Pseudomonas aeruginosa porphobilinogen synthase assembly state regulators: hit discovery and initial SAR studies.

Authors:
Allen B Reitz
Allen B Reitz
Fox Chase Chemical Diversity Center
Doylestown | United States
Ursula D Ramirez
Ursula D Ramirez
Northwestern University Medical School
United States
Linda Stith
Linda Stith
Institute for Cancer Research
United States
Yanming Du
Yanming Du
Institute for Hepatitis and Virus Research
United States
Garry R Smith
Garry R Smith
The Scripps Research Institute
United States
Eileen K Jaffe
Eileen K Jaffe
Institute for Cancer Research
United States

ARKIVOC 2010 Jun;2010:175-188

Fox Chase Chemical Diversity Center, Inc., Pennsylvania Center for Drug Discovery, Pennsylvania Biotechnology Center, Doylestown, PA 18902 USA.

Porphobilinogen synthase (PBGS) catalyzes the first common step in the biosynthesis of the essential heme, chlorophyll and vitamin B(12) heme pigments. PBGS activity is regulated by assembly state, with certain oligomers exhibiting biological activity and others either partially or completely inactive, affording an innovative means of allosteric drug action. Pseudomonas aeruginosa PBGS is functionally active as an octamer, and inactive as a dimer. We have identified a series of compounds that stabilize the inactive P. aeruginosa dimer by a computational prescreen followed by native PAGE gel mobility shift analysis. From those results, we have prepared related thiadiazoles and evaluated their ability to regulate P. aeruginosa PBGS assembly state.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3106444PMC

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June 2010
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