Zhang Zhilong, Li Pengwei, Wang Min, Zhang Yan, Wu Bian, Tao Yong, Pan Guohui, Chen Yihua
State Key Laboratory of Microbial Resources, Institute of Microbiology Chinese Academy of Sciences Beijing China.
University of Chinese Academy of Sciences Beijing China.
mLife. 2022 Jun 21;1(2):146-155. doi: 10.1002/mlf2.12023. eCollection 2022 Jun.
The biosynthetic investigations of microbial natural products continuously provide powerful biocatalysts for the preparation of valuable chemicals. Practical methods for preparing ()-3-aminopiperidine-2,6-dione (), the pharmacophore of thalidomide () and its analog drugs, are highly desired. To develop a biocatalyst for producing ()-, we dissected the domain functions of IdgS, which is responsible for the biosynthesis of indigoidine (), a microbial blue pigment that consists of two -like moieties. Our data supported that the L-glutamine tethered to the indigoidine assembly line is first offloaded and cyclized by the thioesterase domain to form ()-, which is then dehydrogenated by the oxidation (Ox) domain and finally dimerized to yield . Based on this, we developed an IdgS-derived enzyme biocatalyst, IdgS-Ox* R539A, for preparing enantiomerically pure ()-. As a proof of concept, one-pot chemoenzymatic synthesis of was achieved by combining the biocatalytic and chemical approaches.
微生物天然产物的生物合成研究持续为制备有价值的化学品提供强大的生物催化剂。人们迫切需要制备沙利度胺及其类似药物的药效基团（）-3-氨基哌啶-2,6-二酮的实用方法。为开发一种生产（）-的生物催化剂，我们剖析了IdgS的结构域功能，IdgS负责吲哚蓝（一种由两个类似部分组成的微生物蓝色色素）的生物合成。我们的数据表明，连接到吲哚蓝装配线上的L-谷氨酰胺首先由硫酯酶结构域卸载并环化形成（）-，然后由氧化（Ox）结构域脱氢，最后二聚化生成。基于此，我们开发了一种源自IdgS的酶生物催化剂IdgS-Ox* R539A，用于制备对映体纯的（）-。作为概念验证，通过结合生物催化和化学方法实现了的一锅法化学酶合成。
