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Tracing the Origin and Evolution of the Fungal Mycophenolic Acid Biosynthesis Pathway

Summary

Scientists studied how different fungal species produce mycophenolic acid, a drug used to prevent transplant rejection in millions of patients worldwide. By analyzing the genomes of many fungal species, they found that only a few fungi can make this important drug, and they discovered that these fungi have different ways of protecting themselves from being poisoned by their own medicine. This research helps us understand how fungi evolve to produce valuable medicines and could lead to better ways to produce immunosuppressants.

Background

Mycophenolic acid (MPA) is a powerful immunosuppressant drug administered to millions of transplant recipients worldwide, with a global market size of $1.5 billion annually. MPA production is restricted to a very limited number of filamentous fungi, and little is known about its biosynthetic pathways and evolutionary origins across the fungal kingdom.

Objective

This study aimed to decipher the origin and evolution of the fungal mycophenolic acid biosynthetic pathway by identifying new MPA-producing species, analyzing the distribution of MPA biosynthetic gene clusters across fungi, and understanding the mechanisms of MPA resistance in both producers and non-producers.

Results

Several new MPA-producing species were identified including Aspergillus pseudoglaucus, Penicillium samsonianum, and Penicillium sp. CF01. Analysis of 479 fungal genomes revealed complete MPA biosynthetic gene clusters in only a few species from Penicillium, Aspergillus, and Paecilomyces genera. All MPA-producing fungi demonstrated resistance to the compound through different molecular mechanisms involving IMPDH gene variants and dosage effects.

Conclusion

MPA biosynthesis originated early in Aspergillaceae evolution but was repeatedly lost in most species, remaining only in a narrow but diverse set of filamentous fungi. Different fungal producers employ distinct molecular mechanisms for MPA resistance, providing insights into the evolution of specialized fungal metabolism and potential applications for immunosuppressant production.
  • Published in:Genome Biology and Evolution,
  • Study Type:Comparative Genomics Study,
  • Source: 10.1093/gbe/evaf039, PMID: 40052422
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