Computational strategies for genome-based natural product discovery and engineering in fungi

Fungal natural products possess biological activities that are of great value to medicine, agriculture and manufacturing. Recent metagenomic studies accentuate the vastness of fungal taxonomic diversity, and the accompanying specialized metabolic diversity offers a great and still largely untapped resource for natural product discovery. Although fungal natural products show an impressive variation in chemical structures and biological activities, their biosynthetic pathways share a number of key characteristics. First, genes encoding successive steps of a biosynthetic pathway tend to be located adjacently on the chromosome in biosynthetic gene clusters (BGCs). Second, these BGCs are often are located on specific regions of the genome and show a discontinuous distribution among evolutionarily related species and isolates. Third, the same enzyme (super)families are often involved in the production of widely different compounds. Fourth, genes that function in the same pathway are often co-regulated, and therefore co-expressed across various growth conditions. In this mini-review, we describe how these partly interlinked characteristics can be exploited to computationally identify BGCs in fungal genomes and to connect them to their products. Particular attention will be given to novel algorithms to identify unusual classes of BGCs, as well as integrative pan-genomic approaches that use a combination of genomic and metabolomic data for parallelized natural product discovery across multiple strains. Such novel technologies will not only expedite the natural product discovery process, but will also allow the assembly of a high-quality toolbox for the re-design or even de novo design of biosynthetic pathways using synthetic biology approaches.