Department of Biochemistry and Molecular Biology, University of Minnesota Medical School, Duluth, MN 55812, USA.
Adv Nutr. 2011 Mar;2(2):89-95. doi: 10.3945/an.110.000208. Epub 2011 Mar 10.
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.
铜是一种必需的微量元素，大多数北美的饮食都能满足其推荐摄入量。然而，由于胃旁路手术和高锌暴露的并发症，新的继发性铜缺乏症病例的发病率正在上升。患者经常出现共济失调和贫血。铜缺乏性贫血最早于 19 世纪描述，但潜在的生物化学机制仍不清楚。哺乳动物中已经有大约 12 种铜酶被描述。其中 4 种由于其铜结合几何形状而被称为多铜氧化酶（MCO）。它们具有铁氧化酶活性（亚铁氧化酶）。这些包括肝脏分泌的蛋白铜蓝蛋白，代表约 90%的血浆铜，最初在大脑中特征为剪接变体的铜蓝蛋白通过糖基磷脂酰肌醇（GPI）与膜相连，一种肠道丰富的 MCO 称为 hephaestin，以及最近在胎盘描述的 MCO 称为 zyklopen。可用铜的限制似乎限制了 MCO 组的功能，表现为由于 MCO 对其亚铁氧化酶活性的铜需求而导致铁通量受损。饮食铜缺乏与铜蓝蛋白、GPI-铜蓝蛋白和 hephaestin 的水平降低有关。铜的限制似乎不会限制 MCO 的合成，而是限制其稳定性和周转率。然而，MCO 功能的限制与贫血之间似乎存在脱节，因为缺乏铜蓝蛋白的人类和小鼠没有贫血，尽管肝脏铁过载和低血症。此外，贫血的铜缺乏症动物不能通过铁替代得到改善。这表明铜缺乏性贫血不是由铁限制引起的，而是由铁利用受损引起的。
