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Engineering of the Filamentous Fungus Penicillium Chrysogenum As Cell Factory for Natural Products Guzman-Chavez, Fernando; Zwahlen, Reto D.; Bovenberg, Roel A

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Engineering of the Filamentous Fungus Penicillium Chrysogenum As Cell Factory for Natural Products Guzman-Chavez, Fernando; Zwahlen, Reto D.; Bovenberg, Roel A University of Groningen Engineering of the Filamentous Fungus Penicillium chrysogenum as Cell Factory for Natural Products Guzman-Chavez, Fernando; Zwahlen, Reto D.; Bovenberg, Roel A. L.; Driessen, Arnold J. M. Published in: Frontiers in Microbiology DOI: 10.3389/fmicb.2018.02768 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2018 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Guzman-Chavez, F., Zwahlen, R. D., Bovenberg, R. A. L., & Driessen, A. J. M. (2018). Engineering of the Filamentous Fungus Penicillium chrysogenum as Cell Factory for Natural Products. Frontiers in Microbiology, 9, [2768]. https://doi.org/10.3389/fmicb.2018.02768 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 29-04-2019 fmicb-09-02768 November 13, 2018 Time: 17:47 # 1 REVIEW published: 15 November 2018 doi: 10.3389/fmicb.2018.02768 Engineering of the Filamentous Fungus Penicillium chrysogenum as Cell Factory for Natural Products Fernando Guzmán-Chávez1,2†, Reto D. Zwahlen1,2, Roel A. L. Bovenberg2,3 and Arnold J. M. Driessen1,2* 1 Molecular Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, Netherlands, 2 Synthetic Biology and Cell Engineering, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, Netherlands, 3 DSM Biotechnology Centre, Delft, Netherlands 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 Edited by: b-lactam antibiotic producer. For several decades, P. chrysogenum was subjected to Eung-Soo Kim, a classical strain improvement (CSI) program to increase penicillin titers. This resulted Inha University, South Korea in a massive increase in the penicillin production capacity, paralleled by the silencing of Reviewed by: Gang Liu, several other biosynthetic gene clusters (BGCs), causing a reduction in the production Institute of Microbiology (CAS), China of a broad range of BGC encoded natural products (NPs). Several approaches have Juan F. Martin, Universidad de León, Spain been used to restore the ability of the penicillin production strains to synthetize the NPs *Correspondence: lost during the CSI. Here, we summarize various re-activation mechanisms of BGCs, Arnold J. M. Driessen and how interference with regulation can be used as a strategy to activate or silence [email protected] BGCs in filamentous fungi. To further emphasize the versatility of P. chrysogenum as a † Present address: fungal production platform for NPs with potential commercial value, protein engineering Fernando Guzmán-Chávez, Synthetic Biology and of biosynthetic enzymes is discussed as a tool to develop de novo BGC pathways for Reprogramming of Plant Systems, new NPs. Department of Plant Sciences, University of Cambridge, Cambridge, Keywords: Penicillium chrysogenum, natural products, nonribosomal peptides, polyketides, gene activation, United Kingdom biosynthetic gene clusters, cell factory Specialty section: This article was submitted to INTRODUCTION Microbial Physiology and Metabolism, a section of the journal Since the discovery of penicillin by Alexander Fleming produced by the filamentous fungus Frontiers in Microbiology Penicillium notatum, the genus Penicillium has been deeply studied for its capacity to produce a Received: 19 June 2018 wide range of natural products (NPs) (secondary metabolites), many of them with biotechnological Accepted: 29 October 2018 and pharmaceutical applications. P. chrysogenum (recently renamed as P. rubens) is the most Published: 15 November 2018 relevant member of more than 354 Penicillium species that constitute the genus (Nielsen et al., Citation: 2017). Penicillium is usually found in indoor environments and associated with food spoilage. It Guzmán-Chávez F, Zwahlen RD, is known as an industrial producer of b-lactam antibiotic in particularly penicillin, and current Bovenberg RAL and Driessen AJM production strains result from several decades of classical strain improvement (CSI) (Gombert (2018) Engineering of the Filamentous Fungus Penicillium chrysogenum as et al., 2011; Houbraken et al., 2011). The CSI program began in 1943 with the isolation of Cell Factory for Natural Products. P. chrysogenum NRRL 1951 capable of growing in submerged cultures. This strain was subjected Front. Microbiol. 9:2768. to a long serial process of mutations induced by 275 nm ultraviolet and X-ray irradiation, nitrogen doi: 10.3389/fmicb.2018.02768 mustard gas and nitroso-methyl guanidine exposure, single spore selection and selection for loss Frontiers in Microbiology| www.frontiersin.org 1 November 2018| Volume 9| Article 2768 fmicb-09-02768 November 13, 2018 Time: 17:47 # 2 Guzmán-Chávez et al. Penicillium chrysogenum Cell Factory of pigments, improved growth in large scale industrial fermenters THE BUILDING ENZYMES OF THE and enhanced levels of penicillin production. CSI programs NATURAL PRODUCTS were developed in several companies (Barreiro et al., 2012), and this has resulted in an increase of penicillin titers by Nonribosomal peptide synthetases are large, highly structured at least three orders of magnitude (van den Berg, 2010). As and complex enzymatic machineries, closely related to other consequence, numerous genetic modifications were introduced modular enzymes such as PKSs, NRPS–PKS hybrid synthetases in P. chrysogenum. Some have been studied in detail, most and fatty acid synthetases (FASs). They have certain distinct notably the amplification of the penicillin biosynthetic clusters properties in common, the most striking one being their and DNA inversions in this region (Fierro et al., 1995, 2006; structural division in domains and modules, which is manifested Barreiro et al., 2012). Although the CSI had a major impact in their shared evolutionary history (Smith and Sherman, on the production of b-lactams by P. chrysogenum, it also 2008). Every enzyme minimally consists of one module, a affected secondary metabolism in general. Indeed, a proteome functionally distinct unit, which allows for the recruitment and analysis performed between P. chrysogenum NRRL 1951 and subsequent incorporation of a precursor into a growing product. two derived strains (Wisconsin 54-1255 and AS-P-78) showed Domains as well as modules are clearly defined and evolutionary reduced levels of proteins related to secondary metabolism in the exchangeable structures amongst multi-modular enzymes. In the higher penicillin producer strains (Jami et al., 2010). Genome case of PKS and NRPS, this led to the occurrence of a variety of sequencing of P. chrysogenum Wisconsin 54-1255 revealed the NRPS–PKS hybrids (Du and Shen, 2001; Shen et al., 2005; Li et al., presence of several secondary metabolite encoding biosynthetic 2010; Nielsen et al., 2016). gene clusters (BGCs) in addition to the penicillin cluster, most of which have only be poorly studied and remain to be characterized Nonribosomal Peptides (NRPs) and (Figure 1). The products of the BGCs are either nonribosomal peptides (NRPs), polyketides (PKs) or hybrid molecules. Nonribosomal Peptide Synthetases Penicillium chrysogenum produces a broad range of (NRPSs) secondary metabolites such as roquefortines, fungisporin (a In comparison to most ribosomally derived peptides, NRPs cyclic hydrophobic tetrapeptide), siderophores, penitric acid, are low molecular weight products. The structural diversity of &-hydroxyemodin, chrysogenin, chrysogine, sesquiterpene NRPs is tremendous, mostly due to their chemical complexity. PR-toxin and sorbicillinoids, but likely also possesses the ability Significantly contributing to this diversity is the fact that NRPS to produce other compounds not detected before. For most of the are not only reliant on proteinogenic amino acids, but up until identified compounds, the responsible BGCs are unknown. The now more than 500 substrates were identified, which serve as development of new bioinformatics tools (SMURF, AntiSMASH) NRPS building blocks (Caboche et al., 2008). These molecules (Khaldi et al., 2010; Weber et al., 2015; Blin et al., 2017) and are predominantly amino acids, but not exclusively, since fatty the increase in the number of fungal genomes sequenced to acids, carboxylic acids and others substrates have been reported date has opened the possibility to discover new NPs with in NRPs (Marahiel et al., 1997). NRP thus represent a diverse novel properties (genome mining). The genes involved in the group of natural compounds and occur as linear, branched, biosynthesis, regulation and transport of secondary metabolites circular
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