Could new discovery about a shape-shifting protein lead to a mighty 'morpheein' bacteri... ( A small molecule that locks an ess...)

Could new discovery about a shape-shifting protein lead to a mighty 'morpheein' bacteria fighter?

Date:6/20/2008

A small molecule that locks an essential enzyme in an inactive form could one day form the basis of a new class of unbeatable, species-specific antibiotics, according to researchers at Fox Chase Cancer Center.

Their findings, highlighted on the cover of the June 23 issue of the journal Chemistry & Biology, take advantage of an emerging body of science regarding "morpheeins" proteins made from individual components that are capable of spontaneously reconfiguring themselves into different shapes within living cells.

The researchers discovered a small molecule, which they have named morphlock-1, binds the inactive form of a protein known as porphobilinogen synthase (PBGS), an enzyme used by nearly all forms of cellular life. The functioning form of PBGS is built from eight identical component parts in what is called an octamer configuration and is essential among nearly all forms of life in the processes that enable cells to use energy. The other configuration is made of six parts or a hexamer configuration and serves as a "standby" mode for the protein.

"As the name suggests, morphlock-1 essentially locks the hexamer configuration into place, preventing its protein subunits from reconfiguring into the active assembly," says lead investigator Eileen Jaffe, Ph.D, a Senior Member of Fox Chase. "Targeting morpheeins in their inactive assemblies provides an entirely new approach to drug discovery."

While their study was performed using a pea plant-version of PBGS, the researchers have reason to believe the principle could apply to bacterial versions of PBGS as well. "Using morphlock-1 as a base, we are seeking to fine tune the molecule so that it blocks just the bacterial version of the PBGS enzyme, " Jaffe says.

"Because PBGS is so crucial for life, the part of the enzyme where chemistry happens is highly conserved through evolution," Jaffe says, meaning that an all-around PBGS-inhibiting dr
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Contact: Greg Lester
gregory.lester@fccc.edu
215-728-2753
Fox Chase Cancer Center
Source:Eurekalert

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