While bioactive compounds are commonly derived both by human design as well as from living organisms, man-made and natural products typically display very different structural characteristics. As such, a longstanding goal in the discovery of new molecular function is to develop approaches to incorporate the advantageous elements of both groups of molecules, thereby expanding the molecular space accessible for this purpose. In this work, we report the engineering a fluorine-selective enzyme that can complement mutated acyltransferase (AT) domains of a modular polyketide synthase, which are the main determinants of the identity and location of substituents on polyketides, to produce different fluorinated regioisomers of the erythromycin precursor in vitro. We further show that by engineering cell uptake of fluorinated building blocks, we can control fluorine selectivity in vivo to produce selectively fluorinated polyketides using engineered E. coli. These results demonstrate that it is possible to introduce fluorine, a key synthetic design element for drug development, selectively into the scaffold of a complex natural product and produce these analogs by microbial fermentation.

中文翻译：

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工程位点选择性地将氟掺入天然产物类似物中

虽然生物活性化合物通常来自人类设计以及生物体，但人造和天然产品通常表现出非常不同的结构特征。因此，发现新分子功能的长期目标是开发方法来合并两组分子的有利元素，从而扩大可用于此目的的分子空间。在这项工作中，我们报告了一种氟选择性酶的工程，该酶可以补充模块化聚酮化合物合酶的突变酰基转移酶 (AT) 结构域，这是聚酮化合物上取代基的身份和位置的主要决定因素，以产生不同的氟化区域异构体。体外红霉素前体. 我们进一步表明，通过工程化细胞对氟化构建块的吸收，我们可以控制体内氟的选择性，从而使用工程大肠杆菌生产选择性氟化聚酮化合物。这些结果表明，可以将氟（药物开发的关键合成设计元素）选择性地引入复杂天然产物的支架中，并通过微生物发酵生产这些类似物。