Insights into Complex Oxidation during BE-7585A Biosynthesis: Structural Determination and Analysis of the Polyketide Monooxygenase BexE

David R. Jackson, Xia Yu, Guojung Wang, Avinash B. Patel, Jordi Calveras, Jesus F. Barajas, Eita Sasaki, Mikko Metsä-Ketelä, Hung Wen Liu, Jürgen Rohr, Shiou Chuan Tsai

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)1137-1147
Number of pages11
JournalACS chemical biology
Volume11
Issue number4
DOIs
Publication statusPublished - 2016 Apr 15
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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