Natural products and their analogues are often challenging to synthesise due to their complex scaffolds and embedded functional groups. Solely relying on engineering the biosynthesis of natural products may lead to limited compound diversity. Integrating synthetic biology with synthetic chemistry allows rapid access to much more diverse portfolios of xenobiotic compounds which may accelerate the discovery of new therapeutics. As a proof-of-concept, by supplementing an Escherichia coli strain expressing the violacein biosynthesis pathway with 5-bromo-tryptophan in vitro or tryptophan 7-halogenase RebH in vivo, 6 halogenated analogues of violacein or deoxyviolacein were generated, demonstrating promiscuity of the violacein biosynthesis pathway. Furthermore, 20 new derivatives were generated from 5-brominated violacein analogues via Suzuki-Miyaura cross-coupling reaction directly using the crude extract without prior purification. Herein, we demonstrate a flexible and rapid approach to access diverse chemical space that can be applied to a wide range of natural product scaffolds.

中文翻译：

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紫罗兰素天然产物支架衍生化的基因化学策略

由于其复杂的支架和嵌入的官能团，天然产物及其类似物的合成通常具有挑战性。仅依靠工程设计天然产物的生物合成可能会导致化合物多样性有限。将合成生物学与合成化学相结合，可以快速获得更多样化的异生物质组合，这可能会加速新疗法的发现。作为概念验证，通过在体外用 5-溴-色氨酸或在体内用色氨酸 7-卤化酶 RebH补充表达紫罗兰素生物合成途径的大肠杆菌菌株, 产生了 6 种紫罗兰素或脱氧紫罗兰素的卤化类似物，证明了紫罗兰素生物合成途径的混杂性。此外，通过 Suzuki-Miyaura 交叉偶联反应直接使用未事先纯化的粗提取物，从 5-溴化紫罗兰素类似物生成了 20 种新衍生物。在此，我们展示了一种灵活且快速的方法来访问可应用于各种天然产物支架的各种化学空间。