()-3-aminopiperidine-2,6-dione is a biosynthetic intermediate of microbial blue pigment indigoidine.

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.