Abstract
Penicillium chrysogenum (renamed P. rubens) is the most studied member of a family of more than 350 Penicillium species that constitute the genus. Since the discovery of penicillin by Alexander Fleming, this filamentous fungus is used as a commercial β-lactam antibiotic producer. For several decades, P. chrysogenum was subjected to a classical strain improvement (CSI) program to increase penicillin titers. This resulted in a massive increase in the penicillin production capacity, paralleled by the silencing of several other biosynthetic gene clusters (BGCs), causing a reduction in the production of a broad range of BGC encoded natural products (NPs). Several approaches have been used to restore the ability of the penicillin production strains to synthetize the NPs lost during the CSI. Here, we summarize various re-activation mechanisms of BGCs, and how interference with regulation can be used as a strategy to activate or silence BGCs in filamentous fungi. To further emphasize the versatility of P. chrysogenum as a fungal production platform for NPs with potential commercial value, protein engineering of biosynthetic enzymes is discussed as a tool to develop de novo BGC pathways for new NPs.
Highlights
Since the discovery of penicillin by Alexander Fleming produced by the filamentous fungus Penicillium notatum, the genus Penicillium has been deeply studied for its capacity to produce a wide range of natural products (NPs), many of them with biotechnological and pharmaceutical applications
Given the urgent need for new molecules based on novel chemical scaffolds for the use in the medical and biotechnological fields, the use of organisms that have been genetically domesticated offers a promising target solution for NP discovery due to the availability of molecular tools for their genetic modification
We have summarized the main approaches that have been applied for P. chrysogenum and other filamentous fungi to bioengineer secondary metabolite biosynthetic gene clusters (BGCs) pathways which have led to a greater understanding of the main obstacles to be overcome to use this fungus as a generic cell factory
Summary
Since the discovery of penicillin by Alexander Fleming produced by the filamentous fungus Penicillium notatum, the genus Penicillium has been deeply studied for its capacity to produce a wide range of natural products (NPs) (secondary metabolites), many of them with biotechnological and pharmaceutical applications. Penicillium is usually found in indoor environments and associated with food spoilage It is known as an industrial producer of β-lactam antibiotic in penicillin, and current production strains result from several decades of classical strain improvement (CSI) (Gombert et al, 2011; Houbraken et al, 2011). Genome sequencing of P. chrysogenum Wisconsin 54-1255 revealed the presence of several secondary metabolite encoding biosynthetic gene clusters (BGCs) in addition to the penicillin cluster, most of which have only be poorly studied and remain to be characterized (Figure 1). The genes involved in the biosynthesis, regulation and transport of secondary metabolites tend to be arranged in the genome in clusters These gene clusters include the core biosynthetic genes which either encode polyketide synthases (PKSs), nonribosomal peptide synthetases (NRPSs) or terpene synthases genes (Smanski et al, 2016). A brief description of the key biosynthetic enzymes involved in biosynthesis of secondary metabolites in fungi is provided
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