Tracing the Origin and Evolution of the Fungal Mycophenolic Acid Biosynthesis Pathway
2025
Bidon, Baptiste | Yaakoub, Hajar | Lanoue, Arnaud | Géry, Antoine | Seguin, Virginie | Magot, Florent | Hoffmann, Claire | Courdavault, Vincent | Bouchara, Jean-Philippe | Gangneux, Jean-Pierre | Frisvad, Jens C. | Rokas, Antonis | Goldman, Gustavo H. | Nevez, Gilles | Le Gal, Solène | Davolos, Domenico | Garon, David | Papon, Nicolas | National Taïwan University (NTU) | Service Commun d'Imagerie et d'Analyse Microscopique [SFR ICAT - UA] (SCIAM) ; SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT) ; Université d'Angers (UA)-Université d'Angers (UA) | Physiopathologie des Adaptations Nutritionnelles (PhAN) ; Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE) ; Nantes Université - pôle Santé ; Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé ; Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ) | Biomolécules et biotechnologies végétales (BBV) ; Université de Tours (UT) | Aliments Bioprocédés Toxicologie Environnements (ABTE) ; Université de Caen Normandie (UNICAEN) ; Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN) ; Normandie Université (NU) | Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST) | Centre Hospitalier Régional Universitaire de Brest (CHRU Brest) | Infections Respiratoires Fongiques (IRF) ; Université d'Angers (UA)-Université de Brest (UBO) | SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT) ; Université d'Angers (UA) | Laboratoire de Parasitologie-Mycologie, CHU d'Angers, Angers, | Centre Hospitalier Universitaire [Rennes] | Institut de recherche en santé, environnement et travail (Irset) ; Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes (Biosit : Biologie - Santé - Innovation Technologique) | Danmarks Tekniske Universitet = Technical University of Denmark (DTU) | Vanderbilt University [Nashville] | Universidade de São Paulo = University of São Paulo (USP) | Laboratoire de Parasitologie et Mycologiede [CHRU Brest] ; Centre Hospitalier Régional Universitaire de Brest (CHRU Brest) | The authors want to thank the ANAN facility of Angers for help in genome sequencing and the Bird platform facility from the University of Nantes for help in analysis. This work was supported by grants from Angers Loire Métropole (MycoFong) and the Conseil Régional des Pays de la Loire (CRHoMic). D.D. acknowledges the Istituto Nazionale per l'Assicurazione Contro Gli Infortuni sul Lavoro, Rome, Italy, for financially supporting the genome sequencing of Penicillium sp. CF01 as part of the NGS Project in the PAR 2019–2021. Research in A.R.'s lab is supported by grants from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (R01 AI153356), the National Science Foundation (DEB-2110404), and the Burroughs Wellcome Fund. N.P. acknowledges funding from the Agence Nationale de la Recherche (project AspergIS, ANR-24-CE15-2995-01) and European Comission (project COMBO HORIZON-CL6-2023-CircBio-01-11) . | ANR-24-CE15-2995,AspergIS,Les immunosuppresseurs conditionnent les microévolutions chez un pathogène fongique majeur(2024)
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Afficher plus [+] Moins [-]anglais. Like bacteria and plants, fungi produce a remarkable diversity of small molecules with potent activities for human health known as natural products or secondary metabolites. One such example is mycophenolic acid, a powerful immunosuppressant drug that is administered daily to millions of transplant recipients worldwide. Production of mycophenolic acid is restricted to a very limited number of filamentous fungi, and little is known about its biosynthetic modalities. It is therefore a particular challenge to improve our knowledge of the biosynthesis of this valuable natural compound, as this would contribute to a better understanding of the specialized metabolism of fungi and could also lead to the identification of new fungal producers for the supply of immunosuppressants. Here, we were interested in deciphering the origin and evolution of the fungal mycophenolic acid biosynthetic pathway. Large-scale analyses of fungal genomic resources led us to identify several new species that harbor a gene cluster for mycophenolic acid biosynthesis. Phylogenomic analysis suggests that the mycophenolic acid biosynthetic gene cluster originated early in a common ancestor of the fungal family Aspergillaceae but was repeatedly lost and it is now present in a narrow but diverse set of filamentous fungi. Moreover, a comparison of the inosine 5′-monophosphate dehydrogenase protein sequences that are the target of the mycophenolic acid drug as well as analysis of mycophenolic acid production and susceptibility suggest that all mycophenolic acid fungal producers are resistant to this toxic compound, but that this resistance is likely to be based on different molecular mechanisms. Our study provides new insight into the evolution of the biosynthesis of the important secondary metabolite mycophenolic acid in fungi.
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