September 8, 2003
Findings
May Lead to Design of New Drugs
EVANSTON, Ill. — Scientists at Northwestern University have
acquired new insight into how a specialized sensor protein that
acts as an early warning system detects dangerous amounts of the “coinage
metals” — silver, gold and copper — inside cells.
For the first time, researchers can explain this important mechanism
at the atomic level.
The findings, published Sept. 5 in the journal Science and recently
published online by the Journal of the American Chemical Society,
should improve our knowledge of diseases related to copper metabolism
and influence the design of anticancer and antimicrobial drugs.
The research may lead to better methods for removing toxic metals
from the environment.
By studying
the inorganic chemistry of the bacterium E. coli, a research
team led by Thomas V. O’Halloran, professor of
chemistry at Northwestern, established the molecular and structural
basis for the cell’s early detection of miniscule amounts
of copper. The work was done in collaboration with Alfonso Mondragon,
professor of biochemistry, molecular biology and cell biology at
Northwestern, and James E. Penner-Hahn, professor of chemistry
at the University of Michigan.
Having determined
the structures of copper-, silver- and gold-bound forms of the
metalloregulatory protein CueR, the researchers were
able to show the protein’s extraordinary sensitivity to copper
as well as how the cell distinguishes copper from other metals,
such as gold and silver.
“Metals are absolutely essential to the healthy functioning
of all cells in the human body,” said O’Halloran. “But
metals are high-maintenance nutrients. They are finicky and can
be particularly destructive if not managed by the cell in the right
way. Cells must protect themselves against excess amounts.”
O’Halloran likened the cell to a city in which metal ions
are similar to important and reactive fuels that must be imported
and then carefully delivered from one part of the city to another.
Reactive metals such as copper have the potential to catalyze runaway
reactions that could harm the cell, much as a series of explosions
could damage critical systems in a city. Understanding how a cell
properly deals with copper and other potentially toxic metals will
aid biomedical researchers in understanding what happens when things
go awry in cancer and neurodegenerative disorders, such as Wilson’s,
Menkes and Lou Gehrig’s diseases and possibly Alzheimer’s
disease.
“Metals are at the center of many emerging problems in
health, medicine and the environment,” said O’Halloran.
In addition
to O’Halloran and Mondragon, other authors
on the Science paper are Anita Changela (lead author), Kui Chen,
Yi Xue, Jackie Holschen and Caryn Outten, from Northwestern University.
O’Halloran
and Penner-Hahn are joined by Kui Chen (lead author), from Northwestern
University, and Saodat Yuldasheva, from
the University of Michigan, on the paper in the Journal of the
American Chemical Society.
The research
was supported by NIH’s National Institute
of General Medical Sciences and the Robert H. Lurie Comprehensive
Cancer Center of Northwestern University. |