A bacterial anion-translocating ATPase has been identified as the product of the arsenical resistance (ars) operon of resistance plasmid R773. When expressed in Escherichia coli the ATP-driven pump catalyzes extrusion of the oxyanions arsenite, antimonite, and arsenate, thus providing resistance to the toxic compounds.

Although both arsenite and arsenate contain arsenic, they are chemically distinct compounds with quite different properties. This ars operon encodes an anion-translocating ATPase. The genes have cloned and sequenced, and the protein components purified. Two of the structural genes, the arsA and arsB genes, encode the two subunits of the pump. This two-component inner membrane complex binds and transports arsenite and antimonite, oxyanions with the +III oxidation state of arsenic or antimony. This complex neither transports nor provides resistance to arsenate, the oxyanion of the +V oxidation state of arsenic. The third structural gene encodes a 16 kDa polypeptide, the ArsC protein, which alters the substrate specificity of the pump to allow for recognition and transport of the alternate substrate arsenate.

The failure of drug treatment in cancer chemotherapy is related to the appearance of multidrug resistance tumors. The mdr gene is the genetic locus related to multidrug resistance. The gene encodes the P- glycoprotein, an ATP-coupled resistance pump which catalyzes extrusion of cytotoxic drugs from the cells, a process analogous to that catalyzes P- glycoprotein recognizes and transports chemically distinct drugs is unknown. The overall goal of this project is elucidation of the molecular mechanism of recognition of multiple substrates by an ATP-coupled resistance pump.

R01CA054141

1991-05-01

1995-04-30