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

Summary

Scientists studied how different mold species produce mycophenolic acid (MPA), a drug used to prevent transplant rejection in millions of patients worldwide. By examining the genomes of nearly 500 fungal species, they discovered which molds can make MPA and how they evolved this ability. The research found that MPA-producing fungi all have special resistance mechanisms to protect themselves from the toxic compound they produce, and these protection strategies differ between species.

Background

Mycophenolic acid (MPA) is a powerful immunosuppressant used daily by millions of transplant recipients worldwide. MPA production is restricted to a limited number of filamentous fungi, and understanding its biosynthetic pathways and origin remains poorly characterized. This study aims to identify new fungal MPA producers and elucidate the evolutionary history of this important secondary metabolite.

Objective

To decipher the origin and evolution of the fungal mycophenolic acid biosynthetic pathway by identifying new MPA-producing species, characterizing their gene clusters, and analyzing resistance mechanisms across fungal species.

Results

Complete and functional MPA biosynthetic gene clusters were identified in Penicillium and Aspergillus species, with A. pseudoglaucus E42 showing a unique genomic organization differing from Penicillium species. Large-scale analysis revealed MPA BGCs in 16 total species/strains, with partial or pseudogenized clusters in several others. All MPA producers were resistant to MPA, though resistance mechanisms varied, involving combinations of IMPDH gene dosage, expression levels, and specific amino acid substitutions.

Conclusion

MPA biosynthesis likely originated early in Eurotiales evolution and was subsequently lost in most species but retained in a narrow set of filamentous fungi. The presence of the mpaF gene provides self-protection in MPA producers, while different molecular mechanisms underlie resistance in nonproducing species. This study provides unprecedented insight into the evolutionary origin and distribution of MPA biosynthesis across the fungal kingdom.
  • Published in:Genome Biology and Evolution,
  • Study Type:Comparative Genomic Analysis,
  • Source: PMID: 40052422, DOI: 10.1093/gbe/evaf039
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