SUBSTRATE RECOGNITION IN MULTIDRUG RESISTANCE

点击翻译按钮获取中文摘要

In Escherichia coli the clinical resistance plasmid R773 carries the arsenical resistance (ars) operon, which produces resistance to arsenate, arsenite, antimonite and tellurite. The operon encodes a system for the transduction of biological energy into the detoxification of toxic oxyanions arsenite (As+3), and antimonite (Sb+3) by ATP-driven extrusion of the anions. Since the operon also gives resistance to the unrelated oxyanions arsenate (As+5) and tellurite (Te+4), the Ars system is a true multidrug resistance. The mechanism by which this operon can produce resistance to multiple unrelated compounds forms the basis for this proposal. Resistance to arsenate and tellurite requires the arsC gene in addition to the genes for the oxyanion pump. The ArsC protein is the first identified member of a new class of reductases. This novel enzyme catalyzes reduction of oxyanions, extending the range of resistance to arsenate and tellurite by transforming those oxyanions into pump substrates. The enzyme uses glutathione as the source of reductant and is postulated to the directly coupled to the oxyanion pump. Thus this system is the bacterial analog of the glutathione S-transferase conjugation system in higher organisms and provides and excellent model system for resistance mechanisms in humans and animals. The overall goal of this project is first, elucidation of the enzymatic mechanism of the ArsC protein, and second, the role of this protein in resistance.