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

Abstract

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.

Keywords: Angucycline; Biosynthesis; FAD-dependent monooxygenase; Oxygenase; Ring opening oxygenase.

Fig. 1

The biosynthetic pathways of atypical angucyclines.

Fig. 2

Reactions catalyzed by FAD-dependent monooxygenases and SDR family reductases in vitro.

Fig. 3

Reactions catalyzed by ring opening oxygenases in vitro.

Fig. 4

Phylogenetic analysis of ring opening oxygenases involved in known atypical angucycline biosynthetic gene clusters. The tree was generated by MEGA7 using the Le_Gascuel_2008 method and the maximum likelihood algorithm. Bar, 1.0 substitutions per amino acid position. Red, product with jadomycin-type skeleton; orange, products with gilvocarcin-type skeleton; blue, products with kinamycin-type skeleton; green, products with fluostatin-type skeleton. HrbK doesn't catalyze the ring opening reaction as indicated by the chemical structure of hatomarubigins, and shows weak sequence similarities with the ring opening oxygenases, thus it is used as an outgroup. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)