Tracing the Origin and Evolution of Mycophenolic Acid Biosynthesis in Fungi

Author:

Baptiste Bidon, Hajar Yaakoub, Arnaud Lanoue, Antoine Géry, Virginie Séguin, Claire Hoffmann Solène Le Gal, Gilles Nevez, Vincent Courdavault, Jean-Philippe Bouchara, Antonis Rokas, Gustavo H. Goldman, Jean-Pierre Gangneux, Jens C. Frisvad, Domenico Davolos, David Garon, Nicolas Papon

Abstract:

Objective. Mycophenolic acid (MPA) is a natural meroterpenoid known to inhibit inosine monophosphate dehydrogenase (IMPDH) involved in de novo purine synthesis. Because of its adverse effect on proliferation of human lymphocytes, MPA has been used for decades as an immunosuppressive agent. Biosynthesis of MPA was believed to be restricted to a very limited number of Penicillium species, including P. brevicompactum and P. roqueforti. However, recent findings evidenced that few xerophilic Aspergillus species are also capable of producing MPA. On the other hand, the biosynthetic gene cluster (BGC) for MPA production has only been investigated in P. brevicompactum and P. roqueforti. Given the medical and biotechnological importance of members of Penicillium and Aspergillus genera, we were interested in deciphering the origin and evolution of MPA biosynthetic pathway within their respective family Aspergillaceae.
Methods. Large-scale analysis of available genomic resources of Aspergillaceae led us to identifying very few species in Penicillium, Aspergillus, and Paecilomyces genera harboring either a complete or partial MPA BGC. Whole-genome sequencing was conducted for four xerophilic Aspergillus spp strains, including A. pseudoglaucus (E42) previously shown to produce MPA.
Results. Interestingly, genomic data confirmed the presence of a putative BGC for MPA production in A. pseudoglaucus (E42), though it dramatically differs in terms of genomic organisation from that described in P. brevicompactum. None of the three other sequenced Aspergillus species carried a functional BGC for MPA production or was able to produce MPA. We postulate that genetic determinants of MPA biosynthesis emerged early from a common ancestor of Aspergillaceae and were then retained in a narrow set of molds. Moreover, analysis of MPA production, susceptibility to MPA, and IMPDH protein sequences in members of Aspergillaceae showed that MPA producers are inevitably resistant to MPA, and that this resistance is likely the outcome of a combination of molecular events.
Conclusion. The current study provides insight into the origin and evolution of the biosynthesis of the important fungal secondary metabolite MPA. Implications of these findings in clinics and biotechnology are discussed.

Abstract Number: 47

Conference Year: 2024

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