How cells handle copper: A view from microbes

Copper is an essential element, yet toxic to cells. It can damage biomolecu les by radical formation and, therefore, the intracellular copper needs to be carefully controlled. In the Gram-positive bacterium Enterococcus hirae, copper homeostasis is effected by the cop operon. It allows growth under c opper limiting conditions, but also offers resistance to 8 mM copper. The c op operon consists of the four genes copY, copZ, copA, and copB. CopA and c opB encode copper ATPases. CopA serves in copper uptake under copper limita tion, whereas CopB expels copper when copper is excessive. CopA and CopB ar e closely related to the human Menkes and Wilson ATPases. Mutation in these human copper ATPases lead to inherited defects of copper metabolism known as Menkes and Wilson disease, respectively. Copper ATPases and other heavy metal ATPases form a new, evolutionarily distinct subgroup of the P-type AT Pases, called CPx-type ATPases. The cop operon of E. hirae is regulated by the copper responsive repressor CopY. Copper donated to CopY by the copper chaperone CopZ releases it from the promoter. CopZ belongs to a family of c onserved metal chaperones that transfer copper to copper-transporting ATPas es in humans and yeast (HAH1, Atx1), and mercury to a mercury uptake system in bacteria (MerP). CopZ-like motifs are also found in the N-termini of th e CPx-type ATPases and mercuric reductases. A model of copper homeostasis a nd the role of copper chaperones in mammalian cells based on findings in ye ast and E. hirae is presented. J. Trace Elem. Exp. Med. 12:347-360, 1999. ( C) 1999 Wiley-Liss, Inc.