The toxic metalloid arsenic is classified as a group I human carcinogen and affects the health of millions of people in the United States and world-wide through introduction into drinking water and the food chain (4, 15). Despite its toxicity, arsenic has a long history of usage as chemotherapeutic agents. Today, arsenic (and the related metalloid antimony) containing drugs are used for treating acute promyelocytic leukemia and diseases caused by protozoan parasites. To act as a drug or poison, metalloids need to enter cells, which make it imperative to recognize their uptake pathways. Similarly, for detoxification, cells employ systems that remove inorganic arsenic and products of its metabolism from the cytosol via efflux pathways or enzymatically modify arsenic to less toxic forms. For the last three decades the overall goal of my research program has been elucidation of the molecular mechanisms of transport and detoxification of the metalloid arsenic in prokaryotes and eukaryotes. We have focused on the uptake pathways that are the Initial steps in arsenic toxicity and on the efflux pathways that confer tolerance. Arsenic is taken up by cells adventitiously using transporters for required solutes such as phosphate or sugars. In contrast, arsenic effiux is usually very specific by transport proteins evolved for that function. A key contribution of our research was the identification of aquaglyceroporins as pertiaps the primary pathway for A8(lll) uptake In nearty every organism, from E. call to humans. We also showed that, surprisingly, trivalent metalloids are transported by hexose permeases in yeast and humans. The best-characterized detoxification system is the arsenical resistance {arsRDABC) operon encoded by the clinically Isolated resistance plasmid R773 that encodes an ATP-coupled ArsAB extrusion pump for As(lll) and Sb(lll). The operon has five genes, two of which, arsA and arsB, are topics of this proposal. ArsA is an ATPase that sen/es as the catalytic subunit of the pump, and ArsB is the membrane subunit of the pump. ArsD is a metallochaperone that delivers As(lll) to ArsA. and the interactions of these two proteins Is also examined In this proposal, A second - and more widely distributed - family of arsenic efflux/resistance transporters is the Acr3 family, which is found in bacteria, archaea and eukaryotes. Finally, arsenic is modified in the cytosol, and we are characterizing enzymes of arsenic transfonmation
Showing the most recent 10 out of 122 publications
