Abstract
Andrastins (andrastin A-D), produced by several Penicillium species, exhibit inhibitory activity against ras farnesyltransferase, suggesting that these compounds could be promising leads for antitumor agents. Although the genome sequence of Penicillium chrysogenum, an andrastin-producing species, is available, the genetic and molecular bases for the biosynthesis of andrastins have not been elucidated. Here we report the identification and characterization of the gene cluster for andrastin biosynthesis. We reconstituted the biosynthetic pathway in Aspergillus oryzae, a fungal expression host, by the co-expression of five genes, including that of a terpene cyclase, and of four genes encoding the tailoring enzymes, required for the generation of andrastins. Remarkably, we successfully obtained andrastin A, the most complex andrastin molecule, as the metabolite of nine gene products, thus confirming the potential of the fungal expression system to synthesize useful natural products.
| Original language | English |
|---|---|
| Pages (from-to) | 8199-8204 |
| Journal | Tetrahedron |
| Volume | 69 |
| Issue number | 38 |
| Online published | 16 Jul 2013 |
| DOIs | |
| Publication status | Published - 23 Sept 2013 |
| Externally published | Yes |
Funding
We thank Prof. K. Gomi (Graduate School of Agricultural Sciences, Tohoku University) and Prof. K. Kitamoto (Graduate School of Agricultural Sciences, The University of Tokyo) for kindly providing expression vectors in fungi and a fungal strain. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan , and by the CREST program from Japan Science and Technology Agency, Japan .
Research Keywords
- Andrastins
- Biosynthetic enzymes
- Fungal expression system
- Fungal meroterpenoids