Molecular Basis of Diseases of Copper Homeostasis

Abstract

Copper is essential for life because it is a cofactor for a number of important enzymes, including cytochrome-c oxidase, lysyl oxidase, superoxide dismutase, and dopamine β-monooxygenase. The redox reactions carried out by these enzymes are facilitated by the ability of copper to shuttle between the two oxidation states Cu(I) and Cu(II). Deficiencies of copper can lead to profound effects, because of the reduced activity of these copper-dependent enzymes. The effects of copper deficiency are most marked during development, and severe deficiency in this period can prove to be fatal. The serious effects of copper deficiency in infancy are seen in the X-linked genetic disorder of copper transport, Menkes disease (MD) and the molecular basis of this disease will be discussed later in this chapter. The same redox properties that make copper a useful element render it dangerous in a free ionic state. Free copper, particularly Cu(I), can catalyze the formation of the highly reactive hydroxyl radicals that damage many cell components, including membranes, proteins, and nucleic acids (1). The toxic effects of copper are demonstrated in another human genetic disorder, Wilson’s disease (WD). This disease is characterized by excessive accumulation of copper in the liver, brain, and other organs and is fatal if untreated. All organisms have developed mechanisms to supply copper to essential enzymes without damaging cellular constituents and, in recent years, many of the molecules involved in copper homeostasis have been identified. Some interesting new mechanisms used by cells for handling this metal have been discovered. Two important steps forward in understanding the molecular basis of copper homeostasis were the isolation of the genes involved in human genetic disorders of copper—Menkes and Wilson’s diseases. The coding sequences of these genes identified two important components of the copper homeostasis system, the copper ATPases, ATP7A and ATP7B. Genetic studies of micro-organisms, particularly yeast, have proven invaluable for the identification of some of the other molecules involved in cellular copper homeostasis, including copper-uptake molecules and intracellular copper carriers known as copper chaperones. The human orthologs of these genes have been isolated, demonstrating the generality of the copper-transport mechanisms.