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

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.