Strategies for Engineering Natural Product Biosynthesis in Fungi.

Fungi are a prolific source of bioactive compounds, some of which have been developed as essential medicines and life-enhancing drugs. Genome sequencing has revealed that fungi have the potential to produce considerably more natural products (NPs) than are typically observed in the laboratory. Recently, there have been significant advances in the identification, understanding, and engineering of fungal biosynthetic gene clusters (BGCs). This review briefly describes examples of the engineering of fungal NP biosynthesis at the global, pathway, and enzyme level using in vivo and in vitro approaches and refers to the range and scale of heterologous expression systems available, developments in combinatorial biosynthesis, progress in understanding how fungal BGCs are regulated, and the applications of these novel biosynthetic enzymes as biocatalysts. Highlights The antibiotic penicillin revolutionized human medicine, and now fungal natural products (NPs) play a prominent role in the pharmaceutical and healthcare industries. Fungal genomes host a wealth of biosynthetic gene clusters (BGCs) that are silent under conventional laboratory culture conditions due to their tight regulation. Widely applicable methods have been developed to activate or modify these BGCs in both native and heterologous hosts and scalable expression platforms have been established. Fungal BGCs can be engineered to reveal biosynthetic intermediates or increase titers of NPs or combined with biosynthetic pathways from other species and/or other organisms to generate 'unnatural' NPs. Investigation of fungal BGCs often reveals unique enzymes with novel activities that can be applied to a plethora of unnatural substrates and developed as biocatalysts. [ABSTRACT FROM AUTHOR]