TCDB is operated by the Saier Lab Bioinformatics Group

8.A.105.  The Multi-Copper-containing Ferroxidase (MCFO) Family

Multi-copper oxidases (MCOs) are a small group of enzymes that oxidize their substrates with the concomitant reduction of dioxygen to two water molecules. Generally, multi-copper oxidases are promiscuous with regards to their reduced substrates and are capable of performing various functions in different species (Vashchenko and MacGillivray 2013). Three multi-copper oxidases have been characterized in humans -- ceruloplasmin, hephaestin and zyklopen. Each of these enzymes has a high specificity towards iron with the resulting ferroxidase activity being associated with ferroportin, the only known iron exporter in humans. Ferroportin exports iron as Fe2+, but transferrin, the major iron transporter protein of blood, can bind only Fe3+ effectively. Iron oxidation in enterocytes is mediated mainly by hephaestin, thus allowing dietary iron to enter the bloodstream. Zyklopen is involved in iron efflux from placental trophoblasts during iron transfer from mother to fetus. Release of iron from the liver relies on ferroportin and the ferroxidase activity of ceruloplasmin which is found in blood in a soluble form. Ceruloplasmin, hephaestin and zyklopen show distinctive expression patterns and have unique mechanisms for regulating their expression. These features of human multi-copper ferroxidases can serve as a basis for the precise control of iron efflux in different tissues. Vashchenko and MacGillivray 2013 reviewed the biochemical and biological properties of the three human MCOs and discuss their potential roles in human iron homeostasis.

References associated with 8.A.105 family:

Ahn, C., J.S. Choi, and E.B. Jeung. (2018). Organ‑specific expression of the divalent ion channel proteins NCKX3, TRPV2, CTR1, ATP7A, IREG1 and HEPH in various canine organs. Mol Med Rep 18: 1773-1781. 29901089
Vashchenko, G. and R.T. MacGillivray. (2013). Multi-copper oxidases and human iron metabolism. Nutrients 5: 2289-2313. 23807651
Zhang, Y., Z. Chen, J.G. Chen, X.F. Chen, D.H. Gu, Z.M. Liu, Y.D. Gao, and B. Zheng. (2021). Ceruloplasmin overexpression is associated with oncogenic pathways and poorer survival rates in clear-cell renal cell carcinoma. FEBS Open Bio 11: 2988-3004. 34449964