Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou 510632, China.
Clinical Experimental Center, First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
Org Biomol Chem. 2023 Sep 13;21(35):7141-7150. doi: 10.1039/d3ob01110k.
Bisabosqual-type meroterpenoids are fungi-derived polyketide-terpenoid hybrids bearing a 2,3,3a,3a,9,9a-hexahydro-1-benzofuro[4,3,2-]chromene skeleton (6/6/6/5 ring system) or its -C-ring structure, and exhibit diverse bioactivities. Their unique structural architecture and impressive biological activities have led to considerable interest in discovering new analogues. However, to date, only nine analogues have been identified. Herein, we reported the isolation and identification of six new bisabosqual-type meroterpenoids stachybisbins C-H (1-6), together with one known compound bisabosqual C (7), from PYH05-7. Intriguingly, we found that 7, which contains the intact tetracyclic skeleton, can be non-enzymatically converted into its derivative stachybisbin I (8), unveiling the biosynthetic relationship between bisabosquals and -bisabosquals. Moreover, based on CRISPR/Cas9-mediated gene disruption, we revealed that the three-gene cluster responsible for the formation of LL-Z1272β is associated with the biosynthesis of bisabosqual-type meroterpenoids, and then proposed a plausible route to 1-8.
双孢莎草烷型倍半萜类化合物是真菌来源的聚酮萜类杂合体，具有 2,3,3a,3a,9,9a-六氢-1-苯并呋喃[4,3,2-]色烯骨架（6/6/6/5 环系统）或其-C 环结构，并表现出多种生物活性。它们独特的结构架构和令人印象深刻的生物活性引起了人们对发现新类似物的极大兴趣。然而，迄今为止，仅鉴定出了 9 种类似物。在此，我们从 PYH05-7 中分离并鉴定了 6 种新的双孢莎草烷型倍半萜类化合物 stachybisbins C-H（1-6），以及一种已知的化合物 bisabosqual C（7）。有趣的是，我们发现 7 含有完整的四环骨架，可以非酶转化为其衍生物 stachybisbin I（8），揭示了 bisabosquals 和-bisabosquals 之间的生物合成关系。此外，基于 CRISPR/Cas9 介导的基因敲除，我们揭示了负责形成 LL-Z1272β 的三个基因簇与双孢莎草烷型倍半萜类化合物的生物合成有关，然后提出了 1-8 的可能途径。
