Deciphering chemical logic of fungal natural product biosynthesis through heterologous expression and genome mining

Covering: 2010 to 2022 Heterologous expression of natural product biosynthetic gene clusters (BGCs) has become a widely used tool for genome mining of cryptic pathways, bottom-up investigation of biosynthetic enzymes, and engineered biosynthesis of new natural product variants. In the field of fungal natural products, heterologous expression of a complete pathway was first demonstrated in the biosynthesis of tenellin in Aspergillus oryzae in 2010. Since then, advances in genome sequencing, DNA synthesis, synthetic biology, etc. have led to mining, assignment, and characterization of many fungal BGCs using various heterologous hosts. In this review, we will highlight key examples in the last decade in integrating heterologous expression into genome mining and biosynthetic investigations. The review will cover the choice of heterologous hosts, prioritization of BGCs for structural novelty, and how shunt products from heterologous expression can reveal important insights into the chemical logic of biosynthesis. The review is not meant to be exhaustive but is rather a collection of examples from researchers in the field, including ours, that demonstrates the usefulness and pitfalls of heterologous biosynthesis in fungal natural product discovery.