( S )-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 ( S )-3-aminopiperidine-2,6-dione ( 2 ), the pharmacophore of thalidomide ( 1 ) and its analog drugs, are highly desired. To develop a biocatalyst for producing ( S )- 2 , we dissected the domain functions of IdgS, which is responsible for the biosynthesis of indigoidine ( 3 ), a microbial blue pigment that consists of two 2 -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 ( S )- 2 , which is then dehydrogenated by the oxidation (Ox) domain and finally dimerized to yield 3 . Based on this, we developed an IdgS-derived enzyme biocatalyst, IdgS-Ox* R539A, for preparing enantiomerically pure ( S )- 2 . As a proof of concept, one-pot chemoenzymatic synthesis of 1 was achieved by combining the biocatalytic and chemical approaches.