Synthesis of two substrate mimics of thioesterase in the biosynthesis of cyclic depsipeptide WS9326A

doi:10.5246/jcps.2019.09.058

Journal of Chinese Pharmaceutical Sciences ›› 2019, Vol. 28 ›› Issue (9): 605-614.DOI: 10.5246/jcps.2019.09.058

• Original articles • Previous Articles Next Articles

Synthesis of two substrate mimics of thioesterase in the biosynthesis of cyclic depsipeptide WS9326A

Zhongyi Zhang, Hanxuan Wang, Guiyang Wang, Xueyang Ma, Tan Liu, Tongtong Geng, Xiaoxu Sun, Donghui Yang, Suwei Dong, Ming Ma^*

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China

Received:2019-05-21 Revised:2019-06-15 Online:2019-09-30 Published:2019-07-18
Contact: Tel.: +86-10-82805794, E-mail: mma@bjmu.edu.cn
Supported by:
National Natural Science Foundation of China (Grant No. 21877002, 81673332, 81573326 and 81741148).

Abstract

Abstract:

WS9326A is a tachykinin receptor antagonist and quorum sensing inhibitor discovered from several Streptomyces strains. The structure of WS9326A features a (Z)-pentenylcinnamoyl moiety attached on a cyclic depsipeptide skeleton, which is biosynthesized by nonribosomal peptide synthetases (NRPS). The regioselective cyclization in the last step of NRPS catalysis, which is proposed to be catalyzed by a thioesterase (TE) domain in the last module, has not been experimentally characterized. We here reportthe synthesis of two substrate mimics (1 and 2) of the TE (WS9326A-TE) in WS9326A biosynthesis, by using Fmoc-based solid-phase peptide synthesis (SPPS) method. Compounds 1 and 2 are new compounds whose structures have been elucidated based on NMR and HRESIMS analyses. The N-terminal cinnamoyl moiety and C-terminal methylated l-Ser moiety in 2 were incorporated under the mild SPPS conditions. Given the isolation difficulties of substrate of WS9326A-TE from the Streptomyces producers of WS9326A, our synthesis of 1 and 2 set the stage for the reconstitution of WS9326A-TE’s catalytic reaction in vitro in the future.

Key words: Solid-phase peptide synthesis, Thioesterase, WS9326A

CLC Number:

R914.4

Supporting:

Zhongyi Zhang, Hanxuan Wang, Guiyang Wang, Xueyang Ma, Tan Liu, Tongtong Geng, Xiaoxu Sun, Donghui Yang, Suwei Dong, Ming Ma. Synthesis of two substrate mimics of thioesterase in the biosynthesis of cyclic depsipeptide WS9326A[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(9): 605-614.

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Synthesis of two substrate mimics of thioesterase in the biosynthesis of cyclic depsipeptide WS9326A

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