Genomics-driven derivatization of the bioactive fungal sesterterpenoid variecolin : Creation of an unnatural analogue with improved anticancer properties
© 2024 The Authors..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Acta pharmaceutica Sinica. B - 14(2024), 1 vom: 23. Jan., Seite 421-432 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yan, Dexiu [VerfasserIn] |
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| Links: |
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| Themen: |
Animal studies |
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| Anmerkungen: |
Date Revised 25.01.2024 published: Print-Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.apsb.2023.08.025 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM367522594 |
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| 245 | 1 | 0 | |a Genomics-driven derivatization of the bioactive fungal sesterterpenoid variecolin |b Creation of an unnatural analogue with improved anticancer properties |
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| 520 | |a © 2024 The Authors. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Animal studies | |
| 650 | 4 | |a Anticancer properties | |
| 650 | 4 | |a Biosynthesis | |
| 650 | 4 | |a Natural products | |
| 650 | 4 | |a Sesterterpenoids | |
| 650 | 4 | |a Synthetic biology | |
| 650 | 4 | |a Terpene synthases | |
| 650 | 4 | |a Variecolin | |
| 700 | 1 | |a Arakelyan, Jemma |e verfasserin |4 aut | |
| 700 | 1 | |a Wan, Teng |e verfasserin |4 aut | |
| 700 | 1 | |a Raina, Ritvik |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Tsz Ki |e verfasserin |4 aut | |
| 700 | 1 | |a Ahn, Dohyun |e verfasserin |4 aut | |
| 700 | 1 | |a Kushnarev, Vladimir |e verfasserin |4 aut | |
| 700 | 1 | |a Cheung, Tsz Kiu |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Ho Ching |e verfasserin |4 aut | |
| 700 | 1 | |a Choi, Inseo |e verfasserin |4 aut | |
| 700 | 1 | |a Ho, Pui Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Feijun |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Yujeong |e verfasserin |4 aut | |
| 700 | 1 | |a Lau, Hill Lam |e verfasserin |4 aut | |
| 700 | 1 | |a Law, Ying Lo |e verfasserin |4 aut | |
| 700 | 1 | |a Leung, Chi Seng |e verfasserin |4 aut | |
| 700 | 1 | |a Tong, Chun Yin |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Kai Kap |e verfasserin |4 aut | |
| 700 | 1 | |a Yim, Wing Lam |e verfasserin |4 aut | |
| 700 | 1 | |a Karnaukhov, Nikolay S |e verfasserin |4 aut | |
| 700 | 1 | |a Kong, Richard Y C |e verfasserin |4 aut | |
| 700 | 1 | |a Babak, Maria V |e verfasserin |4 aut | |
| 700 | 1 | |a Matsuda, Yudai |e verfasserin |4 aut | |
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