Department of Biochemical and Chemical Engineering, Laboratory of Technical Biology, TU Dortmund University, Emil-Figge-Str. 66, 44227, Dortmund, Germany.
Department of Chemistry and Chemical Biology, NMR Laboratory, TU Dortmund University, Otto-Hahn-Str. 4a, 44227, Dortmund, Germany.
Chembiochem. 2023 Mar 1;24(5):e202200635. doi: 10.1002/cbic.202200635. Epub 2022 Dec 29.
Benzoxazoles are important structural motifs in pharmaceutical drugs. Here, we present the heterologous production of 3-hydroxyanthranilate-derived benzoxazoles in the host bacterium Myxococcus xanthus following the expression of two genes from the nataxazole biosynthetic gene cluster of Streptomyces sp. Tü 6176. The M. xanthus expression strain achieved a benzoxazole titer of 114.6±7.4 mg L upon precursor supplementation, which is superior to other bacterial production systems. Crosstalk between the heterologously expressed benzoxazole pathway and the endogenous myxochelin pathway led to the combinatorial biosynthesis of benzoxazoles featuring a 2,3-dihydroxybenzoic acid (2,3-DHBA) building block. Subsequent in vitro studies confirmed that this crosstalk is not only due to the availability of 2,3-DHBA in M. xanthus, rather, it is promoted by the adenylating enzyme MxcE from the myxochelin pathway, which contributes to the activation of aryl carboxylic acids and delivers them to benzoxazole biosynthesis.
苯并恶唑是药物中重要的结构基序。在这里，我们通过表达来自链霉菌 Tü 6176 的 nataxazole 生物合成基因簇的两个基因，在宿主菌粘球菌中展示了 3-羟基邻氨基苯甲酸衍生的苯并恶唑的异源生产。在添加前体的情况下，M. xanthus 表达菌株的苯并恶唑产量达到 114.6±7.4mg/L，优于其他细菌生产系统。异源表达的苯并恶唑途径与内源性粘霉素途径之间的串扰导致了具有 2,3-二羟基苯甲酸（2,3-DHBA）构建块的苯并恶唑的组合生物合成。随后的体外研究证实，这种串扰不仅归因于 M. xanthus 中 2,3-DHBA 的可用性，而且还受到粘霉素途径中的腺苷酸化酶 MxcE 的促进，该酶有助于芳基羧酸的激活，并将其递送至苯并恶唑生物合成。
