The functional differentiation of the post-PKS tailoring oxygenases contributed to the chemical diversities of atypical angucyclines.

Angucyclines are one of the largest families of aromatic polyketides with various chemical structures and bioactivities. Decades of studies have made it easy for us to depict the picture of their early biosynthetic pathways. Two families of oxygenases, the FAD-dependent oxygenases and the ring opening oxygenases, contribute to the formation of some unique skeletons of atypical angucyclines. The FAD-dependent oxygenases involved in the biosynthetic gene clusters of typical angucyclines catalyze two hydroxylation reactions at C-12 and C-12b of prejadomycin, while their homolog JadH in jadomycin gene cluster catalyze the C-12 hydroxylation and 4a,12b-dehydration reactions of prejadomycin, which leads to the production of dehydrorabelomycin, a common intermediate during the biosynthesis of atypical angucyclines. Ring opening oxygenases of a unique family of oxygenases catalyze the oxidative C-C bond cleavage reaction of dehydrorabelomycin, followed by different rearrangement reactions, resulting in the formation of the various chemical skeletons of atypical angucyclines. These results suggested that the functional differentiation of these oxygenases could apparently enrich the sources of aromatic polyketides with greater structure diversities.