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Copper, zinc, iron, and molybdenum are essential metals that must be acquired from the diet. Their roles vary from electron transfer and oxygen transport to the determination and maintenance of protein structure. There are hundreds of metalloproteins that function in many aspects of cellular metabolism. Thus it is not surprising that abnormalities of metal homeostasis can present with a broad range of clinical symptoms. Disorders of metal metabolism can be divided into three main categories, characterized by either an excess or deficiency, or a defect in intracellular metal metabolism. Disorders characterized by excess metal include hereditary hemochromatosis and Wilson disease, which result from toxic accumulation of iron and copper, respectively. Menkes disease and acrodermatitis enteropathica are examples of disorders that result from metal deficiency (ie, copper and zinc, respectively). The third group of disorders is represented by molybdenum cofactor deficiency, which is caused by defective intracellular synthesis of a molybdenum-containing pterin. The varying pathophysiology of these disorders is also reflected in the variable response to therapy, which ranges from complete cure in acrodermatitis enteropathica to the virtual absence of effective treatment options in molybdenum cofactor deficiency.


Copper is an active redox metal (ie, capable of donating and accepting electrons), which is required for the activity of many critical enzymes functioning in a wide variety of metabolic pathways (Table 41-1). Consequently, copper deficiency has numerous effects on metabolism. Copper excess also has significant clinical consequences that are believed to result from generation of reactive oxygen species (ROS) by copper ions. The Recommended Daily Allowance (RDA) for copper ranges from 200 μg/day in infants to 900 μg/day in adults. To avoid toxicity, copper intake should not exceed 10 mg/day.1

TABLE 41-1Copper-Dependent Enzymes and Their Function

Copper is absorbed in the small intestine via CTR1, a plasma membrane copper transporter localized to the luminal enterocyte membrane.2 CTR1 is also responsible for copper uptake from the circulation in non-intestinal cells. Within the cytosol of cells copper is bound by various copper chaperones, proteins that deliver copper to specific intracellular destinations and compartments (Figure 41-1). Three metallochaperones have been identified in humans.3 The copper chaperone (CCS) delivers copper to the enzyme Cu-Zn superoxide dismutase (SOD1), which breaks down superoxide in the cytosol and mitochondrial intermembrane space. Cytochrome c oxidase copper chaperone 17 (COX17) delivers copper to mitochondria for the incorporation into cytochrome C oxidase. Antioxidant copper chaperone 1 (ATOX1) delivers copper to intracellular copper transporters ATP7A ...

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