Heterologous Expression of Ilicicolin H Biosynthetic Gene Cluster and Production of a New Potent Antifungal Reagent, Ilicicolin J

• Main Authors: Xiaojing Lin, Siwen Yuan, Senhua Chen, Bin Chen, Hui Xu, Lan Liu, Huixian Li, Zhizeng Gao
• Format: Article
• Language: English
• Published: MDPI AG 2019-06-01
• Series: Molecules
• Subjects: ilicicolin H; <i>Neonectria</i> sp. DH2; heterologous production; biosynthetic gene cluster
• Online Access: https://www.mdpi.com/1420-3049/24/12/2267

Ilicicolin H is a broad-spectrum antifungal agent targeting mitochondrial cytochrome bc1 reductase. Unfortunately, ilicicolin H shows reduced activities in vivo. Here, we report our effort on the identification of ilicicolin H biosynthetic gene cluster (BGC) by genomic sequencing a producing strain, <i>Neonectria</i> sp. DH2, and its heterologous production in <i>Aspergillus nidulans</i>. In addition, a shunt product with similar antifungal activities, ilicicolin J, was uncovered. This effort would provide a base for future combinatorial biosynthesis of ilicicolin H analogues. Bioinformatics analysis suggests that the backbone of ilicicolin H is assembled by a polyketide-nonribosomal peptide synthethase (IliA), and then offloaded with a tetramic acid moiety. Similar to tenellin biosynthesis, the tetramic acid is then converted to pyridone by a putative P450, IliC. The decalin portion is most possibly constructed by a <i>S</i>-adenosyl-<span style="font-variant: small-caps;">l</span>-methionine (SAM)-dependent Diels-Alderase (IliD).