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Dr. Gatti has something good to say about E. coli. |
Escherichia coli, the common bacterium that has received its share of bad press over the last few years, is harboring a pumping system with the potential for some very good news.
This system, used by bacteria to pump toxic arsenic out of the cell, is analogous to the system tumor cells employ to survive cancer chemotherapy. "This simple protein system in bacteria will serve as a model for the more complex system in tumor cells, which is responsible for the extrusion of anti-tumor agents," said Domenico Gatti, PhD, assistant professor of biochemistry and molecular biology.
In collaboration with Barry Rosen, PhD, professor and chair of biochemistry and molecular biology, Dr. Gatti is attempting to learn how the pump works. Tongqing Zhou, PhD, one of the members of this research team, has crystallized the primary protein, ArsA, on the E. coli pump and is working on another pump protein, ArsB.
ArsB creates the channel through which the arsenic is transported out of the cell, while ArsA forces the arsenic into the channel. Using crystallization and X-ray diffraction techniques, Dr. Gatti hopes to determine the mechanism behind the pump.
"It turns out that this system of two proteins is conserved throughout evolution: it is present in bacteria, in yeast, in mice and in humans. Thus, in human cells, there is a system to extrude arsenic out of the cell," he explained. "Humans have significant resistance to arsenic, and it’s clearly advantageous, because it’s one of the few known inorganic carcinogens and is present in high concentrations in water in many places in Michigan." Arsenic can, however, become deadly if the intake of the carcinogen exceeds the pumping ability of the cellular system.
A structurally similar system works in tumor cells, he said. "Cells normally have very small amounts of the proteins that extrude anti-tumor agents. In tumor cells, these proteins become more abundant by virtue of a process of gene amplification." The cells become resistant to greater and greater amounts of anti-tumor drugs, and eventually the dosage cannot outrun the resistance without causing toxic side effects to the patient.
"Arsenic is one of the compounds used for the treatment of promyelocytic leukemia and resistance to arsenic has been found in some patients," said Dr. Gatti. He predicts that when these cases are studied in detail it will be found that amplification of the genes encoding the human arsenic pump is responsible for the emergence of the resistance.
"By studying a system that is easily obtainable, we can grow E. coli in the laboratory -- we can get information on the mechanisms those pumps utilize to extrude chemicals," he said. "If we understand the mechanism, we can possibly develop inhibitors for the pumps and reverse the resistance."