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

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.

Chemo-enzymatic synthesis of bioactive compounds from traditional Chinese medicine and medicinal plants

“…[9] Examples of bioactive compounds produced by chemo-enzymatic synthesis are shown in Table 1. [2,[8][9][10][11][12][13][14][15][16][17][18] Thalidomide is first marketed in Germany in the 1950s as a sedative and analgesic, primarily for the relief of nausea and vomiting during pregnancy. It is typically racemic, consisting of a pair of enantiomers: (R)-thalidomide exhibits potent sedative effects, while (S)-thalidomide is associated with immunomodulation.…”

“…LG-23/17β-HSDcl [9] Podophyllotoxin Anti-cancer activity DPS [2,8,10] Digoxin Treating heart failure CYP14A [11] Spiroindimicins Potent antiparasitic activity LaStaO/LzrO-VioB [12] Thalidomide Immunoregulation IdgS-Ox* R539A [13] Gedunin HSP90 inhibition MERO1 L437A [14] C-glycosides Potential SGLT2 inhibitors AbCGT [15] Cotylenol Cytotoxicity on human myeloid leukemia cells BscD/Bsc9 [16] Eponemycin Antitumor cytotoxic agent EpnF [17] C3STQ A unit of anti-Parkinson agent sumanirole ERED-IRED [18] in a specific chiral form. This discovery sheds light on the biosynthesis of (R)-benzylisoquinoline alkaloids for the first time.…”

“…This enzyme was then employed in the one-pot chemo-enzymatic synthesis of ( S )-thalidomide. [13] Limonoids are plant tetranoriterpenoids with remarkable medicinal values, while the structural complexity and complicated steps make them difficult to prepare by chemosynthesis. Studies have reported several synthetic routes of limonoids, such as limonin, azadiradione, and protolimonoid, in 35, 27, and 20 steps, respectively.…”