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

Mycophenolic acid (MPA) is a natural immunosuppressant known to inhibit inosine monophosphate dehydrogenase (IMPDH) involved in de novo purine synthesis. While production of MPA is believed to be restricted to a very limited number of Penicillium species and few xerophilic Aspergillus species, 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 the MPA biosynthetic pathway within their family Aspergillaceae. Large-scale analyses of publicly available genomic resources of Aspergillaceae led us to identify a few species in Penicillium, Aspergillus, and Paecilomyces genera that harbour either a complete or partial MPA BGC. By performing the whole-genome sequencing of four xerophilic Aspergillus species, including A. pseudoglaucus strain E42, we identified an unprecedented putative but distinctly organised BGC for MPA production. A robust phylogenomic analysis suggests that genetic determinants of MPA biosynthesis emerged early from a common ancestor of Aspergillaceae and were then retained in a narrow set of moulds. Moreover, comparison of the MPA target protein sequences (IMPDH) as well as analysis of MPA production and susceptibility in various Aspergillaceae moulds showed that all MPA producers are in turn resistant to MPA, but that this resistance is not the outcome of a common molecular event. The current study provides insight into the origin and evolution of the biosynthesis of the important fungal secondary metabolite MPA.