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

• Published in: Chemical science (Cambridge) Vol. 13; no. 45; pp. 13475 - 13481
• Main Authors: Pan, Jian, Tan, Qingwen, Zhu, Saibin, Yan, Xiaohui, Li, Yu, Zhuang, Zhoukang, Zhu, Xiangcheng, Duan, Yanwen, Huang, Yong
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 23.11.2022; Royal Society of Chemistry; The Royal Society of Chemistry
• Subjects: Ammonia; Biosynthesis; Chemistry; Chemistry, Multidisciplinary; Cinnamic acid; Deactivation; Enediynes; Physical Sciences; Polyols; Science & Technology; ANTITUMOR ANTIBIOTIC C-1027; DYNEMICIN ENEDIYNE; CLONING; POLYKETIDE SYNTHASE; 4-METHYLIDENEIMIDAZOLE-5-ONE-CONTAINING TYROSINE AMINOMUTASE; CHEMISTRY; POLYENE; PROGRAMMED OCTAKETIDE
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d2sc04379c

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 wls PDH 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. Production of three new pentaene polyols 5-7 by an activated enediyne gene cluster and their biosynthetic study suggest the presence of a polyene epoxide intermediate during the early steps of 9-membered enediyne core formation.