Cores of aromatic polyketides are essential for their biological activities. Most type II polyketide synthases (PKSs) biosynthesize these core structures involving the minimal PKS, a PKS-associated ketoreductase (KR) and aromatases/cyclases (ARO/CYCs). Oxygenases (OXYs) are rarely involved. BE-7585A is an anticancer polyketide with an angucyclic core. 13C isotope labeling experiments suggest that its angucyclic core may arise from an oxidative rearrangement of a linear anthracyclinone. Here, we present the crystal structure and functional analysis of BexE, the oxygenase proposed to catalyze this key oxidative rearrangement step that generates the angucyclinone framework. Biochemical assays using various linear anthracyclinone model compounds combined with docking simulations narrowed down the substrate of BexE to be an immediate precursor of aklaviketone, possibly 12-deoxy-aklaviketone. The structural analysis, docking simulations, and biochemical assays provide insights into the role of BexE in BE-7585A biosynthesis and lay the groundwork for engineering such framework-modifying enzymes in type II PKSs.
|Number of pages||11|
|Journal||ACS Chemical Biology|
|State||Published - Apr 15 2016|
Bibliographical noteFunding Information:
This work was supported by NIGMS R01GM076330 (S.-C.T.), National Institutes of Health GM105977 and CA091901 (J.R.), National Institutes of Health GM040541 and GM035906, and Welch Foundation F-1511 (H.-W.L).
© 2016 American Chemical Society.
ASJC Scopus subject areas
- Molecular Medicine