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Gumming Up the Works
by Paul Muhlrad
Rati Verma (left) and Raymond Deshaies found a new way to think about how a cell destroys proteins.
FOR A CELL, DESTROYING PROTEINS IS AS ESSENTIAL AS building them, says Rati Verma, a researcher in the Caltech laboratory of HHMI investigator Raymond J. Deshaies.
The job of mincing proteins is performed by enzymatic machines called proteasomes. "Proteasomes affect almost all biological processes in the cell," Verma says. By their deliberate destruction of regulatory proteins, they orchestrate activities from cell division to cell death.
Ubiquitin is the protein that hands down the death sentences. "Ubiquitin is the most highly conserved protein in eukaryotes [organisms whose cells contain a distinct nucleus]," Verma says, "with only three amino acid differences between yeast and mammals." A chain of ubiquitins gets attached to doomed proteins, marking them for destruction and ushering them to the gates of proteasomes.
Last year, the Caltech researchers and colleagues discovered a class of small molecules that can block proteasomes from degrading proteins. The finding could open new avenues for treating diseases.
Few researchers considered proteasomes likely candidates as drug targets. Because proteasomes control so many processes, most researchers thought that perturbing them with drugs could only wreck havoc with the body, Deshaies says. "Even I initially felt that by inhibiting the proteasome you would just kill everything."
Then, 2 years ago a proteasome inhibitor called bortezomib received quick approval for treating multiple myeloma. "Everyone in the proteasome field started paying attention once the drug was fast-tracked by the FDA," Verma says.
Randall W. King, Deshaies' colleague at Harvard University, initiated the hunt for inhibitors by screening close to 110,000 different small molecules for their ability to prevent proteasomes from destroying proteins. Three of the compounds showed promise as proteasome inhibitors.
Photo: Joe Toreno