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Abstract
A biosynthetic gene cluster for the bioactive fungal sesterterpenoids variecolin (1) and variecolactone (2) was identified in Aspergillus aculeatus ATCC 16872. Heterologous production of 1 and 2 was achieved in Aspergillus oryzae by expressing the sesterterpene synthase VrcA and the cytochrome P450 VrcB. Intriguingly, the replacement of VrcB with homologous P450s from other fungal terpenoid pathways yielded three new variecolin analogues (5–7). Analysis of the compounds’ anticancer activity in vitro and in vivo revealed that although 5 and 1 had comparable activities, 5 was associated with significantly reduced toxic side effects in cancer-bearing mice, indicating its potentially broader therapeutic window. Our study describes the first tests of variecolin and its analogues in animals and demonstrates the utility of synthetic biology for creating molecules with improved biological activities. © 2024 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Original language | English |
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Pages (from-to) | 421-432 |
Journal | Acta Pharmaceutica Sinica B |
Volume | 14 |
Issue number | 1 |
Online published | 30 Aug 2023 |
DOIs | |
Publication status | Published - Jan 2024 |
Research Keywords
- Animal studies
- Anticancer properties
- Biosynthesis
- Natural products
- Sesterterpenoids
Publisher's Copyright Statement
- This full text is made available under CC-BY-NC-ND 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/
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Dive into the research topics of 'Genomics-driven derivatization of the bioactive fungal sesterterpenoid variecolin: Creation of an unnatural analogue with improved anticancer properties'. Together they form a unique fingerprint.Projects
- 1 Finished
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ECS: Comprehensive Understanding and Engineering of Fungal Xanthone Biosynthesis
MATSUDA, Y. (Principal Investigator / Project Coordinator)
1/01/20 → 13/12/23
Project: Research