ferroxidase. Here we show Drosophila MCO3 (dMCO3) is highly likely a bona fide ferroxidase. In vitro activity assay with insect-cell-expressed dMCO3 demonstrated it has potent ferroxidase activity. Meanwhile, the ascorbate oxidase and laccase activities of dMCO3 are much less significant. dMCO3 expression in vivo, albeit at low levels, appears mostly extracellular, reminiscent of mammalian ceruloplasmin in the serum. A null dMCO3 mutant, generated by CRISPR/Cas9 technology, showed disrupted iron homeostasis, evidenced by increased iron level and reduced metal importer Mvl expression. Notably, dMCO3-null flies phenotypically are largely normal at normal or iron stressed-conditions. We speculate the likely existence of a similar iron efflux apparatus as the mammalian ferroportin/ferroxidase in Drosophila. However, its importance to fly iron homeostasis is greatly minimized, which is instead dominated by another iron efflux avenue mediated by the ZIP13-ferritin axis along the ER/Golgi secretion pathway.
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PMID:Drosophila multicopper oxidase 3 is a potential ferroxidase involved in iron homeostasis. 2968 24

Drosophila ZIP13 (dZIP13, CG7816/ZIP99C) belongs to the SLC39A family and is connected to iron homeostasis in the fruit fly. In this study, we show that dZIP13 level is strongly regulated by iron. In addition to a mild response to iron at the mRNA level, dZIP13 is strongly regulated at the protein level. This posttranslational regulation by iron also happens when dZIP13 is expressed in the yeast Saccharomyces cerevisiae. Iron functions to stabilize dZIP13. Domain-swapping experiments between dZIP7 (CG10449/ Catsup) and dZIP13 suggest that the N-terminus of dZIP13 is necessary to mediate this iron regulatory process. Phylogenetic sequence comparison and structural modeling reveal potential iron-binding residues, confirmed by in vitro iron binding assays. Mutations of these potential iron binding sites at the N-terminus, as well as a likely iron binding site at the C-terminus of dZIP13, completely abolish the iron-dependent upregulation in the yeast and the fruit fly. Iron-responsiveness of dZIP13 is consistent with its key role in iron homeostasis. We speculate that this process of dZIP13 regulation, and that of IRE/IRP-controlled ferritin production, work together to better cope with iron repletion in the fly.
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PMID:Drosophila ZIP13 is posttranslationally regulated by iron-mediated stabilization. 3122 49