Impact of copper limitation on expression and function of multicopper oxidases (ferroxidases)

Copper is an essential trace element whose recommended intake is met by most North American diets. However, incidence of new cases of secondary copper deficiency is rising due to complications of gastric bypass surgery and high zinc exposure. Patients frequently are ataxic and anemic. Anemia of copper deficiency was first described in the 19th century, but the underlying biochemistry remains unknown. Approximately one dozen cuproenzymes have been characterized in mammals. Four of these are referred to as multicopper oxidases (MCO) due to their copper binding geometries. They have iron oxidase activity (ferroxidase). These include the hepatic secreted protein ceruloplasmin representing ∼90% of plasma copper, a splice-variant of ceruloplasmin originally characterized in brain linked by glycosylphosphatidylinositol (GPI) to membranes, an intestinal enriched MCO named hephaestin, and newly described MCO in placenta called zyklopen. Limitation in available copper appears to limit function of the MCO group exhibited as impaired iron flux due to the copper requirement of MCO for their ferroxidase activity. Dietary copper deficiency is associated with lower levels of ceruloplasmin, GPI-ceruloplasmin, and hephaestin. Limitation of copper does not appear to limit synthesis of MCO but rather their stability and turnover. However, there appears to be a disconnect between limitation in MCO function and anemia, because humans and mice missing ceruloplasmin are not anemic despite hepatic iron overload and hypoferremia. Furthermore, anemic copper-deficient mammals are not improved by iron replacement. This suggests that the anemia of copper deficiency is not caused by iron limitation but rather impairment in iron utilization.