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1. Characterization of DNA Binding Sites of RokB, a ROK-Family Regulator from Streptomyces coelicolor Reveals the RokB Regulon.

Author

Paulina Bekiesch, Karl Forchhammer, and Alexander Kristian Apel

Subjects
Medicine, Science
Abstract

ROK-family proteins have been described to act either as sugar kinases or as transcriptional regulators. Few ROK-family regulators have been characterized so far and most of them are involved in carbon catabolite repression. RokB (Sco6115) has originally been identified in a DNA-affinity capturing approach as a possible regulator of the heterologously expressed novobiocin biosynthetic gene cluster in Streptomyces coelicolor M512. Interestingly, both, the rokB deletion mutants as well as its overexpressing mutants showed significantly reduced novobiocin production in the host strain S.coelicolor M512. We identified the DNA-binding site for RokB in the promoter region of the novobiocin biosynthetic genes novH-novW. It overlaps with the novH start codon which may explain the reduction of novobiocin production caused by overexpression of rokB. Bioinformatic screening coupled with surface plasmon resonance based interaction studies resulted in the discovery of five RokB binding sites within the genome of S. coelicolor. Using the genomic binding sites, a consensus motif for RokB was calculated, which differs slightly from previously determined binding motifs for ROK-family regulators. The annotations of the possible members of the so defined RokB regulon gave hints that RokB might be involved in amino acid metabolism and transport. This hypothesis was supported by feeding experiments with casamino acids and L-tyrosine, which could also explain the reduced novobiocin production in the deletion mutants.

Published
2016
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2. The Draft Whole-Genome Sequence of the Antibiotic Producer Empedobacter haloabium ATCC 31962 Provides Indications for Its Taxonomic Reclassification

Author

Stefan Czemmel, Sven Nahnsen, Tilmann Weber, Henrike Miess, Patricia Arlt, Kay Nieselt, Alexander Kristian Apel, Harald Gross, and Friederike Hanssen

Subjects
Whole genome sequencing, Strain atcc, Genetics, 0303 health sciences, medicine.drug_class, Genome Sequences, Antibiotics, Lipopeptide, Empedobacter, Biology, Empedopeptin, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Immunology and Microbiology (miscellaneous), chemistry, medicine, Molecular Biology, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Strain ATCC 31962 was formerly taxonomically classified as Empedobacter haloabium and reported to be the producer of the lipopeptide antibiotic empedopeptin. Here, we report the draft genome sequence of ATCC 31962, which encodes regions that suggest a distinct biosynthetic capacity and suggests its taxonomic reclassification.

Published
2019

3. Challenges in the Heterologous Production of Antibiotics inStreptomyces

Author

Paulina Bekiesch, Alexander Kristian Apel, and Patrick Basitta

Subjects
0301 basic medicine, Expression vector, biology, Pharmaceutical Science, Heterologous, Computational biology, Secondary metabolite, biology.organism_classification, Streptomyces, Genome, Microbiology, 03 medical and health sciences, 030104 developmental biology, Drug Discovery, medicine, Heterologous expression, Secondary metabolism, Gene, medicine.drug
Abstract

The fast growing genome databases provide us with a large number of so far unknown secondary metabolite biosynthetic gene clusters. A key method to study these gene clusters is their heterologous expression in an engineered host strain. Gene clusters derived from actinomycetes are usually expressed in a Streptomyces host strain to identify and investigate the corresponding compounds. However, heterologous expression is often accompanied with some challenges affecting the production rates of secondary metabolites. The first step is therefore the selection of a suitable expression vector and host strain. Once production has been established, there are several possibilities to improve compound yields either by media screens, by overexpression of regulatory or transport genes or by introduction of constitutive or inducible promoters. A surely important, but hitherto little studied factor is also the regulation of a heterologously expressed gene cluster by its host strain. This review gives a short overview on the chances and challenges provided by heterologous production of secondary metabolites in Streptomyces.

Published
2016

4. Minimum Information about a Biosynthetic Gene cluster

Author

Patrick Caffrey, Renzo Kottmann, Eriko Takano, Sean Doyle, Axel A. Brakhage, Matthew Cummings, Juan Pablo Gomez-Escribano, Yvonne Mast, Ryan F. Seipke, Rob Lavigne, Markus Nett, Hans-Wilhelm Nützmann, Jan Claesen, David H. Sherman, Daniel Petras, Pablo Cruz-Morales, Carl J. Balibar, Anne Osbourn, Oscar P. Kuipers, Leonilde M. Moreira, Xinyu Liu, Marcia S. Osburne, Bohdan Ostash, David P. Fewer, Changsheng Zhang, Pelin Yilmaz, Mohamed S. Donia, Anja Greule, Hyun Uk Kim, Nicholas J. Tobias, Frank Oliver Glöckner, Christoph Geiger, Chia Y. Lee, William H. Gerwick, Philipp Wiemann, Bertolt Gust, Susan E. Jensen, Wilfred A. van der Donk, Jan Kormanec, Ben Shen, Christopher M. Thomas, Jason Micklefield, Srikanth Duddela, R. Cameron Coates, René De Mot, Anthony S. Haines, Neha Garg, Guohui Pan, Roderich D. Süssmuth, Hyung Jin Kwon, Jonathan D. Walton, Lena Gerwick, Jörn Piel, Monika Ehling-Schulz, Zhenhua Tian, Jonathan L. Klassen, Xiaohui Yan, Emily A. Monroe, Yunchang Xie, Russell J. Cox, Keishi Ishida, Grace Yim, Stefano Donadio, Nadine Ziemert, Yuta Tsunematsu, Matthew L. Hillwig, Miroslav Petricek, Sylvie Lautru, Tilmann Weber, Andrew W. Truman, Rainer Breitling, Peter Kötter, Nikos C. Kyrpides, Stephanie Düsterhus, Christian Hertweck, Hideaki Oikawa, Sean F. Brady, Christopher T. Walsh, Adam C. Jones, Marcus A. Moore, Bradley S. Moore, Barrie Wilkinson, Simone M. Mantovani, Nathan A. Moss, Elizabeth E. Wyckoff, Emily P. Balskus, Kapil Tahlan, Fengan Yu, Monica Höfte, Jos M. Raaijmakers, Taifo Mahmud, Yit-Heng Chooi, Yi Tang, Andreas Bechthold, Douglas A. Mitchell, Joanne M. Willey, Helge B. Bode, John B. Biggins, Margherita Sosio, Yi-Qiang Cheng, Carmen Méndez, Leonard Kaysser, Joleen Masschelein, Daniel Krug, Federico Rosconi, Marnix H. Medema, Kaarina Sivonen, Tomohisa Kuzuyama, Mikko Metsä-Ketelä, Esther K. Schmitt, Carsten Kegler, Andriy Luzhetskyy, Gilles P. van Wezel, Bai Linquan, Kai Blin, Jens Nielsen, Bertrand Aigle, Amrita Pati, Harald Gross, Muriel Viaud, Pieter C. Dorrestein, Carla S. Jones, Michael A. Fischbach, Shelley M. Payne, Zhe Rui, Gerard D. Wright, Wen Liu, Alexey V. Melnik, Barry Scott, Brett A. Neilan, Nancy P. Keller, Rainer Borriss, Katrin Jungmann, Michalis Hadjithomas, Evi Stegmann, Daniel J. Edwards, F. Jerry Reen, Alexander Kristian Apel, Wolfgang Wohlleben, Michael J. Smanski, Leonard Katz, Fergal O'Gara, Eric J. N. Helfrich, Sergey B. Zotchev, Olivier Ploux, Arnold J. M. Driessen, Rolf Müller, Jean-Luc Pernodet, K. D. Entian, José A. Salas, Irene de Bruijn, Francisco Barona-Gómez, Jianhua Ju, Jon Clardy, Molecular Microbiology, Molecular Genetics, Jacobs University [Bremen], Microbial genomics and bioinformatics research group, Max Planck Institute for Marine Microbiology, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Max-Planck-Gesellschaft, Atmospheric Chemistry Observations and Modeling Laboratory (ACOML), National Center for Atmospheric Research [Boulder] (NCAR), Department of Food and Environmental Sciences, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Collaborative Mass Spectrometry Innovation Center, University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), Heilongjiang Institute of Science and Technology, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Merck Stiftungsprofessur fûr Molekulare Biotechnologie Fachbereich Biowissenscharten, Goethe-University Frankfurt am Main, Department of Opto-Mechatronics Engineering and Cogno-Mechatronics Engineering, Pusan National University, University of Liverpool, College of Computer Science and Technology [Zhejiang] (Zhejiang University), University of Florida [Gainesville] (UF), School of Management, University of Science and Technology of China [Hefei] (USTC), State Key Laboratory of Nuclear Physics and Technology (SKL-NPT), Peking University [Beijing], Massachusetts Institute of Technology (MIT), Memorial Sloane Kettering Cancer Center [New York], South China Sea Institute of Oceanology, Chinese Academy of Sciences [Beijing] (CAS), Dynamique des Génomes et Adaptation Microbienne (DynAMic), Institut National de la Recherche Agronomique (INRA)-Université de Lorraine (UL), Institut für Biologie [Berlin] (IFB), Humboldt University Of Berlin, School of Biomolecular and Biomedical Science and Centre for Synthesis and Chemical Biology, University College Dublin [Dublin] (UCD), Parallélisme, Réseaux, Systèmes, Modélisation (PRISM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Centre National de la Recherche Scientifique (CNRS), Skaggs School of Pharmacy and Pharmaceutical Sciences [San Diego], Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pixyl Medical [Grenoble], Integrated Optical MicroSystems (IOMS), University of Twente-MESA+ Institute for Nanotechnology, 7Lehrstuhl für Mikrobielle Ökologie, Department für Grundlagen der Biowissenschaften, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Service Néphrologie Pédiatrique, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Advanced Resources and Risk Technology, Laboratory of Phytopathology (K.C., H.S., B.A., M.H.), Universiteit Gent = Ghent University (UGENT), Trifork Aarhus C, Aalborg University [Denmark] (AAU), Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, Groupe d'Etude de la Matière Condensée (GEMAC), Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen [Groningen], DOE Joint Genome Institute [Walnut Creek], Microbiologie Moléculaire des Actinomycètes (ACTINO), Département Microbiologie (Dpt Microbio), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et microbiologie [Orsay] (IGM), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Gene Technology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Joint Center for Structural Genomics (JCSG), Stanford University, Centre européen de recherche et d'enseignement des géosciences de l'environnement (CEREGE), Institut de Recherche pour le Développement (IRD)-Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches et d'Applications Pédagogiques en Langues (CRAPEL), Université Nancy 2, Space Sciences Laboratory [Berkeley] (SSL), University of California [Berkeley] (UC Berkeley), Polytechnic Institute of Leiria, NMR Laboratory, Université de Mons, Université de Mons (UMons), School of Biomedical Science, Curtin University [Perth], Planning and Transport Research Centre (PATREC)-Planning and Transport Research Centre (PATREC), BIOMERIT Research Centre, School of Microbiology, University College Cork (UCC), Department of Engineering Science, University of Oxford, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire Charles Friedel, Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Phytopathology, Wageningen University and Research [Wageningen] (WUR), Department of Microbial Ecology, Netherlands Institute of Ecology, Department of Animal Production, Universidad de Córdoba = University of Córdoba [Córdoba], IMV Technologies, Gulliver (UMR 7083), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Institut für Chemie, Technical University of Berlin / Technische Universität Berlin (TU), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre de Recherche Paul Pascal (CRPP), Université de Bordeaux (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), DEPARTMENT OF CHEMISTRY, Durham University, Molekulare Ökologie, Joint Attosecond Science Laboratory, University of Ottawa and National Research Council, Department of Mechanical and Aerospace Engineering [Univ California Davis] (MAE - UC Davis), University of California [Davis] (UC Davis), University of Helsinki, University of California-University of California, Université de Lorraine (UL)-Institut National de la Recherche Agronomique (INRA), Humboldt-Universität zu Berlin, University of Twente [Netherlands]-MESA+ Institute for Nanotechnology, Technische Universität München [München] (TUM), Universiteit Gent = Ghent University [Belgium] (UGENT), Department of Biosystems, KU Leuven, Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Collège de France (CdF (institution))-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), University of California [Berkeley], NMR and Molecular Imaging Laboratory [Mons], University of Mons [Belgium] (UMONS), University of Oxford [Oxford], Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC), Universidad de Córdoba [Cordoba], Technische Universität Berlin (TU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Department of Mechanical and Aerospace Engineering [Davis], Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), University of Florida [Gainesville], Institut für Biologie, Humboldt Universität zu Berlin, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Ghent University [Belgium] (UGENT), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Stanford University [Stanford], Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Collège de France (CdF)-Institut national des sciences de l'Univers (INSU - CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), NMR and Molecular Imaging Laboratory, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS), Wageningen University and Research Centre [Wageningen] (WUR), Gulliver, ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS), Technische Universität Berlin (TUB), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Max Planck Society (GERMANY), Max Planck Society (GERMANY)-Max Planck Society (GERMANY), Laboratoire Leprince-Ringuet ( LLR ), Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -École polytechnique ( X ) -Centre National de la Recherche Scientifique ( CNRS ), Atmospheric Chemistry Observations and Modeling Laboratory ( ACOML ), National Center for Atmospheric Research [Boulder] ( NCAR ), University of California [San Diego] ( UC San Diego ), Eidgenössische Technische Hochschule [Zürich] ( ETH Zürich ), University of Science and Technology of China [Hefei] ( USTC ), State Key Laboratory of Nuclear Physics and Technology ( SKL-NPT ), Massachusetts Institute of Technology ( MIT ), Memorial Sloan Kettering Cancer Center ( MSKCC ), Shanghai Ocean University, Dynamique des Génomes et Adaptation Microbienne ( DynAMic ), Institut National de la Recherche Agronomique ( INRA ) -Université de Lorraine ( UL ), University College Dublin [Dublin] ( UCD ), Parallélisme, Réseaux, Systèmes, Modélisation ( PRISM ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Centre National de la Recherche Scientifique ( CNRS ), Grenoble Institut des Neurosciences ( GIN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Grenoble-Université Joseph Fourier - Grenoble 1 ( UJF ), Integrated Optical MicroSystems ( IOMS ), Technische Universität München [München] ( TUM ), Ghent University [Belgium] ( UGENT ), Aalborg University [Denmark] ( AAU ), Centers for Disease Control and Prevention [Atlanta] ( CDC ), Groupe d'Etude de la Matière Condensée ( GEMAC ), Groningen Biomolecular Sciences and Biotechnology Institute ( GBB ), Microbiologie Moléculaire des Actinomycètes ( ACTINO ), Département Microbiologie ( Dpt Microbio ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Institut de génétique et microbiologie [Orsay] ( IGM ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), Joint Center for Structural Genomics ( JCSG ), Centre européen de recherche et d'enseignement de géosciences de l'environnement ( CEREGE ), Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Collège de France ( CdF ) -Institut National de la Recherche Agronomique ( INRA ) -Institut national des sciences de l'Univers ( INSU - CNRS ), Centre de Recherches et d'Applications Pédagogiques en Langues ( CRAPEL ), Space Sciences Laboratory [Berkeley] ( SSL ), Université de Mons ( UMons ), Planning and Transport Research Centre ( PATREC ) -Planning and Transport Research Centre ( PATREC ), University College Cork ( UCC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ), Wageningen University and Research Centre [Wageningen] ( WUR ), ESPCI ParisTech, Technische Universität Berlin ( TUB ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre de recherche Paul Pascal, CNRS, Université de Bordeaux ( UPR8641 ), Centre de Recherche Paul Pascal, CNRS, Université de Bordeaux, University Durham, University of California [Davis] ( UC Davis ), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), [GIN] Grenoble Institut des Neurosciences (GIN), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), and Saarland University, Building A4.1, 66123 Saarbruecken, Germany.

Subjects
MESH : Protein Biosynthesis, protein synthesis, Operon, MESH : Polysaccharides, International Cooperation, MESH: Plants, plant, Review, MESH: Terpenes, gene cluster, polyketide, data base, genetic database, Gene cluster, acyltransferase, Databases, Genetic, MESH : Metagenome, MESH : Genetic Markers, genetics, terpene, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), ComputingMilieux_MISCELLANEOUS, MESH : Peptides, MESH: Peptides, biology, fungus, nonribosomal peptide synthesis, Plants, bacterium, peptide, priority journal, MESH: Protein Biosynthesis, Multigene Family, MESH : Terpenes, MESH: Computational Biology, Genetic Markers, MESH: Terminology as Topic, Bioinformatics, MESH : Multigene Family, biological activity, Article, metagenome, Alkaloids, Manchester Institute of Biotechnology, Terminology as Topic, Bioinformatica, MESH : Bacteria, Peptide Biosynthesis, MESH : Databases, Genetic, Molecular Biology, MESH : Fungi, MESH: Polyketides, standardization, secondary metabolism, [ SDV ] Life Sciences [q-bio], Bacteria, ta1182, Computational Biology, MESH : Terminology as Topic, operon, Laboratorium voor Phytopathologie, MESH: International Cooperation, gene function, Metagenomics, polysaccharide, Laboratory of Phytopathology, chemical structure, Metagenome, MESH: Multigene Family, EPS, biosynthesis, Peptides, MESH : Computational Biology, MESH : International Cooperation, [SDV]Life Sciences [q-bio], MESH: Genetic Markers, information, MESH : Alkaloids, Synthetic biology, MESH: Peptide Biosynthesis, Nucleic Acid-Independent, database, MESH: Databases, Genetic, Genetics, MESH : Polyketides, MESH : Peptide Biosynthesis, Nucleic Acid-Independent, ddc:540, standards, Peptide Biosynthesis, Nucleic Acid-Independent, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, nomenclature, genetic marker, alkaloid derivative, MESH: Fungi, Biology, MESH : Plants, peptide derivative, Polyketide, MESH: Alkaloids, Polysaccharides, ddc:570, Life Science, 14. Life underwater, Secondary metabolism, enzyme specificity, Gene, nonhuman, Terpenes, Fungi, nucleotide sequence, Cell Biology, MESH: Metagenome, ResearchInstitutes_Networks_Beacons/manchester_institute_of_biotechnology, alkaloid, MESH: Bacteria, MESH: Polysaccharides, 13. Climate action, Polyketides, Protein Biosynthesis, synthetic biology, metabolism
Abstract

M.H.M. was supported by a Rubicon fellowship of the Netherlands Organization for Scientific Research (NWO;Rubicon 825.13.001). The work of R.K. was supported by the European Union’s Seventh Framework Programme(Joint Call OCEAN.2011–2: Marine microbial diversity—new insights into marine ecosystems functioning and its biotechnological potential) under the grant agreement no.287589 (Micro B3). M.C. was supported by a Biotechnology and Biological Sciences Research Council (BBSRC)studentship (BB/J014478/1). The GSC is supported by funding from the Natural Environment Research Council(UK), the National Institute for Energy Ethics and Society(NIEeS; UK), the Gordon and Betty Moore Foundation,the National Science Foundation (NSF; US) and the US Department of Energy. The Manchester Synthetic Biology Research Centre, SYNBIOCHEM, is supported by BBSRC/Engineering and Physical Sciences Research Council(EPSRC) grant BB/M017702/1, Medema, M.H., Kottmann, R., Yilmaz, P., Cummings, M., Biggins, J.B., Blin, K., De Bruijn, I., Chooi, Y.H., Claesen, J., Coates, R.C., Cruz-Morales, P., Duddela, S., Düsterhus, S., Edwards, D.J., Fewer, D.P., Garg, N., Geiger, C., Gomez-Escribano, J.P., Greule, A., Hadjithomas, M., Haines, A.S., Helfrich, E.J.N., Hillwig, M.L., Ishida, K., Jones, A.C., Jones, C.S., Jungmann, K., Kegler, C., Kim, H.U., Kötter, P., Krug, D., Masschelein, J., Melnik, A.V., Mantovani, S.M., Monroe, E.A., Moore, M., Moss, N., Nützmann, H.-W., Pan, G., Pati, A., Petras, D., Reen, F.J., Rosconi, F., Rui, Z., Tian, Z., Tobias, N.J., Tsunematsu, Y., Wiemann, P., Wyckoff, E., Yan, X., Yim, G., Yu, F., Xie, Y., Aigle, B., Apel, A.K., Balibar, C.J., Balskus, E.P., Barona-Gómez, F., Bechthold, A., Bode, H.B., Borriss, R., Brady, S.F., Brakhage, A.A., Caffrey, P., Cheng, Y.Q., Clardy, J., Cox, R.J., De Mot, R., Donadio, S., Donia, M.S., Van Der Donk, W.A., Dorrestein, P.C., Doyle, S., Driessen, A.J.M., Ehling-Schulz, M., Entian, K.-D., Fischbach, M.A., Gerwick, L., Gerwick, W.H., Gross, H., Gust, B., Hertweck, C., Höfte, M., Jensen, S.E., Ju, J., Katz, L., Kaysser, L., Klassen, J.L., Keller, N.P., Kormanec, J., Kuipers, O.P., Kuzuyama, T., Kyrpides, N.C., Kwon, H.-J., Lautru, S., Lavigne, R., Lee, C.Y., Linquan, B., Liu, X., Liu, W., Luzhetskyy, A., Mahmud, T., Mast, Y., Méndez, C., Metsä-Ketelä, M., Micklefield, J., Mitchell, D.A., Moore, B.S., Moreira, L.M., Müller, R., Neilan, B.A., Nett, M., Nielsen, J., O'Gara, F., Oikawa, H., Osbourn, A., Osburne, M.S., Ostash, B., Payne, S.M., Pernodet, J.-L., Petricek, M., Piel, J., Ploux, O., Raaijmakers, J.M., Salas, J.A., Schmitt, E.K., Scott, B., Seipke, R.F., Shen, B., Sherman, D.H., Sivonen, K., Smanski, M.J., Sosio, M., Stegmann, E., Süssmuth, R.D., Tahlan, K., Thomas, C.M., Tang, Y., Truman, A.W., Viaud, M., Walton, J.D., Walsh, C.T., Weber, T., Van Wezel, G.P., Wilkinson, B., Willey, J.M., Wohlleben, W., Wright, G.D., Ziemert, N., Zhang, C., Zotchev, S.B., Breitling, R., Takano, E., Glöckner, F.O.

Published
2015

5. dRNA-seq transcriptional profiling of the FK506 biosynthetic gene cluster in Streptomyces tsukubaensis NRRL18488 and general analysis of the transcriptome

Author

Katrin Flinspach, Alexander Herbig, Sven Fillinger, Harald Gross, Kay Nieselt, Judith S. Bauer, Konrad U. Förstner, Adam C. Jones, Alexander Kristian Apel, and Cynthia M. Sharma

Subjects
DNA, Bacterial, 0301 basic medicine, Streptomyces tsukubaensis, 030106 microbiology, Biology, Tacrolimus, Transcriptome, 03 medical and health sciences, Bacterial Proteins, Transcription (biology), Operon, Gene cluster, Consensus sequence, Promoter Regions, Genetic, Molecular Biology, Gene, Gene Library, Genetics, Base Sequence, Shotgun sequencing, Gene Expression Profiling, Gene Expression Regulation, Bacterial, Sequence Analysis, DNA, Cell Biology, biology.organism_classification, Streptomyces, Gene expression profiling, 030104 developmental biology, Multigene Family, Transcription Initiation Site, 5' Untranslated Regions, Research Paper
Abstract

FK506 (tacrolimus) is a valuable immunosuppressant produced by several Streptomyces strains. In the genome of the wild type producer Streptomyces tsukubaensis NRRL184888, FK506 biosynthesis is encoded by a gene cluster that spans 83.5 kilobases. A whole transcriptome differential shotgun sequencing (dRNA-seq) of S. tsukubaensis was performed to analyze transcription at two different time points; before and during active FK506 production. In total, 8,914 transcription start sites were identified in either condition, which enabled precise determination of the 5′-UTR length of the corresponding transcripts as well as the identification of two consensus sequence motifs in the promoter regions. The transcription start sites of all gene operons within the FK506 cluster were identified, including three examples of leaderless RNA transcripts. These data provide detailed insight into the transcription of the FK506 biosynthetic gene cluster to support future regulatory studies, genetic manipulation, and industrial production.

Published
2017
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6. ChemInform Abstract: Challenges in the Heterologous Production of Antibiotics in Streptomyces

Author

Patrick Basitta, Paulina Bekiesch, and Alexander Kristian Apel

Subjects
Expression vector, biology, Chemistry, Heterologous, General Medicine, Computational biology, Secondary metabolite, biology.organism_classification, Genome, Streptomyces, Gene expression, medicine, Heterologous expression, Gene, medicine.drug
Abstract

The fast growing genome databases provide us with a large number of so far unknown secondary metabolite biosynthetic gene clusters. A key method to study these gene clusters is their heterologous expression in an engineered host strain. Gene clusters derived from actinomycetes are usually expressed in a Streptomyces host strain to identify and investigate the corresponding compounds. However, heterologous expression is often accompanied with some challenges affecting the production rates of secondary metabolites. The first step is therefore the selection of a suitable expression vector and host strain. Once production has been established, there are several possibilities to improve compound yields either by media screens, by overexpression of regulatory or transport genes or by introduction of constitutive or inducible promoters. A surely important, but hitherto little studied factor is also the regulation of a heterologously expressed gene cluster by its host strain. This review gives a short overview on the chances and challenges provided by heterologous production of secondary metabolites in Streptomyces.

Published
2016

7. DNA affinity capturing identifies new regulators of the heterologously expressed novobiocin gene cluster in Streptomyces coelicolor M512

Author

Melanie Brocker, Paulina Bekiesch, Bertolt Gust, Alexander Kristian Apel, Mirita Franz-Wachtel, Karl Forchhammer, and Andreas Kulik

Subjects
0301 basic medicine, DNA, Bacterial, 030106 microbiology, Streptomyces niveus, Sigma Factor, Streptomyces coelicolor, Applied Microbiology and Biotechnology, 03 medical and health sciences, Bacterial Proteins, Gene expression, Gene cluster, medicine, Promoter Regions, Genetic, Gene, Novobiocin, Glutathione Transferase, Genetics, biology, Promoter, General Medicine, Gene Expression Regulation, Bacterial, biology.organism_classification, Culture Media, DNA-Binding Proteins, Genes, Bacterial, Multigene Family, Heterologous expression, Gene Deletion, Biotechnology, medicine.drug, Plasmids
Abstract

Understanding the regulation of a heterologously expressed gene cluster in a host organism is crucial for activation of silent gene clusters or overproduction of the corresponding natural product. In this study, Streptomyces coelicolor M512(nov-BG1) containing the novobiocin biosynthetic gene cluster from Streptomyces niveus NCIMB 11891 was chosen as a model. An improved DNA affinity capturing assay (DACA), combined with semi-quantitative mass spectrometry, was used to identify proteins binding to the promoter regions of the novobiocin gene cluster. Altogether, 2475 proteins were identified in DACA studies with the promoter regions of the pathway-specific regulators novE (PnovE) and novG (PnovG), of the biosynthetic genes novH-W (PnovH) and of the vegetative σ-factor hrdB (PhrdB) as a negative control. A restrictive classification for specific binding reduced this number to 17 proteins. Twelve of them were captured by PnovH, among them, NovG, two were captured by PnovE, and three by PnovG. Unexpectedly some well-known regulatory proteins, such as the global regulators NdgR, AdpA, SlbR, and WhiA were captured in similar intensities by all four tested promoter regions. Of the 17 promoter-specific proteins, three were studied in more detail by deletion mutagenesis and by overexpression. Two of them, BxlRSc and BxlR2Sc, could be identified as positive regulators of novobiocin production in S. coelicolor M512. Deletion of a third gene, sco0460, resulted in reduced novobiocin production, while overexpression had no effect. Furthermore, binding of BxlRSc to PnovH and to its own promoter region was confirmed via surface plasmon resonance spectroscopy.

Published
2015

8. ChemInform Abstract: New Aminocoumarins from the Rare Actinomycete Catenulispora acidiphila DSM 44928: Identification, Structure Elucidation, and Heterologous Production

Author

Haiyang Xia, Judith Zettler, Andreas Kulik, Nadja Burkard, Stephanie Grond, Lutz Heide, and Alexander Kristian Apel

Subjects
Aminocoumarins, biology, Stereochemistry, Chemistry, Sequence analysis, Putative gene, Streptomyces coelicolor, Gene cluster, Heterologous, General Medicine, Heterologous expression, biology.organism_classification, Structural motif
Abstract

Genome mining led to the discovery of a novel aminocoumarin gene cluster in the rare actinomycete Catenulispora acidiphila DSM 44928. Sequence analysis revealed the presence of genes putatively involved in export/resistance, regulation, and biosynthesis of the aminocoumarin moiety and its halogenation, as well as several genes with so far unknown function. Two new aminocoumarins, cacibiocin A and B, were identified in the culture broth of C. acidiphila. Heterologous expression of the putative gene cluster in Streptomyces coelicolor M1152 confirmed that this cluster is responsible for cacibiocin biosynthesis. Furthermore, total production levels of cacibiocins could be increased by heterologous expression and screening of different culture media from an initial yield of 4.9 mg L(-1) in C. acidiphila to 60 mg L(-1) in S. coelicolor M1152. By HR-MS and NMR analysis, cacibiocin A was found to contain a 3-amino-4,7-dihydroxycoumarin moiety linked by an amide bond to a pyrrole-2,5-dicarboxylic acid. The latter structural motif has not been identified previously in any natural compound. Additionally, cacibiocin B contains two chlorine atoms at positions 6' and 8' of the aminocoumarin moiety.

Published
2014

9. Draft Genome Sequence of Streptomyces niveus NCIMB 11891, Producer of the Aminocoumarin Antibiotic Novobiocin

Author

Lutz Heide, Alexander Kristian Apel, Katrin Flinspach, Jörn Kalinowski, and Christian Rückert

Subjects
Whole genome sequencing, Genetics, Streptomyces niveus, Secondary metabolite, Biology, DNA gyrase, Microbiology, Putative gene, Gene cluster, medicine, Prokaryotes, Molecular Biology, Gene, Novobiocin, medicine.drug
Abstract

Streptomyces niveus NCIMB 11891 is the producer of the gyrase inhibitor novobiocin, which belongs to the aminocoumarin class of antibiotics. The genome sequence of this strain was found to contain, besides the gene cluster for novobiocin, a putative gene cluster for the macrolactam antibiotic BE-14106 and further secondary metabolite gene clusters.

Published
2014

10. Draft Genome Sequence of Streptomyces roseochromogenes subsp. oscitans DS 12.976, Producer of the Aminocoumarin Antibiotic Clorobiocin

Author

Jörn Kalinowski, Christian Rückert, Alexander Kristian Apel, and Lutz Heide

Subjects
Genetics, Whole genome sequencing, Clorobiocin, medicine.drug_class, Antibiotics, Biology, Secondary metabolite, biology.organism_classification, Streptomyces, Microbiology, Gene cluster, medicine, Prokaryotes, Molecular Biology, medicine.drug
Abstract

Streptomyces roseochromogenes subsp. oscitans DS 12.976 is the producer of the gyrase-inhibiting aminocoumarin antibiotic clorobiocin. Here, we present a draft genome sequence of this strain, in which we identified the clorobiocin gene cluster as well as an unusually high number (43) of further putative secondary metabolite clusters.

Published
2014

11. New aminocoumarins from the rare actinomycete Catenulispora acidiphila DSM 44928: identification, structure elucidation, and heterologous production

Author

Alexander Kristian Apel, Nadja Burkard, Andreas Kulik, Judith Zettler, Lutz Heide, Haiyang Xia, and Stephanie Grond

Subjects
Aminocoumarins, Sequence analysis, Molecular Conformation, Heterologous, Gram-Positive Bacteria, Biochemistry, Bacterial Proteins, Putative gene, Gene cluster, Actinomycetales, Gram-Negative Bacteria, Pyrroles, Structural motif, Molecular Biology, Biological Products, biology, Organic Chemistry, Streptomyces coelicolor, biology.organism_classification, Recombinant Proteins, Streptomyces, Anti-Bacterial Agents, Multigene Family, Molecular Medicine, Heterologous expression, Genome, Bacterial
Abstract

Genome mining led to the discovery of a novel aminocoumarin gene cluster in the rare actinomycete Catenulispora acidiphila DSM 44928. Sequence analysis revealed the presence of genes putatively involved in export/resistance, regulation, and biosynthesis of the aminocoumarin moiety and its halogenation, as well as several genes with so far unknown function. Two new aminocoumarins, cacibiocin A and B, were identified in the culture broth of C. acidiphila. Heterologous expression of the putative gene cluster in Streptomyces coelicolor M1152 confirmed that this cluster is responsible for cacibiocin biosynthesis. Furthermore, total production levels of cacibiocins could be increased by heterologous expression and screening of different culture media from an initial yield of 4.9 mg L(-1) in C. acidiphila to 60 mg L(-1) in S. coelicolor M1152. By HR-MS and NMR analysis, cacibiocin A was found to contain a 3-amino-4,7-dihydroxycoumarin moiety linked by an amide bond to a pyrrole-2,5-dicarboxylic acid. The latter structural motif has not been identified previously in any natural compound. Additionally, cacibiocin B contains two chlorine atoms at positions 6' and 8' of the aminocoumarin moiety.

Published
2013

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