Inactivation of the urdGT2 gene, which encodes a glycosyltransferase responsible for the C-glycosyltransfer of activated D-olivose, leads to formation of the novel urdamycins I, J, and K

A targeted search for glycosyltransferase (GT) encoding genes in the gene cluster of the urdamycin A producer Streptomyces fradiae Tu2717 resulted in the discovery of urdGT2, a GT encoding gene located approximately 7 kb downstream of the minimal polyketide synthase (PKS) encoding genes. Subsequent inactivation of this gene created a mutant strain, which produces completely different metabolites than the wild-type strain, consisting of the three new urdamycins I, J, and K. Their structures provide new insight into the important C-glycosyl-transfer step of the urdamycin biosynthetic pathway. The structures indicate that the corresponding gene product UrdGT2 catalyzes the C-glycosyl transfer of activated D-olivose to an angucyclinone precursor, which already bears the angular 12b-OH group. The structures of the new urdamycins could not have arisen without the involvement of substrate flexible post-PKS modifying genes, i.e., glycosyltransferases and oxidoreductases. This work proves that targeted gene disruption experiments can lead to novel biologically active 'unnatural' natural products, which arise through a formerly nonactivated shunt pathway. This approach is especially fruitful in work toward antitumor drugs. Urdamycin J shows a good anticancer activity in in vitro tests.