Hephaestin is involved in the metabolism and homeostasis of iron and possibly copper. It is a transmembrane copper-dependent ferroxidase responsible for transporting dietary iron from intestinal enterocytes into the circulatory system. The highest expression of hephaestin is found in small intestine. It is limited to enterocytes of the villi (where the iron absorption takes place), being almost absent in crypt cells. Hephaestin converts iron(II) state, Fe2+, to iron(III) state, Fe3+, and mediates iron efflux most likely in cooperation with the basolateral iron transporter, ferroportin 1. To a lesser extent hephaestin has been detected in colon, spleen, kidney, breast, placenta and bone trabecular cells but its role in these tissues remains to be established. Hephaestin presents homology with ceruloplasmin, a serum dehydrogenase protein involved in copper detoxification and storage.
Hephaestin is a protein of 1135 aminoacids formed from a precursor of 1158 aminoacids and is 130.4 kDa. It is predicted to bind 6 copper ions per monomer.
Hephaestin was first identified by Dr. Christopher D. Vulpe of the University of California, Berkeley in 1999. They named the newfound protein after Hephaestus, the Greek god of metal working.
Human hephaestin, lacking the putative transmembrane domain, was first recombinantly expressed in 2005 by Drs. Tanya Griffiths, Grant Mauk, and Ross MacGillivray at the University of British Columbia. They demonstrated that recombinant human hephaestin (rhHp) bound copper (determined by inductively coupled plasma mass spectrometry) and exhibited an absorption maximum at ~610 nm consistent with other blue multicopper oxidases such as ceruloplasmin. By using ferrous ammonium sulfate as a substrate, rhHp was shown to have ferroxidase activity with a Km of 2.1 μM for Fe(II).
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