4-Hydroxy Pyridones from Heterologous Expression and Cultivation of the Native Host

Abstract

4-Hydroxy pyridones are a class of fungi-derived polyketide–nonribosomal peptide products featuring a core of 4-hydroxy-2-pyridone which have a wide range of biological activities. Genome mining of in-house strains using polyketide synthase–nonribosomal peptide synthase as a query identified an endophyte Tolypocladium sp. 49Y, which possesses a potential 4-hydroxy pyridone biosynthetic gene cluster. Heterologous expression in Aspergillus oryzae NSAR1 revealed that this gene cluster is functional and able to produce a rare type of 4-hydroxy pyridones called tolypyridones (compounds 3 and 4). Tolypocladium sp. 49Y was grown in a variety of media which led to the isolation of six 4-hydroxy pyridones (5–10) and one pyrrolidone (11) from a rice culture, and compounds 3 and 9 showed antifungal activity. These latter compounds are different from those obtained by heterologous expression. This study shows that both heterologous expression and cultivation of the native host are complementary approaches to discover new natural products.

Heterologous Expression of Macrollins from Phytopathogenic Macrophomina phaseolina Revealed a Cytochrome P450 Mono-oxygenase in the Biosynthesis of β-Hydroxyl Tetramic Acid

“…22,26,27,46−48 AdpE, HarG, ApnG, and TolB have been shown to exhibit three different activities: one is to form 2-pyridone molecules, similar to TenA, another is hydroxylation at the β-carbon of the amino acid moiety, and the last one is oxidative dephenylation (Figure 5). 28,49,50 MacC does not clade with the other P450 enzymes based on the analysis. The phylogenetic analysis suggested that P450 enzymes encoded in PKS-NRPS-containing BGCs have evolved to perform different oxidative functions to generate structural and functional diversity.…”

Biological Dark Matter Exploration using Data Mining for the Discovery of Antimicrobial Natural Products

“…Fungal 4-hydroxy pyridones are polyketide-NRP compounds with diverse structures and biological activities [114]. The biosynthesis of these compounds is initiated by the PKS-NRPS and a trans-acting enoyl reductase (ER) to yield a pentacyclic intermediate, acryltetramic acid.…”

Genome Mining of α-Pyrone Natural Products from Ascidian-Derived Fungus Amphichordafelina SYSU-MS7908

“…However, we had not observed the production of such metabolites from the wild type of A. felina SYSU-MS7908, suggesting that this BGC might be silent. We decided to activate this BGC by heterologous expression in A. oryzae NSAR1 as it is a robust host to mine fungal natural products [ 19 , 20 , 21 ].…”