Activation of an unconventional meroterpenoid gene cluster in Neosartorya glabra leads to the production of new berkeleyacetals

• Published in: Acta pharmaceutica Sinica. B Vol. 8; no. 3; pp. 478 - 487
• Main Authors: Zhang, Tao, Wan, Jun, Zhan, Zhajun, Bai, Jian, Liu, Bingyu, Hu, Youcai
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-05-2018; Elsevier
• Subjects: Berkeleyacetals; Biosynthesis; Cryptic gene cluster; Genome mining; Meroterpenoid; Neosartorya glabra; Original; Berkeleyacetals; Cryptic gene cluster; Neosartorya glabra; Meroterpenoid; Biosynthesis; Genome mining
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2017.12.005

Fungal genomes carry many gene clusters seemingly capable of natural products biosynthesis, yet most clusters remain cryptic or down-regulated. Genome mining revealed an unconventional paraherquonin-like meroterpenoid biosynthetic gene cluster in the chromosome of Neosartorya glabra. The cryptic or down-regulated pathway was activated by constitutive expression of pathway-specific regulator gene berA encoded within ber biosynthetic gene cluster. Chemical analysis of mutant Ng-OE: berA extracts enabled the isolation of four berkeleyacetal congeners, in which two of them are new. On the basis of careful bioinformatic analysis of the coding enzymes in the ber gene cluster, the biosynthetic pathway of berkeleyacetals was proposed. These results indicate that this approach would be valuable for discovery of novel natural products and will accelerate the exploitation of prodigious natural products in filamentous fungi.
Genome mining revealed an unconventional paraherquonin-like meroterpenoid biosynthetic gene cluster in the chromosome of Neosartorya glabra. Overexpression of the pathway specific transcriptional regulator (BerA) led to the production of two new compounds berkeleyacetal D (1) and 11-epi-berkeleyacetal C (2). The biosynthetic pathway of berkeleyacetals was proposed by a combined approach, comprising molecular biology, bioinformatics and chemical analysis. [Display omitted]