Evolutionary formation of gene clusters by reorganization: the meleagrin/roquefortine paradigm in different fungi

Abstract

The biosynthesis of secondary metabolites in fungi is catalyzed by enzymes encoded by genes linked in clusters that are frequently co-regulated at the transcriptional level. Formation of gene clusters may take place by de novo assembly of genes recruited from other cellular functions, but also novel gene clusters are formed by reorganization of progenitor clusters and are distributed by horizontal gene transfer. This article reviews (i) the published information on the roquefortine/meleagrin/neoxaline gene clusters of Penicillium chrysogenum (Penicillium rubens) and the short roquefortine cluster of Penicillium roqueforti, and (ii) the correlation of the genes present in those clusters with the enzymes and metabolites derived from these pathways. The P. chrysogenum roq/mel cluster consists of seven genes and includes a gene (roqT) encoding a 12-TMS transporter protein of the MFS family. Interestingly, the orthologous P. roquefortine gene cluster has only four genes and the roqT gene is present as a residual pseudogene that encodes only small peptides. Two of the genes present in the central region of the P. chrysogenum roq/mel cluster have been lost during the evolutionary formation of the short cluster and the order of the structural genes in the cluster has been rearranged. The two lost genes encode a N1 atom hydroxylase (nox) and a roquefortine scaffold-reorganizing oxygenase (sro). As a consequence P. roqueforti has lost the ability to convert the roquefortine-type carbon skeleton to the glandicoline/meleagrin-type scaffold and is unable to produce glandicoline B, meleagrin and neoxaline. The loss of this genetic information is not recent and occurred probably millions of years ago when a progenitor Penicillium strain got adapted to life in a few rich habitats such as cheese, fermented cereal grains or silage. P. roqueforti may be considered as a "domesticated" variant of a progenitor common to contemporary P. chrysogenum and related Penicillia.

The Biosynthetic Gene Cluster for Andrastin A in Penicillium roqueforti

“…Recently, it has been suggested that some fungal gene clusters can suffer reorganization processes leading to the total or partial loss of some genes (Martín and Liras, 2016). In accordance with this suggestion, it can be hypothesized that the adrB gene originally present in P. chrysogenum was entirely or partially lost in the adr cluster from P. roqueforti .…”

“…MSF proteins are ubiquitous membrane proteins that are responsible for the movement of a wide range of substrates across biological membranes (Quistgaard et al, 2016). In the case of genes encoding for MSF proteins located into fungal biosynthetic gene clusters, it has been suggested that these proteins could be involved in the secretion of the secondary metabolites produced (Martín et al, 2005; Martín and Liras, 2016). Therefore, we tested if adrC could influence andrastin A production and/or secretion.…”

“…In P. chrysogenum , this cluster contains seven genes, whereas in P. roqueforti it is shorter and contains four genes (Kosalková et al, 2015). In this case, the evolutionary reorganization of the cluster produced that two genes present in P. chrysogenum were entirely lost in P. roqueforti , whereas a third gene was partially lost and now is found as a residual pseudogene (Kosalková et al, 2015; Martín and Liras, 2016). These data and our observation about the pseudogenization of adrB in the adr cluster suggest that the evolutionary reorganization in clusters from P. chrysogenum and P. roqueforti may be a common and extended process.…”

“…Recently, Martín and Liras (2016) have suggested that during their evolutionary formation, some fungal gene clusters can suffer drastic reorganization processes. As a product of this reorganization, some genes could be entirely lost, whereas other genes could be partially lost and found as residual pseudogenes.…”

“…Callahan et al (1999) suggested that the lack of MSF protein leads to the accumulation of the secondary metabolite above a critical threshold, producing the inhibition of biosynthetic enzymes or the down-regulation of the transcription of the biosynthetic genes. Another possibility is that these MSF proteins be intracellular transporters involved in the traffic of some intermediates of the biosynthesis (Martín and Liras, 2016). The absence of these transporters could be interfering in the normal intracellular transport of these intermediates, hence decreasing the production of the final secondary metabolite.…”