Journal
TETRAHEDRON
Volume 69, Issue 38, Pages 8199-8204Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tet.2013.07.029
Keywords
Andrastins; Fungal meroterpenoids; Biosynthetic enzymes; Fungal expression system
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Funding
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- CREST program from Japan Science and Technology Agency, Japan
- Grants-in-Aid for Scientific Research [23241068, 22108004] Funding Source: KAKEN
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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. (C) 2013 Published by Elsevier Ltd.
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