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G. oxydans Metabolism and respiration of Metabolism Janine Richhardt Gesundheit Health Gluconobacter oxydans strain development: Studies on central carbon metabolism and respiration Janine Richhardt Gesundheit / Health Band / Volume 63 Member of the Helmholtz Association Member of the ISBN 978-3-89336-851-8 63 Schriften des Forschungszentrums Jülich Reihe Gesundheit / Health Band / Volume 63 Forschungszentrum Jülich GmbH Institute of Bio- and Geosciences (IBG) Biotechnology (IBG-1) Gluconobacter oxydans strain development: Studies on central carbon metabolism and respiration Janine Richhardt Schriften des Forschungszentrums Jülich Reihe Gesundheit / Health Band / Volume 63 ISSN 1866-1785 ISBN 978-3-89336-851-8 Bibliographic information published by the Deutsche Nationalbibliothek. The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available in the Internet at http://dnb.d-nb.de. Publisher and Forschungszentrum Jülich GmbH Distributor: Zentralbibliothek 52425 Jülich Phone +49 (0) 24 61 61-53 68 · Fax +49 (0) 24 61 61-61 03 e-mail: [email protected] Internet: http://www.fz-juelich.de/zb Cover Design: Grafische Medien, Forschungszentrum Jülich GmbH Printer: Grafische Medien, Forschungszentrum Jülich GmbH Copyright: Forschungszentrum Jülich 2013 Schriften des Forschungszentrums Jülich Reihe Gesundheit / Health Band / Volume 63 D 61 (Diss., Düsseldorf, Univ., 2012) ISSN 1866-1785 ISBN 978-3-89336-851-8 The complete volume is freely available on the Internet on the Jülicher Open Access Server (JUWEL) at http://www.fz-juelich.de/zb/juwel Neither this book nor any part of it may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. The thesis in hand has been performed at the Institute of Bio- and Geosciences 1: Biotechnology, Forschungszentrum Jülich GmbH, from October 2009 until November 2012 under the supervision of Prof. Dr. Michael Bott. Printed with the permission of the Faculty of Mathematics and Natural Sciences of the Heinrich-Heine-University Düsseldorf Examiner: Prof. Dr. Michael Bott Institute of Bio- and Geosciences 1: Biotechnology Forschungszentrum Jülich GmbH Coexaminer: Prof. Dr. Joachim Ernst Department Biologie Molekulare Mykologie Heinrich-Heine-University Düsseldorf Date of oral examination: 13.12.2012 Results described in this this dissertation have been published in the following original publications: Hanke T, Richhardt J, Polen T, Sahm H, Bringer S, Bott M (2012) Influence of oxygen limitation, absence of the cytochrome bc1 complex and low pH on global gene expression in Gluconobacter oxydans 621H using DNA microarray technology. Journal of Biotechnology 157:359– 372 Richhardt J, Bringer S, Bott M (2012) Mutational Analysis of the Pentose Phosphate and Entner-Doudoroff Pathway in Gluconobacter oxydans Reveals Improved Growth of an Δedd Δeda Mutant on Mannitol. Applied and Environmental Microbiology (2012) Applied and Environmental Microbiology 78: 6975 - 6986 Richhardt J, Bringer S, Bott M (2013) Role of the pentose phosphate pathway and the Entner-Doudoroff pathway in glucose metabolism of Gluconobacter oxydans 621H Δupp. Appl Microbiol Biotechnol DOI 10.1007/s00253-013-4707-2 Richhardt J*, Luchterhand, B*, Bringer S, Büchs J, Bott M (2013) Characterization of cytochrome bd- and cytochrome bo3-terminal oxidase deletion mutants of G. oxydans reveals bo3 oxidase as the rate-limiting factor of the respiratory chain To be submitted to the Journal of Bacteriology * both authors contributed equally to this work Results of further projects not discussed in this thesis: Ostermann S, Richhardt J, Bringer S, Bott M, Oldiges M (2013) Use of 13C glucose for focused pathway discrimination in G. oxydans 621H. Manuscript in preparation Table of Contents Table of contents Table of contents ................................................................................................................I Abbreviations .................................................................................................................... III 1. Abstract .........................................................................................................................1 1. Zusammenfassung ........................................................................................................2 2. Introduction ....................................................................................................................4 2.1. The genus Gluconobacter ...........................................................................................4 2.1.1 Biotechnological importance of G. oxydans........................................................6 2.2. Carbon metabolism .................................................................................................6 2.2.1 Mannitol metabolism ..........................................................................................7 2.2.2 Glucose metabolism ..........................................................................................9 2.2.3 PPP vs. EDP in the light of energetic efficiency ............................................... 12 2.3. Respiratory chain .................................................................................................. 12 2.3.1 The respiratory chain of G. oxydans................................................................. 13 2.3.2 Energy generation via the respiratory chain ..................................................... 15 2.4. Aims of this work ................................................................................................... 16 3. Results ......................................................................................................................... 18 3.1. Improved growth of G. oxydans Δedd Δeda on mannitol ........................................ 19 3.2. Glucose metabolism of G. oxydans 621H .............................................................. 46 3.3. Global gene expression in G. oxydans 621H ......................................................... 57 3.4. Terminal oxidases in G. oxydans 621H ............................................................... 119 4. Discussion ................................................................................................................. 146 4.1. Carbon metabolism of G. oxydans....................................................................... 146 4.1.1 The role of the EDP and the PPP in sugar metabolism .................................. 146 4.2. The respiratory chain of G. oxydans .................................................................... 151 4.2.1 The role of the cytochrome bc1 complex in G. oxydans .................................. 152 I Table of Contents 4.2.2 The role of the terminal oxidases in G. oxydans ............................................. 152 4.3 Conclusion ........................................................................................................... 157 4.4. Outlook ................................................................................................................ 158 5. Literature ................................................................................................................ 160 6. Appendix .................................................................................................................... 165 6.1. Supplementary data: DNA-microarray analysis of strain G. oxydans Δbo3 versus the reference strain ......................................................................................................... 165 II Abbreviations Abbreviations 2-KGA 2-ketogluconate 5-KGA 5-ketogluconate ATP Adenosine-5'-triphosphate DH Dehydrogenase DO Dissolved oxygen EDP Entner-Doudoroff pathway EMP Embden-Meyerhoff-Parnas pathway et al. et alii NADH Nicotinamide adenine dinucleotide NADPH Nicotinamide adenine dinucleotide phosphate OD600 Optical density at 600 nm PPP Pentose phosphate pathway TCA cycle Tricarboxylic acid cycle UQ Ubiquinone Further abbreviations not included in this section are according to international standards, as for example listed in the author guidelines of the FEBS Journal. III 1. Abstract/Zusammenfassung 1. Abstract Even though Gluconobacter oxydans has been used since a long time in industrial processes, knowledge on the metabolism and physiology of this organism, which is characterized by superb oxidation capabilities on the one hand and a very low cell yield on the other hand, is quite limited. To promote a rational design of new producer strains, central carbon metabolism and respiration of G. oxydans was investigated in this work by construction and characterization of defined deletion mutants. The role of the two functional sugar degradation pathways, the pentose phosphate pathway (PPP) and the Entner-Doudoroff pathway (EDP), was studied with mutants lacking the genes for 6-phosphogluconate dehydratase and 2-keto-3-deoxy-6-phosphogluconate aldolase (Δedd-eda) or the gene for 6-phosphogluconate dehydrogenase (Δgnd). During growth with mannitol, inactivation of the EDP (Δedd-eda mutant), but also overexpression of 6-phosphogluconate dehydrogenase (gnd), resulted in a 24% increase in final optical density (OD600) compared to the reference strain and in a 43% increase of the cell yield in the first growth phase. This positive effect was not observed with glucose
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