A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Insights into Complex Oxidation during BE-7585A Biosynthesis: Structural Determination and Analysis of the Polyketide Monooxygenase BexE
Tekijät: Jackson DR, Yu X, Wang GJ, Patel AB, Calveras J, Barajas JF, Sasaki E, Metsa-Ketela M, Liu HW, Rohr J, Tsai SC
Kustantaja: AMER CHEMICAL SOC
Julkaisuvuosi: 2016
Journal: ACS Chemical Biology
Tietokannassa oleva lehden nimi: ACS CHEMICAL BIOLOGY
Lehden akronyymi: ACS CHEM BIOL
Vuosikerta: 11
Numero: 4
Aloitussivu: 1137
Lopetussivu: 1147
Sivujen määrä: 11
ISSN: 1554-8929
eISSN: 1554-8937
DOI: https://doi.org/10.1021/acschembio.5b00913
Tiivistelmä
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. C-13 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.
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. C-13 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.
Turun yliopiston Tutkimustietojärjestelmän portaali