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Monooxygenase Diversity and Oxygen Activation Within Polyketide Antibiotic Biosynthesis

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Monooxygenase Diversity and Oxygen Activation Within Polyketide Antibiotic Biosynthesis MONOOXYGENASE DIVERSITY AND OXYGEN ACTIVATION WITHIN POLYKETIDE ANTIBIOTIC BIOSYNTHESIS Thadée Remy Pierre Grocholski TURUN YLIOPISTON JULKAISUJA – ANNALES UNIVERSITATIS TURKUENSIS Sarja - ser. AI osa - tom. 535 | Astronomica - Chemica - Physica - Mathematica | Turku 2016 University of Turku Faculty of Mathematics and Natural Sciences Department of Biochemistry Biochemistry Doctoral Programme in Molecular Life Sciences Supervised by Docent Mikko Metsä-Ketelä, Ph.D. Docent Jarmo Niemi, Ph.D. Department of Biochemistry Department of Biochemistry University of Turku University of Turku Reviewed by Nina Hakulinen, Ph.D. (Academy Research Fellow) Robert Schnell, Ph.D. (senior researcher) Department of Chemistry Department of Medical Biochemistry University of Eastern Finland and Biophysics Joensuu, Finland Karolinska Institutet, MBB, Stockholm, Sweden Opponent Professor Timothy Bugg, Ph.D. Department of Chemistry University of Warwick Coventry, UK The originality of this thesis has been checked in accordance with the University of Turku quality assurance system using the Turnitin OriginalityCheck service. ISBN 978-951-29-6421-5 (PRINT) ISBN 978-951-29-6422-2 (PDF) ISSN 0082-7002 (Print) ISSN 2343-3175 (Online) Painosalama Oy - Turku, Finland 2016 Contents 3 CONTENTS LIST OF ORIGINAL PUBLICATIONS ........................................................................................... 4 ABSTRACT .............................................................................................................................. 5 TIIVISTELMÄ ........................................................................................................................... 6 ABBREVIATIONS ..................................................................................................................... 7 1. INTRODUCTION ................................................................................................................. 8 1.1. Dioxygen and Oxygen Activation ..................................................................................... 8 1.1.1. Origins of Dioxygen in the Atmosphere ........................................................................ 8 1.1.2. Photoprotective Role of Dioxygen to Surface‐Dwelling Life ......................................... 8 1.1.3. Dioxygen within Biological Reactions ............................................................................ 9 1.1.4. Spin Barrier ................................................................................................................... 9 1.1.5. Oxygen Activation ....................................................................................................... 10 1.2. Oxygenases ................................................................................................................... 11 1.2.1. Heme‐Dependent Monooxygenases ........................................................................... 12 1.2.2. Cytochrome P450 Monooxygenases ........................................................................... 13 1.2.3. Non‐Heme Iron‐Dependent Monooxygenases ........................................................... 15 1.2.5. Copper‐Dependent Monooxygenase .......................................................................... 20 1.2.6. Type 2 Copper Monooxygenases ................................................................................ 20 1.2.7. Type 3 Copper Oxygenases ......................................................................................... 23 1.2.8. Substrate Activation of Oxygen in Metal‐Dependent Oxygenases ............................. 25 1.2.9. Flavoenzymes and Flavin‐Dependent Monooxygenases ............................................ 27 1.2.10. Pterin‐Dependent Monooxygenases .......................................................................... 29 1.2.11. Cofactor‐Independent Monooxygenases .................................................................... 31 2. AIMS OF THIS STUDY ....................................................................................................... 34 3. MATERIALS AND METHODS ............................................................................................. 35 4. RESULTS AND DISCUSSION .............................................................................................. 37 4.1. Introduction – Oxygenases within Polyketide Biosynthesis .......................................... 37 4.2. Cofactor‐Independent Monooxygenases (papers I and II) ............................................ 37 4.2.1. Results from the SnoaB Studies .................................................................................. 39 4.2.2. Investigations into the Mechanism of SnoaB .............................................................. 39 4.3. Two‐Component Flavin‐Dependent Monooxygenases (paper III) ................................ 41 4.3.1. Discovery of the Functions of AlnT and AlnH .............................................................. 42 4.3.2. Mechanism of the Two‐Component Monooxygenases .............................................. 43 4.4. Atypical SAM Dependent Monooxygenase (paper IV) .................................................. 45 4.4.1. S‐Adenosyl‐L‐Methionine (SAM) as a Cosubstrate ...................................................... 45 4.4.2. Comparison of Methyltransferase Homologs Involved in Aromatic Polyketide Biosynthesis ................................................................................................................ 46 4.4.3. Engineering a Methyltransferase into a Hydroxylase ................................................. 46 4.4.4. The Divergence of RdmB and DnrK Reaction Mechanisms ......................................... 48 5. CONCLUDING REMARKS .................................................................................................. 50 6. ACKNOWLEDGEMENTS .................................................................................................... 52 REFERENCES ......................................................................................................................... 53 REPRINTS OF ORIGINAL PUBLICATIONS ................................................................................ 61 4 List of Original Publications LIST OF ORIGINAL PUBLICATIONS This thesis is based on the following original publications, referred to as roman numerals I‐IV in the text. I Koskiniemi, H. *, Grocholski, T. *, Schneider, G. & Niemi, J. (2009) Expression, purification and crystallization of the cofactor‐independent monooxygenase SnoaB from the nogalamycin biosynthetic pathway. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun., 65(Pt 3), 256‐9. *Equal contribution. II Grocholski, T.*, Koskiniemi, H. *, Lindqvist, Y., Mäntsälä, P., Niemi, J. & Schneider, G. (2010) Crystal structure of the cofactor‐independent monooxygenase SnoaB from Streptomyces nogalater: implications for the reaction mechanism. Biochemistry., 49(5), 934‐44. *Equal contribution. III Grocholski, T.*, Oja, T.*, Humphrey, L., Mäntsälä, P., Niemi, J. & Metsä‐Ketelä, M. (2012) Characterization of the two‐component monooxygenase system AlnT/AlnH reveals early timing of quinone formation in alnumycin biosynthesis. J Bacteriol., 194(11), 2829‐ 36.*Equal contribution. IV Grocholski, T., Dinis, P., Niiranen, L., Niemi, J. & Metsä‐Ketelä M (2015) Divergent evolution of an atypical S‐adenosyl‐l‐methionine‐dependent monooxygenase involved in anthracycline biosynthesis. Proc. Natl. Acad. Sci. USA., 112(32), 9866‐71. The original article I was reprinted with the permission from © International Union of Crystallography, article II was reprinted with the permission from © the American Chemical Society, article III was reprinted with the permission from © the American Society for Microbiology and article IV with the permission from the Copyright (2015) National Academy of Sciences, USA. Abstract 5 ABSTRACT Molecular oxygen (O2) is a key component in cellular respiration and aerobic life. Through the redox potential of O2, the amount of free energy available to organisms that utilize it is greatly increased. Yet, due to the nature of the O2 electron configuration, it is non‐reactive to most organic molecules in the ground state. For O2 to react with most organic compounds it must be activated. By activating O2, oxygenases can catalyze reactions involving oxygen incorporation into organic compounds. The oxygen activation mechanisms employed by many oxygenases to have been studied, and they often include transition metals and selected organic compounds. Despite the diversity of mechanisms for O2 activation explored in this thesis, all of the monooxygenases studied in the experimental part activate O2 through a transient carbanion intermediate. One of these enzymes is the small cofactorless monooxygenase SnoaB. Cofactorless monooxygenases are unusual oxygenases that require neither transition metals nor cofactors to activate oxygen. Based on our biochemical characterization and the crystal structure of this enzyme, the mechanism most likely employed by SnoaB relies on a carbanion intermediate to activate oxygen, which is consistent with the proposed substrate‐assisted mechanism for this family of enzymes. From the studies conducted on the two‐component system AlnT and AlnH, both the functions of the NADH‐dependent flavin reductase, AlnH, and the reduced flavin dependent monooxygenase, AlnT, were confirmed. The unusual regiochemistry proposed for AlnT was also confirmed on the basis of the structure of a reaction product. The mechanism
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