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:
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.
Vashchenko, G. and R.T. MacGillivray. (2013). Multi-copper oxidases and human iron metabolism. Nutrients 5: 2289-2313.
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.
Examples:
TC#	Name	Organismal Type	Example
8.A.105.1.1	Ferrooxidase, Hephaestin, HEPH, of 1158 aas with one C-terminal TMS and possible another TMS near the N-terminus. It oxidizes ferrous ion (II) to ferric ion (III), and is involved in iron and possibly copper transport and homeostasis. It promotes iron efflux in associated with ferroportin 1 (TC# 2.A.100.1.4) (Vashchenko and MacGillivray 2013). The distribution of HEPH in various tissues has been studied (Ahn et al. 2018).		Hephaestin of Homo sapiens

8.A.105.1.2	Ferrooxidase, Ceruoplasmin, of 1065 aas. Ceruloplasmin is a blue, copper-binding (6 atoms per molecule) glycoprotein. It oxidizes Fe²⁺ to Fe³⁺ without releasing radical oxygen species. It is involved in iron transport across the cell membrane. Ceruloplasmin overexpression is associated with oncogenic pathways and poorer survival rates in clear-cell renal cell carcinoma (Zhang et al. 2021).		Ceruloplasmin of Homo sapiens

8.A.105.1.3	Zyklopen, or hephaestin-like protein 1 precursor, of 1159 aas. It functions as a ferroxidase and is involved in copper transport and homeostasis (Vashchenko and MacGillivray 2013).		Zyklopen of Homo sapiens