TY - JOUR
T1 - Insights into Complex Oxidation during BE-7585A Biosynthesis
T2 - Structural Determination and Analysis of the Polyketide Monooxygenase BexE
AU - Jackson, David R.
AU - Yu, Xia
AU - Wang, Guojung
AU - Patel, Avinash B.
AU - Calveras, Jordi
AU - Barajas, Jesus F.
AU - Sasaki, Eita
AU - Metsä-Ketelä, Mikko
AU - Liu, Hung Wen
AU - Rohr, Jürgen
AU - Tsai, Shiou Chuan
N1 - Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/4/15
Y1 - 2016/4/15
N2 - 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.
AB - 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.
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U2 - 10.1021/acschembio.5b00913
DO - 10.1021/acschembio.5b00913
M3 - Article
C2 - 26813028
AN - SCOPUS:84966312230
SN - 1554-8929
VL - 11
SP - 1137
EP - 1147
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 4
ER -