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Harnessing the yeast Saccharomyces cerevisiae for the production of fungal secondary metabolites

Summary

Scientists have learned to use common baker’s yeast (S. cerevisiae) as a biological factory to produce valuable medicines and compounds that naturally come from fungi and mushrooms. By transferring the genetic instructions for making these compounds into yeast cells and improving them with genetic engineering, researchers can now produce therapeutically important substances like cancer-fighting drugs and antibiotics in large quantities. This approach is more practical and cost-effective than trying to extract these rare compounds directly from their native fungal sources or using other production methods.

Background

Fungal secondary metabolites (FSMs) are bioactive compounds with potential applications as pharmaceuticals, nutraceuticals, and agrochemicals. However, these molecules are typically produced in limited amounts by their native fungal hosts, which are often difficult to cultivate and genetically engineer. Recombinant production in industrial microorganisms like baker’s yeast offers an alternative approach for efficient large-scale manufacturing.

Objective

This review summarizes the development of Saccharomyces cerevisiae as a cell factory for producing fungal secondary metabolites, including polyketides, terpenoids, and amino acid derivatives derived from filamentous fungi and mushrooms. The review also describes metabolic engineering approaches, biosynthetic pathway engineering, and advanced tools like genome-scale engineering and machine learning for strain improvement.

Results

The review documents successful production of various FSMs in S. cerevisiae including 6-methylsalicylic acid (1.7 g/l), simvastatin (55 mg/l), psilocybin (627 mg/l in fed-batch), ergothioneine (598 mg/l), and numerous terpenoids and non-ribosomal peptides. Advanced engineering approaches such as CRISPR-based multiplexing, high-throughput screening with biosensors, and machine learning have significantly improved production titers.

Conclusion

S. cerevisiae has emerged as a robust chassis organism for heterologous production of fungal secondary metabolites due to its genetic tractability and well-characterized metabolism. Further development requires addressing protein folding challenges, improving precursor supply through central carbon flux reprogramming, and enhancing metabolite secretion through transporter engineering and emerging synthetic biology approaches.
  • Published in:Essays in Biochemistry,
  • Study Type:Review,
  • Source: PMID: 34061167, DOI: 10.1042/EBC20200137
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