Diterpenoids form a diverse group of natural products, many of which are or could become pharmaceuticals or industrial chemicals. The modular character of diterpene biosynthesis and the promiscuity of the enzymes involved make combinatorial biosynthesis a promising approach to generate libraries of diverse diterpenoids. Here, we report on the combinatorial assembly in yeast of ten diterpene synthases producing (+)-copalyl diphosphate-derived backbones and four cytochrome P450 oxygenases (CYPs) in diverse combinations. This resulted in the production of over 200 diterpenoids. Based on literature and chemical database searches, 162 of these compounds can be considered new-to-Nature. The CYPs accepted most substrates they were given but remained regioselective with few exceptions. Our results provide the basis for the systematic exploration of the diterpenoid chemical space in yeast using sequence databases.

中文翻译：

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酵母中的组合生物合成可产生 200 多种二萜类化合物

二萜类化合物形成了多种天然产物，其中许多是或可能成为药物或工业化学品。二萜生物合成的模块化特征和所涉及酶的混杂性使得组合生物合成成为生成不同二萜类化合物库的有前途的方法。在这里，我们报告了酵母中十种二萜合酶的组合组装，这些二萜合酶产生（+）-柯巴基二磷酸衍生的主链和四种细胞色素P450加氧酶（CYP）以不同的组合。这导致产生了超过 200 种二萜类化合物。根据文献和化学数据库检索，其中 162 种化合物可以被认为是新的自然化合物。CYP 接受大部分给它们的底物，但除少数例外外仍保持区域选择性。我们的结果为使用序列数据库系统探索酵母中的二萜化学空间提供了基础。