Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States.
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States.
ACS Chem Biol. 2023 Jul 21;18(7):1624-1631. doi: 10.1021/acschembio.3c00241. Epub 2023 Jun 20.
Bacteria produce natural products (NPs) via biosynthetic gene clusters. Unfortunately, many biosynthetic gene clusters are silent under traditional laboratory conditions. To access novel NPs, a better understanding of their regulation is needed. γ-Butyrolactones, including the A-factor and butanolides, SCBs, are a major class of ' hormones. Study of these hormones has been limited due to challenges in accessing them in stereochemically pure forms. Herein, we describe an efficient route to ()-paraconyl alcohol, a key intermediate for these molecules, as well as a biocatalytic method to access the exocyclic hydroxyl group that differentiates A-factor-type from SCB-type hormones. Utilizing these methods, a library of hormones have been synthesized and tested in a green fluorescent protein reporter assay for their ability to relieve repression by the repressor ScbR. This allowed the most quantitative structure-activity relationship of γ-butyrolactones and a cognate repressor to date. Bioinformatics analysis strongly suggests that many other repressors of NP biosynthesis likely bind similar molecules. This efficient, diversifiable synthesis will enable further investigation of the regulation of NP biosynthesis.
细菌通过生物合成基因簇产生天然产物（NPs）。不幸的是，许多生物合成基因簇在传统的实验室条件下是沉默的。为了获得新的 NPs，需要更好地了解它们的调控。γ-丁内酯，包括 A 因子和丁内酯、SCB 是一类主要的“激素”。由于难以获得它们的立体纯形式，这些激素的研究受到限制。在此，我们描述了一种高效的方法来制备（）-对甲酰基醇，这是这些分子的关键中间体，以及一种生物催化方法来获得区分 A 因子型和 SCB 型激素的外环羟基。利用这些方法，我们合成了一系列激素，并在绿色荧光蛋白报告基因测定中测试了它们缓解抑制剂 ScbR 抑制的能力。这使得迄今为止对 γ-丁内酯和同源抑制剂进行了最定量的构效关系研究。生物信息学分析强烈表明，许多其他 NP 生物合成抑制剂可能结合类似的分子。这种高效、多样化的合成将能够进一步研究 NP 生物合成的调控。
