In vitro reconstitution of TDP-2-deoxynogalamine
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Nogalamycin is an anthracycline compound produced by Streptomyces nogalater. Anthracyclines have been shown to be highly effective against cancer tissues, and anthracyclines such as daunorubicin are at the center of many chemotherapy treatments. However, anthracyclines are also highly toxic, particularly to the heart, making it necessary for the continuing study of this group of compounds. Similar to other anthracyclines, nogalamycin also shows antitumor activity. However, also similar to many other anthracyclines, its cardiotoxicity precludes its use as a clinical drug. In the past, semisynthesis has been successful in producing anthracycline analogs that have greater efficacy and lower cardiotoxicity. However, the success rate has been very low, with only a handful of potential candidates out of thousands of new compounds ever making it to clinical trials. Therefore, a more efficient way of generating new anthracyclines is needed to find better chemotherapy drugs. Towards this end, we have expressed and purified several proteins in the nogalamycin biosynthesis gene cluster in order to better understand how nature produces these products and harness that knowledge for future bioengineering efforts. Specifically, we have focused on the enzymes involved in modification and synthesis of nogalamine, the amino sugar essential for nogalamycin activity, and assayed the activities of SnogF, SnogG, SnogA, and SnogX.