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
E. Kunzel et al., 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, J AM CHEM S, 121(48), 1999, pp. 11058-11062
A targeted search for glycosyltransferase (GT) encoding genes in the gene c
luster of the urdamycin A producer Streptomyces fradiae Tu2717 resulted in
the discovery of urdGT2, a GT encoding gene located approximately 7 kb down
stream of the minimal polyketide synthase (PKS) encoding genes. Subsequent
inactivation of this gene created a mutant strain, which produces completel
y different metabolites than the wild-type strain, consisting of the three
new urdamycins I, J, and K. Their structures provide new insight into the i
mportant C-glycosyl-transfer step of the urdamycin biosynthetic pathway. Th
e structures indicate that the corresponding gene product UrdGT2. catalyzes
the C-glycosyl transfer of activated D-olivose to an angucyclinone precurs
or, which already bears the angular 12b-OH group. The structures of the new
urdamycins could not have arisen without the involvement of substrate flex
ible post-PKS modifying genes, i.e., glycosyltransferases and oxidoreductas
es. 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 fruitfu
l in work toward antitumor drugs. Urdamycin J shows a good anticancer activ
ity in in vitro tests.