title: Insights into Complex Oxidation during BE-7585A Biosynthesis: Structural Determination and Analysis of the Polyketide Monooxygenase BexE.
abstract: 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. (13)C 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.
authors.affiliation: Department of Molecular Biology and Biochemistry, Department of Chemistry, and Department of Pharmaceutical Sciences, University of California , Irvine, California 92697, United States.
authors.forename: David R
authors.initials: DR
authors.lastname: Jackson
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky , Lexington, Kentucky 40536, United States.
authors.forename: Xia
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky , Lexington, Kentucky 40536, United States.
authors.forename: Guojung
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Molecular Biology and Biochemistry, Department of Chemistry, and Department of Pharmaceutical Sciences, University of California , Irvine, California 92697, United States.
authors.forename: Avinash B
authors.initials: AB
authors.lastname: Patel
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy and Department of Chemistry, University of Texas at Austin , Austin, Texas 78712, United States.
authors.forename: Jordi
authors.initials: J
authors.lastname: Calveras
authors.affiliation: Department of Molecular Biology and Biochemistry, Department of Chemistry, and Department of Pharmaceutical Sciences, University of California , Irvine, California 92697, United States.
authors.forename: Jesus F
authors.initials: JF
authors.lastname: Barajas
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy and Department of Chemistry, University of Texas at Austin , Austin, Texas 78712, United States.
authors.forename: Eita
authors.initials: E
authors.lastname: Sasaki
authors.affiliation: Department of Biochemistry, University of Turku , 20014 Turku, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Metsä-Ketelä
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy and Department of Chemistry, University of Texas at Austin , Austin, Texas 78712, United States.
authors.forename: Hung-Wen
authors.initials: HW
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky , Lexington, Kentucky 40536, United States.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Rohr
authors.affiliation: Department of Molecular Biology and Biochemistry, Department of Chemistry, and Department of Pharmaceutical Sciences, University of California , Irvine, California 92697, United States.
authors.forename: Shiou-Chuan
authors.initials: SC
authors.lastname: Tsai
mesh_terms: D008968:Molecular Conformation; D010084:Oxidation-Reduction; D048630:Polyketide Synthases / Q000378:metabolism*; D054330:Thiosugars / Q000378:metabolism*
chemical_list: C551748:BE-7585A; D054330:Thiosugars; D048630:Polyketide Synthases
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