A TRANSFERASE IN DISORAZOLE SYNTHASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Microtubules have been an attractive target for anticancer drugs since the identification and use of taxols for the treatment of lung, ovarian, and breast cancers. Taxol binds to and stabilizes microtubules, resulting in an arrest in cell division and eventual cell death. Compounds identified more recently with a similar action to taxol are the epothilones and discodermolides, both of which are in clinical trials. The disorazole A1, one of 29 related macrocyclic polyketides from a strain of Sorangium cellulosum, has been shown to inhibit the polymerization of tubulin, inducing apoptosis at picomolar concentrations. In contrast to the vincristine group of drugs, disorazoles are effective against multidrug-resistant cell lines. The structural study is aimed at understanding the mechanism of the catalysis of a transferase in disorazole synthase.