Dokument: Identification of microbial amino acid producers by biosensor-based high-throughput screenings and comparative genome analyses
| Titel: | Identification of microbial amino acid producers by biosensor-based high-throughput screenings and comparative genome analyses | |||||||
| Weiterer Titel: | Identifizierung mikrobieller Aminosäureproduzenten durch biosensorgestützte Hochdurchsatz-Screenings und vergleichende Genomanalysen | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=64137 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20231117-081751-1 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Baumann, Philipp Tobias [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Bott, Michael [Gutachter] Prof. Dr. Pietruszka, Jörg [Gutachter] | |||||||
| Stichwörter: | Mutagenesis, FACS-Screening, Whole Genome Sequencing, Comparative Genome Analysis, Reverse Engineering, Metabolic Engineering | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibungen: | The modern life style of our ever growing world population is mainly based on the consumption of fossil resources. These developments are the cause of environmental damage and uncontrolled release of greenhouse gases as main drivers of climate change. Therefore, the implementation of more sustainable biotechnological production processes at industrial scale is needed. Such (mostly) sugar-based bioprocesses of the industrial biotechnology rely on microorganisms as catalysts, which need to be constantly improved to become more resource-efficient. In fact, most microbial production strains used today, operate below their theoretical maximum in terms of product yield. However, increasing the production performance of already highly engineered industrial production strains poses a challenge, since novel beneficial targets for rational engineering are difficult to identify. With the availability of biosensor-based FACS-screening technologies, classical strain development strategies comprising random mutagenesis and screening for an improved production phenotype are coming back into fashion.
In this thesis, the biosensor-based FACS-screening of randomly mutated cells was combined with comparative genome analyses and reverse engineering to reveal novel targets in the genome of an industrial Corynebacterium glutamicum production strain for the proteinogenic amino acid L histidine. Since the starting strain was already highly engineered, novel beneficial mutations were expected to be difficult to identify as they might not be directly linkable to L histidine biosynthesis. Therefore, 100 independently FACS-isolated improved strain variants were subjected to a comparative genome analyses to look for reoccurring mutations in single genes, certain pathways or modules of the microbial metabolism. To achieve the independent isolation of 100 improved strain variants, > 600 chemical mutagenesis and > 200 biosensor-based FACS-screenings were performed, which allowed for the isolation of > 50,000 variants with increased fluorescence. The characterization of > 4,500 variants with regard to biomass formation and L-histidine production, yielded 100 improved strain variants, accumulating 10-80 % more L-histidine in comparison to the starting variant. Comparative analyses of their genomes and reconstruction of point mutations/introduction of gene deletions allowed for the identification of six novel targets with a positive impact on L histidine accumulation in cultures of C. glutamicum. In this context, combination of four genome modifications resulted in an improved L histidine production strain, which was characterized by a doubled product titer (29 mM) and a doubled product yield (0.13 mol L histidine mol D glucose 1) in lab-scale batch-mode bioreactor fermentations. This approach holds the promise to identify novel genomic targets in already highly engineered production strains in a more systematic manner within a very limited time-frame, and might help to push the performance of industrial bioprocesses quickly towards maximum yields.Die ständig wachsende Weltbevölkerung und ihr Konsumverhalten, das zu einem großen Teil auf fossilen Ressourcen basiert, verursachen Umweltschäden und treiben die Produktion von Treibhausgasen als Hauptverursacher der Klimaveränderung an. Diese Entwicklung erfordert die Implementierung ressourcenschonender und umweltfreundlicher Produktionsverfahren im industriellen Maßstab. Daher müssen auch die (meist) zuckerbasierten Bioprozesse der industriellen Biotechnologie und ihre mikrobiellen Katalysatoren ständig verbessert werden, um ressourceneffizienter zu werden. Tatsächlich arbeiten die meisten der heute verwendeten mikrobiellen Produktionsstämme hinsichtlich der Produktausbeute unterhalb des theoretischen Maximums. Die Steigerung der Produktionsleistung bereits hochentwickelter industrieller Produktionsstämme stellt jedoch eine Herausforderung dar, da neue genomische Ziele für das rationale Engineering schwer zu identifizieren sind. Mit der Verfügbarkeit biosensorbasierter FACS-Screening-Technologien gewinnen die klassischen Stammentwicklungsverfahren mit Zufallsmutagenese und Screening auf einen verbesserten Produktionsphänotyp wieder an Bedeutung. In dieser Dissertation wurden Zufallsmutagenesen und biosensorbasierte FACS-Screenings in Kombination mit vergleichenden Genomanalysen und genomischen Rekonstruktionen eingesetzt, um leistungssteigernde Modifikationen im Genom eines industriellen Corynebacterium glutamicum Stammes für die Produktion der Aminosäure L Histidin zu identifizieren. Der Ausgangsstamm war bereits stark genetisch modifiziert, sodass die Identifizierung neuer Modifikationen eine Herausforderung darstellte, weil diese nicht rational mit dem L Histidin-Biosyntheseweg zusammenhängen müssen. Aus diesem Grunde wurden 100 unabhängige, jeweils FACS-isolierte, verbesserte Stammvarianten einer vergleichenden Genomanalyse unterzogen, um nach einer Häufung von Mutationen in einzelnen Genen, bestimmten Stoffwechselwegen oder Modulen des mikrobiellen Stoffwechsels zu suchen, die letztendlich für die beobachtete Steigerung der L Histidin-Produktion verantwortlich sind. Zur unabhängigen Isolierung der 100 Stammvarianten wurden über 600 chemische Mutagenesen und über 200 FACS-Screenings durchgeführt, durch welche über 50.000 Varianten mit erhöhter Fluoreszenz isoliert werden konnten. Im Rahmen einer detaillierten Charakterisierung von über 4.500 Varianten hinsichtlich ihrer Biomasse- und Produktbildung, wurden 100 Varianten mit 10-80 % gesteigerter L Histidin-Produktion identifiziert. Mithilfe vergleichender Genomanalysen und genetischer Rekonstruktionen wurden sechs bisher unbekannte genomische Modifikationen mit positivem Einfluss auf die L Histidin-Produktion entdeckt. Durch Kombination der Modifikationen wurde ein L Histidin-Produktionsstamm generiert, welcher sich in einem Batch-Fermentationsprozess im Labormaßstab durch einen verdoppelten Produkttiter (29 mM L Histidin) und eine verdoppelte Produktausbeute (0,13 mol L Histidine mol D Glukose 1) auszeichnete. Mit diesem neuen Ansatz können neuartige genetische Modifikationen in bereits hochentwickelten Produktionsstämmen systematischer und im Hochdurchsatzverfahren identifiziert werden. Dies birgt ein hohes Potenzial, um die Entwicklung industrieller Bioprozesse schnell in Richtung einer maximalen Ausbeute voranzutreiben. | |||||||
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| Rechtliche Vermerke: | Ich versichere an Eides Statt, dass die Dissertation von mir selbständig und ohne unzulässige fremde Hilfe unter Beachtung der „Grundsätze zur Sicherung guter wissenschaftlicher Praxis an der Heinrich-Heine-Universität Düsseldorf“ erstellt worden ist. Die Dissertation wurde in der vorgelegten oder ähnlichen Form noch bei keiner anderen Institution eingereicht. Ich habe bisher keine erfolglosen Promotionsversuche unternommen.
Jülich, den 30.03.2023 Philipp Tobias Baumann | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Bezug: | The laboratory work conducted for this thesis in hand has been performed at the Institute of Bio- and Geosciences, IBG-1: Biotechnology, Forschungszentrum Jülich GmbH, from April 2018 until March 2022 under the supervision of Prof. Dr. Michael Bott and Prof. Dr. Jan Marienhagen. | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät | |||||||
| Dokument erstellt am: | 17.11.2023 | |||||||
| Dateien geändert am: | 17.11.2023 | |||||||
| Promotionsantrag am: | 20.04.2023 | |||||||
| Datum der Promotion: | 10.10.2023 |
