نبذة مختصرة : Abstract 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.
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