Saccharomyces cerevisiae as a tool for mining, studying and engineering fungal polyketide synthases

Abstract

Small molecule secondary metabolites produced by organisms such as plants, bacteria, and fungi form a fascinating and important group of natural products, many of which have shown promise as medicines. Fungi in particular have been important sources of natural product polyketide pharmaceuticals. While the structural complexity of these polyketides makes them interesting and useful bioactive compounds, these same features also make them difficult and expensive to prepare and scale-up using synthetic methods. Currently, nearly all commercial polyketides are prepared through fermentation or semi-synthesis. However, elucidation and engineering of polyketide pathways in the native filamentous fungi hosts are often hampered due to a lack of established genetic tools and of understanding of the regulation of fungal secondary metabolisms. Saccharomyces cerevisiae has many advantages beneficial to the study and development of polyketide pathways from filamentous fungi due to its extensive genetic toolbox and well-studied metabolism. This review highlights the benefits S. cerevisiae provides as a tool for mining, studying, and engineering fungal polyketide synthases (PKSs), as well as notable insights this versatile tool has given us into the mechanisms and products of fungal PKSs.

A cryptic pigment biosynthetic pathway uncovered by heterologous expression is essential for conidial development in Pestalotiopsis fici

“…Recently, heterologous expression in model fungal systems have been used successfully to activate silent or cryptic gene clusters (Bond et al, 2016;Sun et al, 2016;Wanka et al, 2016). Using A. nidulans as heterologous host, a number of cryptic polyketides including neosartoricins, asperfuranone, citreoviridin from different fungal species were activated (Chiang et al, 2013;Yin et al, 2013;Lin et al, 2016).…”

Collaborative Biosynthesis of a Class of Bioactive Azaphilones by Two Separate Gene Clusters Containing Four PKS/NRPSs with Transcriptional Crosstalk in Fungi

“…[5] Undoubtedly, heterologous reconstitution of the biosynthetic pathway is an effective strategy to explore silent BGCs in native microorganisms, and the previous characterizations of these two BGCs were both performed in this way. [4,6] However, it may not always be possible to reveal the original biosynthetic pathway in the natural host. [1b, 7] To clarify the original biosynthetic pathway of 1 in A. terreus, a total of thirty genes in two clusters were deleted, and twelve of them were confirmed as essential for the biosynthesis of 1 (Figure S2, Scheme 1).…”

Genome-wide analysis and prediction of genes involved in the biosynthesis of polysaccharides and bioactive secondary metabolites in high-temperature-tolerant of wild Flammulina filiformis

“…Polyketides are a major group of secondary metabolites isolated from bacteria and fungi and fungi in particular have been important sources of natural product polyketide pharmaceuticals. The structural complexity of these polyketides makes them interesting and useful bioactive compounds and these same features also make them difficult and expensive to prepare and scale-up using synthetic methods [54]. In the past, understanding the biosynthesis and regulation of polyketides in fungi was extremely difficult because of the lack of established genetic tools.…”

“…In the past, understanding the biosynthesis and regulation of polyketides in fungi was extremely difficult because of the lack of established genetic tools. Recent studies have illustrated that Saccharomyces cerevisiae has potential as a tool for mining, studying and engineering fungal polyketide synthases due to its many advantages such as being a unicellular organism well suited for large-scale fermentation, having limited native secondary metabolism and having a number of developed genetic tools for protein expression and pathway constriction [54].…”