环肽WS9326A生物合成中硫酯酶两个底物类似物的合成

doi:10.5246/jcps.2019.09.058

中国药学(英文版) ›› 2019, Vol. 28 ›› Issue (9): 605-614.DOI: 10.5246/jcps.2019.09.058

环肽WS9326A生物合成中硫酯酶两个底物类似物的合成

张中义, 王翰轩, 王贵阳, 马学洋, 刘谈, 耿彤彤, 孙晓旭, 杨东辉, 董甦伟, 马明^*

北京大学药学院天然药物及仿生药物国家重点实验室, 北京 100191

收稿日期:2019-05-21 修回日期:2019-06-15 出版日期:2019-09-30 发布日期:2019-07-18
通讯作者: Tel.: +86-10-82805794, E-mail: mma@bjmu.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 21877002, 81673332, 81573326 and 81741148).

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).

摘要/Abstract

摘要：

WS9326A是一个从链霉菌中发现的速激肽受体拮抗剂和细菌群体感应抑制剂。WS9326A的结构为一个戊烯肉桂酰取代的环肽。其生物合成由非核糖体肽合成酶(NRPS)完成。其NRPS最后一个模块中的硫酯酶(TE)功能域被推测催化了WS9326A生物合成中的最后一步反应-位置选择性的环化反应。目前还未见对此TE的催化功能的研究报道。本文报道了运用固相多肽合成(SPPS)法合成了WS9326A生物合成中TE(WS9326A-TE)的两个底物类似物1和2。化合物1和2均为新化合物, 它们的结构经NMR和HRESIMS分析得到了确证。化合物2中N末端的肉桂酰片段和C末端甲基化的丝氨酸残基的合成均在SPPS温和的条件下完成。由于WS9326A-TE的底物或底物类似物很难从产WS9326A的野生链霉菌中分离得到, 本研究对1和2的合成为将来开展WS9326A-TE的体外催化表征打下了基础。

关键词: WS9326A, 底物类似物, 固相多肽合成法, 硫酯酶

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

中图分类号:

R914.4

Supporting:

张中义, 王翰轩, 王贵阳, 马学洋, 刘谈, 耿彤彤, 孙晓旭, 杨东辉, 董甦伟, 马明. 环肽WS9326A生物合成中硫酯酶两个底物类似物的合成[J]. 中国药学(英文版), 2019, 28(9): 605-614.

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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环肽WS9326A生物合成中硫酯酶两个底物类似物的合成

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

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