Structural basis of the stereoselective formation of the spirooxindole ring in the biosynthesis of citrinadins

Zhiwen Liu, Fanglong Zhao, Boyang Zhao, Jie Yang, Joseph Ferrara, Banumathi Sankaran, B. V. Venkataram Prasad, Biki Bapi Kundu, George N. Phillips, Yang Gao, Liya Hu, Tong Zhu () and Xue Gao ()
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Zhiwen Liu: Rice University
Fanglong Zhao: Rice University
Boyang Zhao: Baylor College of Medicine
Jie Yang: Rice University
Joseph Ferrara: Rigaku Americas Corporation
Banumathi Sankaran: Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory
B. V. Venkataram Prasad: Baylor College of Medicine
Biki Bapi Kundu: PhD Program in Systems, Synthetic, and Physical Biology, Rice University
George N. Phillips: Rice University
Yang Gao: Rice University
Liya Hu: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine
Tong Zhu: Shanghai Engineering Research Center of Molecular Therapeutics & New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University
Xue Gao: Rice University

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Prenylated indole alkaloids featuring spirooxindole rings possess a 3R or 3S carbon stereocenter, which determines the bioactivities of these compounds. Despite the stereoselective advantages of spirooxindole biosynthesis compared with those of organic synthesis, the biocatalytic mechanism for controlling the 3R or 3S-spirooxindole formation has been elusive. Here, we report an oxygenase/semipinacolase CtdE that specifies the 3S-spirooxindole construction in the biosynthesis of 21R-citrinadin A. High-resolution X-ray crystal structures of CtdE with the substrate and cofactor, together with site-directed mutagenesis and computational studies, illustrate the catalytic mechanisms for the possible β-face epoxidation followed by a regioselective collapse of the epoxide intermediate, which triggers semipinacol rearrangement to form the 3S-spirooxindole. Comparing CtdE with PhqK, which catalyzes the formation of the 3R-spirooxindole, we reveal an evolutionary branch of CtdE in specific 3S spirocyclization. Our study provides deeper insights into the stereoselective catalytic machinery, which is important for the biocatalysis design to synthesize spirooxindole pharmaceuticals.

Date: 2021
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DOI: 10.1038/s41467-021-24421-0

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