Prof. Barbara Gerratana, University of Maryland

Biosynthesis of Pyrrolobenzodiazepines, naturally produced antitumor compounds

Biochemistry Division Seminar Series (joint with Georgia State University)

Pyrrolo[1,4]benzodiazepines (PBDs), produced by actinomycetes, are sequence selective DNA alkylating agents with anti-tumor and antibiotic properties. Sibiromycin and tomaymycin are two naturally produced PBDs. Sibiromycin is the most potent naturally produced PBDs and only one of two available glycosylated PBDs. Tomaymycin was used as the template for SJG-136, a synthetic PBD dimer. Phase I clinical trials of SJG-136 have been successful for the treatment of metastatic or unresectable solid tumors. We have identified and sequenced the tomaymycin and sibiromycin gene clusters. We have confirmed the assignment of the gene clusters and identified their boundaries. Using gene inactivation and chemical complementation experiments we have elucidated the biosynthetic pathway for the anthranilate moiety of sibiromycin and tomaymycin. Initial in vitro characterization of the biosynthetic enzymes involved in the unusual tyrosine to pyrrole transformation will be presented.

For more information contact Prof. Wendy Kelly (404-385-1154).