Porphobilinogen Synthase: A Novel Specific Inhibitor of Tetrapyrrole Biosynthesis in Plants

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Introduction:

Porphobilinogen synthase (PBGS) is a key enzyme in the biosynthesis of tetrapyrrole pigments including the heme component of hemoglobin, vitamin B12, and chlorophyll. PBGS has recently been proposed to be a metabolic control point for tetrapyrrole biosynthesis in all photosynthetic species and a variety of bacterial species, including some notorious human pathogens.

Up to this point, PBGS was known to exist in an active, octameric form consisting of eight copies of the enzyme in a cloverleaf structure. Dr. Eileen Jaffe and colleagues of Fox Chase Cancer Center have identified the structure of a new form of PBGS that appears to be present in significant amounts only in plants and certain bacterial species. This new form of PBGS is an inactive hexamer that exists in these organisms together with the active octamer. Jaffe and colleagues are working to identify and synthesize drugs and chemicals that inhibit or kill selected organisms by locking PBGS in the inactive hexameric form.

Applications:

• Human and animal pathogens - Pseudomonas aeruginosa, Vibrio cholerae, Bordetella pertussis, Neisseria meningiditis, Nisseria gonorrhea, Chlamydia spp. and others
• Oil pipeline corrosion by bacteria
• Fish spoilage by bacteria
• Plant pathogens such as crown gall on fruit trees, black spot on tomatoes and southern wilt (note that variations in the PBGS of plants and plant pathogens may allow development of agents specific to the pathogen but benign to the plant).
• Herbicides - pre-emergent herbicides safe to animals and insects
• Potential bioterrorism agents such as Burkholderia mallei

Safety and Specificity:

Hexameric PBGS will be a safe target for humans, animals, insects and fungi because PBGS is not a control point for tetrapyrrole biosynthesis in these organisms.

Opportunity:

Fox Chase is seeking collaborations with companies that have established positions in target industries - pharmaceuticals, agricultural chemicals and industrial chemicals.

Publications:

• Lawrence S.H., Ramirez U.D., et al. "Shape-shifting leads to small molecule allosteric drug discovery," (2008) Chem Biol;(6): 586-96
• Breinig, S. et al. "Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase," (2003) Nat. Struct. Biol. 10:757-763
• Jaffe, E.K., "An unusual phylogenetic variation in the metal ion binding sites of porphobilinogen synthase," (2003) Chem & Biol. 10:25-34

Patent Status:

U.S. Patent pending

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