Reinhard Wimmer Charles T Dameron and Marc Solioz

1. INTRODUCTION

In the past, copper transport in bacteria has been considered only in terms of resistance mechanisms to permit survival of the cells in adverse copper-rich environments. Indeed, most of the systems characterized early on are plasmid encoded, as is typical for defense mechanisms of prokaryotes. Recently, similar copper "resistance" systems were also identified in chromosomal locations, giving rise to the concept that bacteria may need systems for copper homeostasis not only in extreme environments but also under normal growth conditions.

The system for copper homeostasis in Enterococcus hirae is currently the best understood example of heavy-metal homeostasis. Because E. hirae can easily be genetically manipulated, it represents an ideal system for the study of fundamental aspects of the regulation of cytoplasmic copper. It appears that the major components of this system are encoded by the cop operon. It is located on the chromosome and consists of four closely spaced genes in the order cop Y, copZ, cop A, and copB. CopY and copZ encode regulatory proteins, whereas cop A and copB encode P-type ATPases of 727 and 745 amino acids, respectively (1). Figure 1 summarizes the function of these four gene products and they will be discussed in detail in Section 2. All four cop gene products can be purified in milligram quantities for direct structural and functional investigations. This allows the study of fundamental aspects of copper homeostasis in vitro.

2. THE COPPER ATPASES: A NEW CLASS OF P-TYPE ATPASES

Copper ATPases are a key element of most, if not all, copper homeostatic mechanisms and have only recently been discovered and are a milestone in the field of trace element research. Following the discovery of the copper-transporting ATPases CopA and CopB in E. hirae (2), highly homologous ATPases were reported from humans as underlying the copper metabolic defects of Menkes (3,4) and Wilson's disease (5), respectively. Later, copper ATPases were described from yeast and other organisms and over two dozen putative copper ATPases have been described today (6,7). In fact, highly homologous copper ATPase genes have been found in every genome that has been completely sequenced, suggesting that these enzymes are ubiquitous. Homologous ATPases specific for other transition metals such as cadmium and zinc have also been discovered (8,9).

From: Handbook of Copper Pharmacology and Toxicology Edited by: E. J. Massaro © Humana Press Inc., Totowa, NJ

Fig. 1. Schematic drawing of the cop operon and model of copper homeostasis in E. hirae. Copper(I) is taken up by CopA under copper-limiting conditions. Inside the cell, CopZ complexes copper(I) to safely deliver it to the CopY repressor, which regulates expression of the cop operon. If intracellular copper is excessive, CopZ delivers copper to CopB for secretion.

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