ArticleProtein science : a publication of the Protein Society2020
A structural determinant of mycophenolic acid resistance in eukaryotic inosine 5'-monophosphate dehydrogenases.
Article in Protein science : a publication of the Protein Society, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 18 citations in OpenAlex.
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- Tracing the Origin and Evolution of the Fungal Mycophenolic Acid Biosynthesis Pathway.Genome biology and evolution · 2025Article
- Construction of an expression platform for fungal secondary metabolite biosynthesis in Penicillium crustosum.Applied microbiology and biotechnology · 2024Article
- Advanced Fungal Biotechnologies in Accomplishing Sustainable Development Goals (SDGs): What Do We Know and What Comes Next?Journal of fungi (Basel, Switzerland) · 2024Review
- Fungal Drug Discovery for Chronic Disease: History, New Discoveries and New Approaches.Biomolecules · 2023Review
- Selection ofJournal of fungi (Basel, Switzerland) · 2021Article
- Discovery of Novel GMPS Inhibitors ofBiology · 2021Article
- Evaluation of Bronopol and Disulfiram as PotentialMolecules (Basel, Switzerland) · 2020Article
- A structural determinant of mycophenolic acid resistance in eukaryotic inosine 5'-monophosphate dehydrogenases.Protein science : a publication of the Protein Society · 2020Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Mycophenolic acid (MPA) is a potent natural product inhibitor of fungal and other eukaryotic inosine 5'-monophosphate dehydrogenases (IMPDHs) originally isolated from spoiled corn silage. MPA is produced by the filamentous fungi Penicillium brevicompactum, which contains two IMPDHs, PbIMPDHA and PbIMPDHB, both of which are MPA-resistant. The MPA binding sites of these enzymes are identical to MPA-sensitive IMPDHs, so the structural determinants of resistance are unknown. Here we show that a single residue, Ser267, accounts for the MPA resistance of PbIMPDHA. Substitution of Ser267 with Ala, the residue most commonly found in this position in eukaryotic IMPDHs, makes PbIMPDHA sensitive to MPA. Conversely, Aspergillus nidulans IMPDH becomes MPA-resistant when the analogous Ala residue is substituted with Ser. These substitutions have little effect on the catalytic cycles of either enzyme, suggesting the fitness costs are negligible despite the strong conservation of Ala at this position. Intriguingly, while only 1% of fungal IMPDHs contain Ser or Thr at position 267, these residues are found in the IMPDHs from several Aspergillus species that grow at the low temperatures also favored by Penicillium. Perhaps Ser/Thr267 is an evolutionary signature of MPA exposure.
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