Salo, Oleksandr

English

Penicillium chrysogenum is de filamenteuze schimmel die in de industrie gebruikt voor de productie van het antibioticum penicilline. Penicillines worden nog steeds veel gebruikt maar voor de productie worden tegenwoordig stammen gebruikt die een zeer hoge opbrengst van β-lactams vertonen en die zijn verkregen middels een uitgebreide klassieke stamverbetering (CSI) programma dat bijna zeven decennia heeft geduurd. Bij CSI worden cellen blootgesteld aan agressieve behandelingen zoals UV-straling en mostertgas waardoor er mutaties ontstaan waarvan sommige gunstig zijn voor β-lactam productie veroorzaakt. Echter, de invloed van CSI op de productie van andere secundaire metabolieten is onbekend gebleven.In dit proefschrift is een vergelijkende analyse uitgevoerd van P. chrysogenum mutanten uit het CSI-programma waarbij de genoomsequentie, het transcriptoom en de metaboliet productie is gemeten. De gegevens suggereren dat tijdens de CSI de meeste secundaire metaboliet routes zijn geïnactiveerd ten gunsten van de β-lactams. Dit betreft ondermeer een groep van bioactieve verbindingen, de sorbicillinoids. Dit zijn gele pigmenten die tevens antimicrobiële, anti-HIV en anti-kanker activiteiten vertonen. Met behulp van de genoomsequentie gegevens is een belangrijke mutatie in een van de sorbicillinoid biosynthese genen gerestaureerd in een industriële P. chrysogenum stam waardoor eenvoudig een hoge productie werd bereikt. Dit systeem kan nu worden gebruikt om het mechanisme van biosynthese van sorbicillinoids op te helderen en derivaten te produceren met verhoogde activiteit en specificiteit.Penicillium chrysogenum is the filamentous fungus employed for the industrial production of the antibiotic penicillin. Penicillins are still widely used but produced by high yielding β-lactam strains that resulted from an extensive classical strain improvement (CSI) program that lasted for almost seven decades. CSI involves harsh treatments such as UV radiation and muster gas exposure that causes mutations some of which are beneficial for β-lactam production. However, the impact of CSI on other secondary metabolite pathways remained unknown.In this thesis, a comparative analysis of the P. chrysogenum mutants from the CSI program was conducted that involved genome sequencing, transcriptome and metabolite production. The data indicates that during CSI most secondary metabolite pathways have been silenced by mutation in favor of the β-lactams. Among others, this resulted in the elimination of a group of bioactive compounds sorbicillinoids. These are yellow pigments that exhibit antimicrobial, anti-HIV and anti-cancer activities. Using the genome sequencing data, a key mutation in a sorbicillinoid biosynthetic gene was restored in an industrial P. chrysogenum strain readily allowing high level production. This system can now be used to resolve the biosynthetic pathway for sorbicillinoids and design methods to produce high bioactive derivatives

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   University of GroningenSecondary metabolism by industrially improved Penicillium chrysogenum strainsSalo, OleksandrIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2016Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Salo, O. (2016). Secondary metabolism by industrially improved Penicillium chrysogenum strains.University of Groningen.CopyrightOther 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 theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 08-06-2022Secondary metabolism by industrially improvedPenicillium chrysogenum strainsOleksandr SaloISBN: 978-90-367-8461-0ISBN: 978-90-367-8460-3 (electronic)The research described in this thesis was carried out in the research group in Department of Molecular Microbiology in the Groningen Biotechnology and Biomolecular Sciences (GBB), University of Groningen in the Netherlands. The work was supported by the Perspective Genbiotics program subsidized by Stichting toegepaste wetenschappen (STW) and (co)financed by the Netherlands Metabolomics Centre (NMC) which is a part of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO) and the Integration of Biosynthesis andOrganic Synthesis (IBOS) programme residing under Advanced Chemical Technologies for Sustainability (ACTS) which is subsidized by NWO.Cover design and layout of the book:   Oleksandr Salo                                                                                                                                                                                                                                                                          Cover: ‘‘A talk on how to cure the World’’Clockwise from left: Alexander Fleming, Howard Walter Flore, Ernst Boris Chain and Norman Heatley. The tree represents a genealogy of  the improved β-lactam producing  Penicillium chrysogenum strains.© Copyright 2016 by O.Salo. All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, without prior permission of the author.      Secondary metabolism by industrially improved  Penicillium chrysogenum strains       Proefschrift     ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties.  De openbare verdediging zal plaatsvinden op   vrijdag 8 januari 2016 om 12.45 uur     door     Oleksandr Salo  geboren op 6 augustus 1985 te Yampil, Oekraïne Promotor Prof. A.J.M. Driessen    Beoordelingscommissie Prof. L. Dijkhuizen  Prof. D.B. Janssen  Prof. H. van Veen Поїдеш далеко, Побачиш багато; Задивишся, зажуришся,— Згадай мене, брате!Т.Шевченко, 1840р.ContentChapter 1 Secondary metabolite production by Penicillium chrysogenum .............. 3Chapter 2 Genomic mutational analysis of the impact of the classical strain improvement program on β–lactam producing Penicillium chrysogenum ........................................................................ 49Chapter 3 Deregulated secondary metabolite production in a histone deacetylase mutant of Penicillium chrysogenum ................. 103Chapter 4 Identification of a polyketide synthase involved in sorbicillin biosynthesis by Penicillium chrysogenum ............................................... 137Chapter 5 Activation of two silent 6-methylsalycilic acid synthases in Penicillium chrysogenum ........................................................................ 165Chapter 6 Summary ................................................................................................. 183Samenvatting .......................................................................................... 189Резюме українською .............................................................................. 197Acknowledgements ................................................................................. 203

Secondary metabolism by industrially improved Penicillium chrysogenum strains

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Secondary metabolism by industrially improved Penicillium chrysogenum strains

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