Discovery of pentaene polyols by the activation of an enediyne gene cluster: biosynthetic implications for 9-membered enediyne core structures

Jian Pan; Qingwen Tan; Saibin Zhu; Xiaohui Yan; Yu Li; Zhoukang Zhuang; Xiangcheng Zhu; Yanwen Duan; Yong Huang

doi:10.1039/d2sc04379c

Discovery of pentaene polyols by the activation of an enediyne gene cluster: biosynthetic implications for 9-membered enediyne core structures

Chem Sci. 2022 Oct 31;13(45):13475-13481. doi: 10.1039/d2sc04379c. eCollection 2022 Nov 23.

Authors

Jian Pan¹, Qingwen Tan¹, Saibin Zhu¹, Xiaohui Yan², Yu Li¹, Zhoukang Zhuang¹, Xiangcheng Zhu^{1

3}, Yanwen Duan^{1

4

3}, Yong Huang^{1

4}

Affiliations

¹ Xiangya International Academy of Translational Medicine, Central South University Changsha Hunan 410013 China jonghuang@csu.edu.cn.
² State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China, State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine Tianjin China.
³ National Engineering Research Center of Combinatorial Biosynthesis for Drug Discovery Changsha Hunan 410205 China.
⁴ Hunan Engineering Research Center of Combinatorial Biosynthesis and Natural Product Drug Discovery Changsha Hunan 410205 China.

Abstract

The identification and characterization of enediyne polyketide synthases (PKSEs) revealed that PKSE-bound polyene is a common intermediate, while its subsequent tailoring steps to enediyne cores remain obscure. Herein, we report pentaene polyols 5-7 and cinnamic acid derivatives 8 and 9 biosynthesized from an activated enediyne biosynthetic gene cluster in Streptomyces sp. CB02130. The C-1027 pksE could partially complement production of these polyene polyols in a CB02130 mutant where the native pksE is inactivated. The yields of 5-7 were improved by increasing the cellular pool of l-Phe through either gene inactivation of a prephenate dehydrogenase WlsPDH or supplementation of l-Phe. A flexible ammonia lyase WlsC4 is responsible for biosynthesis of 8 and 9 from l-Phe. The co-localization of wlsPDH and PKSE gene cassette supports their close evolutionary relationships and an enediyne genome mining strategy using WlsPDH. These findings not only provide a facile approach to activate silent enediyne BGCs, but suggest that a polyene epoxide intermediate may be formed for construction of 9-membered enediyne macrocycles.