Families of soft-metal-ion-transporting ATPases

Abstract

Within the last 5 years, much progress has been made in understanding the mechanism of action and evolution of soft-metal ATPases. The evolutionary pressure to flourish despite the geological omnipresence of metals has ensured that gene families for soft-metal resistances are not confined to a single species or even a single kingdom. Many questions remain to be answered, and we look forward to an accelerated acquisition of knowledge in the near future. One question is the function of ArsA homologues. Clearly in bacteria the arsA gene encodes the catalytic subunit of the ArsAB pump. It is not known whether the eukaryotic and archeal arsA homologues are orthologues or encode proteins with unrelated functions. Eukaryotes have resistance mechanisms for arsenicals. In both Leishmania and Chinese hamster cells we have shown that resistance is related to active extrusion of arsenite (44). But at this time the genes or gene products that produce the resistance have not been identified. A second question is the distribution of chaperones for soft metals in bacteria. While homologues of copper chaperones such as Atx1p and Lys7p are widely distributed in eukaryotes (12), they do not appear to exist in bacteria. CopZ serves a chaperone function in E. hirae (10), but homologues with copper chaperone activity have not been found in other bacteria. Additionally, it is not clear whether cells require chaperones for non-redox-active metals such as Zn(II), Cd(II), and Pb(II). A third question is the distribution of ZntA homologues in nature. The related Cu(I)- translocating P-type ATPases are found in most organisms. In humans these pumps are required for copper homeostasis, and mutations in either the ATP7A or ATP7B gene produce inborn errors of copper metabolism, resulting in Menkes or Wilson disease, respectively. Even though zinc is not as toxic as copper, in part because it is not a redox-active metal, it is still toxic in excess, and mechanisms to prevent overaccumulation must be present. To date a growing number of zntA and cadA genes for zinc-translocating P-type ATPases have been identified. Genes for putative ATP-dependent zinc pumps are being discovered in other kingdoms, for example in the genome of the archeaon Methanobacterium thermoautotrophicum (GenBank accession no. 2621474) and in the genome of the plant A. thaliana (GenBank accession no. 4210504). Within the next 5 years the sequencing of the human genome - and many others - will be completed. At that point the phylogenic distribution of zinc pumps and their involvement in human health and disease will be better understood.