Gober Joshua G, Ghodge Swapnil V, Bogart Jonathan W, Wever Walter J, Watkins Richard R, Brustad Eric M, Bowers Albert A
Department of Chemistry, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27514, United States.
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27514, United States.
ACS Chem Biol. 2017 Jul 21;12(7):1726-1731. doi: 10.1021/acschembio.7b00358. Epub 2017 Jun 1.
Thiopeptides are a growing class of ribosomally synthesized and post-translationally modified peptide (RiPP) natural products. Many biosynthetic enzymes for RiPPs, especially thiopeptides, are promiscuous and can accept a wide range of peptide substrates with different amino acid sequences; thus, these enzymes have been used as tools to generate new natural product derivatives. Here, we explore an alternative route to molecular complexity by engineering thiopeptide tailoring enzymes to do new or non-native chemistry. We explore cytochrome P450 enzymes as biocatalysts for cyclopropanation of dehydroalanines, chemical motifs found widely in thiopeptides and other RiPP-based natural products. We find that P450 and P450 selectively cyclopropanate dehydroalanines in a number of complex thiopeptide-based substrates and convert them into 1-amino-2-cyclopropane carboxylic acids (ACCAs), which are important pharmacophores. This chemistry takes advantage of the innate affinity of these biosynthetic enzymes for their substrates and enables incorporation of new pharmacophores into thiopeptide architectures. This work also presents a strategy for diversification of natural products through rationally repurposing biosynthetic enzymes as non-natural biocatalysts.
硫肽是一类不断增加的核糖体合成及翻译后修饰肽（RiPP）天然产物。许多RiPPs的生物合成酶，尤其是硫肽的生物合成酶，具有底物宽泛性，能够接受多种具有不同氨基酸序列的肽底物；因此，这些酶已被用作生成新的天然产物衍生物的工具。在此，我们探索了一条通过改造硫肽修饰酶以进行新的或非天然化学反应来增加分子复杂性的替代途径。我们研究了细胞色素P450酶作为生物催化剂用于脱氢丙氨酸环丙烷化反应的情况，脱氢丙氨酸是在硫肽和其他基于RiPP的天然产物中广泛存在的化学基序。我们发现P450酶能够选择性地使多种基于硫肽的复杂底物中的脱氢丙氨酸发生环丙烷化反应，并将其转化为1-氨基-2-环丙烷羧酸（ACCA），这是一类重要的药效基团。这种化学反应利用了这些生物合成酶对其底物的固有亲和力，并能够将新的药效基团引入硫肽结构中。这项工作还提出了一种通过合理地将生物合成酶重新用作非天然生物催化剂来实现天然产物多样化的策略。
