2024-03-29T10:28:36Zhttp://repository.helmholtz-hzi.de/oai/requestoai:repository.helmholtz-hzi.de:10033/3048242019-08-30T11:37:23Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Strobel, Tina
author
Schmidt, Yvonne
author
Linnenbrink, Anton
author
Luzhetskyy, Andriy N
author
Luzhetska, Marta
author
Taguchi, Takaaki
author
Brötz, Elke
author
Paululat, Thomas
author
Stasevych, Maryna
author
Stanko, Oleg
author
Novikov, Volodymyr
author
Bechthold, Andreas
department
Albert Ludwigs University of Freiburg, Department of Pharmaceutical Biology and Biotechnology, Freiburg, Germany.
2013-10-30T15:19:00Z
2013-09
Tracking down biotransformation to the genetic level: identification of a highly flexible glycosyltransferase from Saccharothrix espanaensis. 2013, 79 (17):5224-32 Appl. Environ. Microbiol.
1098-5336
23793643
10.1128/AEM.01652-13
http://hdl.handle.net/10033/304824
Applied and environmental microbiology
Saccharothrix espanaensis is a member of the order Actinomycetales. The genome of the strain has been sequenced recently, revealing 106 glycosyltransferase genes. In this paper, we report the detection of a glycosyltransferase from Saccharothrix espanaensis which is able to rhamnosylate different phenolic compounds targeting different positions of the molecules. The gene encoding the flexible glycosyltransferase is not located close to a natural product biosynthetic gene cluster. Therefore, the native function of this enzyme might be not the biosynthesis of a secondary metabolite but the glycosylation of internal and external natural products as part of a defense mechanism.
en
Archived with thanks to Applied and environmental microbiology
Tracking down biotransformation to the genetic level: identification of a highly flexible glycosyltransferase from Saccharothrix espanaensis.
Article
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https://hzi.openrepository.com/bitstream/10033/304824/1/Strobel%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/3261942019-08-30T11:30:58Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Horbal, Liliya
author
Rebets, Yuriy
author
Rabyk, Mariya
author
Makitrynskyy, Roman
author
Luzhetskyy, Andriy N
author
Fedorenko, Victor
author
Bechthold, Andreas
2014-09-17T11:36:55Z
2012
SimReg1 is a master switch for biosynthesis and export of simocyclinone D8 and its precursors. 2012, 2 (1):1 AMB Express
2191-0855
22214346
10.1186/2191-0855-2-1
http://hdl.handle.net/10033/326194
AMB Express
Analysis of the simocyclinone biosynthesis (sim) gene cluster of Streptomyces antibioticus Tü6040 led to the identification of a putative pathway specific regulatory gene simReg1. In silico analysis places the SimReg1 protein in the OmpR-PhoB subfamily of response regulators. Gene replacement of simReg1 from the S. antibioticus chromosome completely abolishes simocyclinone production indicating that SimReg1 is a key regulator of simocyclinone biosynthesis. Results of the DNA-shift assays and reporter gene expression analysis are consistent with the idea that SimReg1 activates transcription of simocyclinone biosynthesis, transporter genes, regulatory gene simReg3 and his own transcription. The presence of extracts (simocyclinone) from S. antibioticus Tü6040 × pSSimR1-1 could dissociate SimReg1 from promoter regions. A preliminary model for regulation of simocyclinone biosynthesis and export is discussed.
en
Archived with thanks to AMB Express
SimReg1 is a master switch for biosynthesis and export of simocyclinone D8 and its precursors.
Article
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https://hzi.openrepository.com/bitstream/10033/326194/1/Horbal%20et%20al_final.pdf
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oai:repository.helmholtz-hzi.de:10033/6210462019-08-30T11:33:30Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Rebets, Yuriy
author
Tokovenko, Bogdan
author
Lushchyk, Igor
author
Rückert, Christian
author
Zaburannyi, Nestor
author
Bechthold, Andreas
author
Kalinowski, Jörn
author
Luzhetskyy, Andriy N
2017-08-04T09:04:35Z
2014-10-10
BMC Genomics. 2014 Oct 10;15(1):885
http://dx.doi.org/10.1186/1471-2164-15-885
Abstract Background Kutzneria is a representative of a rarely observed genus of the family Pseudonocardiaceae. Kutzneria species were initially placed in the Streptosporangiaceae genus and later reconsidered to be an independent genus of the Pseudonocardiaceae. Kutzneria albida is one of the eight known members of the genus. This strain is a unique producer of the glycosylated polyole macrolide aculeximycin which is active against both bacteria and fungi. Kutzneria albida genome sequencing and analysis allow a deeper understanding of evolution of this genus of Pseudonocardiaceae, provide new insight in the phylogeny of the genus, as well as decipher the hidden secondary metabolic potential of these rare actinobacteria. Results To explore the biosynthetic potential of Kutzneria albida to its full extent, the complete genome was sequenced. With a size of 9,874,926 bp, coding for 8,822 genes, it stands alongside other Pseudonocardiaceae with large circular genomes. Genome analysis revealed 46 gene clusters potentially encoding secondary metabolite biosynthesis pathways. Two large genomic islands were identified, containing regions most enriched with secondary metabolism gene clusters. Large parts of this secondary metabolism “clustome” are dedicated to siderophores production. Conclusions Kutzneria albida is the first species of the genus Kutzneria with a completely sequenced genome. Genome sequencing allowed identifying the gene cluster responsible for the biosynthesis of aculeximycin, one of the largest known oligosaccharide-macrolide antibiotics. Moreover, the genome revealed 45 additional putative secondary metabolite gene clusters, suggesting a huge biosynthetic potential, which makes Kutzneria albida a very rich source of natural products. Comparison of the Kutzneria albida genome to genomes of other actinobacteria clearly shows its close relations with Pseudonocardiaceae in line with the taxonomic position of the genus.
en
Complete genome sequence of producer of the glycopeptide antibiotic Aculeximycin Kutzneria albida DSM 43870T, a representative of minor genus of Pseudonocardiaceae
Journal Article
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https://hzi.openrepository.com/bitstream/10033/621046/1/12864_2014_Article_6593.pdf
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oai:repository.helmholtz-hzi.de:10033/6207782019-08-30T11:25:43Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Zaburannyi, Nestor
author
Rabyk, Mariia
author
Ostash, Bohdan
author
Fedorenko, Victor
author
Luzhetskyy, Andriy N
2017-01-27T10:45:08Z
2014-02-05
BMC Genomics. 2014 Feb 05;15(1):97
http://dx.doi.org/10.1186/1471-2164-15-97
Abstract Background The Streptomyces albus J1074 strain is one of the most widely used chassis for the heterologous production of bioactive natural products. The fast growth and an efficient genetic system make this strain an attractive model for expressing cryptic biosynthetic pathways to aid drug discovery. Results To improve its capabilities for the heterologous expression of biosynthetic gene clusters, the complete genomic sequence of S. albus J1074 was obtained. With a size of 6,841,649 bp, coding for 5,832 genes, its genome is the smallest within the genus streptomycetes. Genome analysis revealed a strong tendency to reduce the number of genetic duplicates. The whole transcriptomes were sequenced at different time points to identify the early metabolic switch from the exponential to the stationary phase in S. albus J1074. Conclusions S. albus J1074 carries the smallest genome among the completely sequenced species of the genus Streptomyces. The detailed genome and transcriptome analysis discloses its capability to serve as a premium host for the heterologous production of natural products. Moreover, the genome revealed 22 additional putative secondary metabolite gene clusters that reinforce the strain’s potential for natural product synthesis.
en
Insights into naturally minimised Streptomyces albus J1074 genome
Journal Article
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oai:repository.helmholtz-hzi.de:10033/5826012019-08-30T11:36:05Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Wardecki, Tina
author
Brötz, Elke
author
De Ford, Christian
author
von Loewenich, Friederike D
author
Rebets, Yuriy
author
Tokovenko, Bogdan
author
Luzhetskyy, Andriy N
author
Merfort, Irmgard
department
Helmholtz Institute for Pharmaceutical Research Saarland,Saarbrücken, Saarland 66123, Germany.
2015-11-24T12:46:26Z
2015-08
Endophytic Streptomyces in the traditional medicinal plant Arnica montana L.: secondary metabolites and biological activity. 2015, 108 (2):391-402 Antonie Van Leeuwenhoek
1572-9699
26036671
10.1007/s10482-015-0492-5
http://hdl.handle.net/10033/582601
Antonie van Leeuwenhoek
Arnica montana L. is a medical plant of the Asteraceae family and grows preferably on nutrient poor soils in mountainous environments. Such surroundings are known to make plants dependent on symbiosis with other organisms. Up to now only arbuscular mycorrhizal fungi were found to act as endophytic symbiosis partners for A. montana. Here we identified five Streptomyces strains, microorganisms also known to occur as endophytes in plants and to produce a huge variety of active secondary metabolites, as inhabitants of A. montana. The secondary metabolite spectrum of these strains does not contain sesquiterpene lactones, but consists of the glutarimide antibiotics cycloheximide and actiphenol as well as the diketopiperazines cyclo-prolyl-valyl, cyclo-prolyl-isoleucyl, cyclo-prolyl-leucyl and cyclo-prolyl-phenylalanyl. Notably, genome analysis of one strain was performed and indicated a huge genome size with a high number of natural products gene clusters among which genes for cycloheximide production were detected. Only weak activity against the Gram-positive bacterium Staphylococcus aureus was revealed, but the extracts showed a marked cytotoxic activity as well as an antifungal activity against Candida parapsilosis and Fusarium verticillioides. Altogether, our results provide evidence that A. montana and its endophytic Streptomyces benefit from each other by completing their protection against competitors and pathogens and by exchanging plant growth promoting signals with nutrients.
en
Endophytic Streptomyces in the traditional medicinal plant Arnica montana L.: secondary metabolites and biological activity.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/582601/1/Wardecki%20et%20al_final.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/5834852019-08-30T11:36:05Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Lopatniuk, M
author
Ostash, B
author
Makitrynskyy, R
author
Walker, S
author
Luzhetskyy, Andriy N
author
Fedorenko, V
department
Helmholtz Institute for Pharmaceutical Research Saarland,Saarbrücken, Saarland 66123, Germany.
2015-12-09T13:27:03Z
2015-11
Testing the utility of site-specific recombinases for manipulations of genome of moenomycin producer Streptomyces ghanaensis ATCC14672. 2015, 56 (4):547-50 J. Appl. Genet.
2190-3883
25801470
10.1007/s13353-015-0283-8
http://hdl.handle.net/10033/583485
Journal of applied genetics
Streptomyces ghanaensis ATCC14672 is the producer of phosphoglycolipid antibiotics moenomycins that for almost 40 years were used worldwide as an animal feed additive. As the use of moenomycins narrows down (due to bans in the EU and some other countries), it opens the opportunity to develop much-needed antibiotics against Gram-positive human pathogens, such as cocci. It is desirable to develop ATCC14672 strains accumulating only certain members of moenomycin family which would facilitate their purification, analysis and/or chemical modification. Here we tested site-specific recombinases (SSRs) as a tool to manipulate the genome of ATCC14672 and to achieve aforementioned goals. We show that of three SSRs tested - Cre, Dre, and Flp - the first two efficiently catalyzed recombination reactions, while Flp showed no activity in ATCC14672 cells. Cre recombinase can be reused at least three times to modify ATCC14672 genome without detrimental effects, such as large-scale inversions or deletions. Properties of the generated strains and SSRs are discussed.
en
Testing the utility of site-specific recombinases for manipulations of genome of moenomycin producer Streptomyces ghanaensis ATCC14672.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/583485/1/JAG_MLO1.pdf
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oai:repository.helmholtz-hzi.de:10033/5935752019-08-30T11:36:05Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Rebets, Yuriy
author
Tokovenko, Bogdan
author
Lushchyk, Igor
author
Rückert, Christian
author
Zaburannyi, Nestor
author
Bechthold, Andreas
author
Kalinowski, Jörn
author
Luzhetskyy, Andriy N
department
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS);Saarland University, Building A4.1, 66123 Saarbruecken, Germany.
2016-01-15T15:37:09Z
2014
Complete genome sequence of producer of the glycopeptide antibiotic Aculeximycin Kutzneria albida DSM 43870T, a representative of minor genus of Pseudonocardiaceae. 2014, 15:885 BMC Genomics
1471-2164
25301375
10.1186/1471-2164-15-885
http://hdl.handle.net/10033/593575
BMC genomics
Kutzneria is a representative of a rarely observed genus of the family Pseudonocardiaceae. Kutzneria species were initially placed in the Streptosporangiaceae genus and later reconsidered to be an independent genus of the Pseudonocardiaceae. Kutzneria albida is one of the eight known members of the genus. This strain is a unique producer of the glycosylated polyole macrolide aculeximycin which is active against both bacteria and fungi. Kutzneria albida genome sequencing and analysis allow a deeper understanding of evolution of this genus of Pseudonocardiaceae, provide new insight in the phylogeny of the genus, as well as decipher the hidden secondary metabolic potential of these rare actinobacteria.
en
Complete genome sequence of producer of the glycopeptide antibiotic Aculeximycin Kutzneria albida DSM 43870T, a representative of minor genus of Pseudonocardiaceae.
Article
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oai:repository.helmholtz-hzi.de:10033/6008902019-08-30T11:36:33Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Axenov-Gibanov, Denis V
author
Voytsekhovskaya, Irina V
author
Tokovenko, Bogdan T
author
Protasov, Eugeniy S
author
Gamaiunov, Stanislav V
author
Rebets, Yuriy V
author
Luzhetskyy, Andriy N
author
Timofeyev, Maxim A
department
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarbrucken, Germany, 3 Universität des Saarlandes–Pharmazeutische Biotechnologie, Saarbrucken, Germany.
2016-03-08T13:24:21Z
2016
Actinobacteria Isolated from an Underground Lake and Moonmilk Speleothem from the Biggest Conglomeratic Karstic Cave in Siberia as Sources of Novel Biologically Active Compounds. 2016, 11 (2):e0149216 PLoS ONE
1932-6203
26901168
10.1371/journal.pone.0149216
http://hdl.handle.net/10033/600890
PloS one
Actinobacteria isolated from unstudied ecosystems are one of the most interesting and promising sources of novel biologically active compounds. Cave ecosystems are unusual and rarely studied. Here, we report the isolation and characterization of ten new actinobacteria strains isolated from an ancient underground lake and moonmilk speleothem from the biggest conglomeratic karstic cave in Siberia with a focus on the biological activity of the obtained strains and the metabolite dereplication of one active strain. Streptomyces genera isolates from moonmilk speleothem demonstrated antibacterial and antifungal activities. Some of the strains were able to inhibit the growth of pathogenic Candida albicans.
en
Actinobacteria Isolated from an Underground Lake and Moonmilk Speleothem from the Biggest Conglomeratic Karstic Cave in Siberia as Sources of Novel Biologically Active Compounds.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6184992019-08-30T11:33:05Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Horbal, L
author
Luzhetskyy, Andriy N
department
Helmholtz Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2016-08-17T14:06:58Z
2016-09
Dual control system - A novel scaffolding architecture of an inducible regulatory device for the precise regulation of gene expression. 2016, 37:11-23 Metab. Eng.
1096-7184
27040671
10.1016/j.ymben.2016.03.008
http://hdl.handle.net/10033/618499
Metabolic engineering
Here, we present a novel scaffolding architecture of an inducible regulatory device. This dual control system is completely silent in the off stage and is coupled to the regulation of gene expression at both the transcriptional and translational levels. This system also functions as an AND gate. We demonstrated the effectiveness of the cumate-riboswitch dual control system for the control of pamamycin production in Streptomyces albus. Placing the cre recombinase gene under the control of this system permitted the construction of synthetic devices with non-volatile memory that sense the signal and respond by altering DNA at the chromosomal level, thereby producing changes that are heritable. In addition, we present a library of synthetic inducible promoters based on the previously described cumate switch. With only one inducer and different promoters, we demonstrate that simultaneous modulation of the expression of several genes to different levels in various operons is possible. Because all modules of the AND gates are functional in bacteria other than Streptomyces, we anticipate that these regulatory devices can be used to control gene expression in other Actinobacteria. The features described in this study make these systems promising tools for metabolic engineering and biotechnology in Actinobacteria.
en
openAccess
Dual control system - A novel scaffolding architecture of an inducible regulatory device for the precise regulation of gene expression.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6184972019-08-30T11:31:49Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Bilyk, Oksana
author
Sekurova, Olga N
author
Zotchev, Sergey B
author
Luzhetskyy, Andriy N
department
Helmholtz Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2016-08-17T13:17:27Z
2016
Cloning and Heterologous Expression of the Grecocycline Biosynthetic Gene Cluster. 2016, 11 (7):e0158682 PLoS ONE
1932-6203
27410036
10.1371/journal.pone.0158682
http://hdl.handle.net/10033/618497
PloS one
Transformation-associated recombination (TAR) in yeast is a rapid and inexpensive method for cloning and assembly of large DNA fragments, which relies on natural homologous recombination. Two vectors, based on p15a and F-factor replicons that can be maintained in yeast, E. coli and streptomycetes have been constructed. These vectors have been successfully employed for assembly of the grecocycline biosynthetic gene cluster from Streptomyces sp. Acta 1362. Fragments of the cluster were obtained by PCR and transformed together with the "capture" vector into the yeast cells, yielding a construct carrying the entire gene cluster. The obtained construct was heterologously expressed in S. albus J1074, yielding several grecocycline congeners. Grecocyclines have unique structural moieties such as a dissacharide side chain, an additional amino sugar at the C-5 position and a thiol group. Enzymes from this pathway may be used for the derivatization of known active angucyclines in order to improve their desired biological properties.
en
openAccess
Cloning and Heterologous Expression of the Grecocycline Biosynthetic Gene Cluster.
Article
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oai:repository.helmholtz-hzi.de:10033/6206742019-08-30T11:27:46Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Horbal, Liliya
author
Ostash, Bohdan
author
Luzhetskyy, Andriy N
author
Walker, Suzanne
author
Kalinowski, Jorn
author
Fedorenko, Victor
department
Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS),Saarland Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2016-12-19T12:49:33Z
2016-09
A gene cluster for the biosynthesis of moenomycin family antibiotics in the genome of teicoplanin producer Actinoplanes teichomyceticus. 2016, 100 (17):7629-38 Appl. Microbiol. Biotechnol.
1432-0614
27344593
10.1007/s00253-016-7685-3
http://hdl.handle.net/10033/620674
Applied microbiology and biotechnology
Moenomycins are phosphoglycolipid antibiotics notable for their extreme potency, unique mode of action, and proven record of use in animal nutrition without selection for resistant microflora. There is a keen interest in manipulation of structures of moenomycins in order to better understand their structure-activity relationships and to generate improved analogs. Only two almost identical moenomycin biosynthetic gene clusters are known, limiting our knowledge of the evolution of moenomycin pathways and our ability to genetically diversify them. Here, we report a novel gene cluster (tchm) that directs production of the phosphoglycolipid teichomycin in Actinoplanes teichomyceticus. Its overall genetic architecture is significantly different from that of the moenomycin biosynthesis (moe) gene clusters of Streptomyces ghanaensis and Streptomyces clavuligerus, featuring multiple gene rearrangements and two novel structural genes. Involvement of the tchm cluster in teichomycin biosynthesis was confirmed via heterologous co-expression of amidotransferase tchmH5 and moe genes. Our work sets the background for further engineering of moenomycins and for deeper inquiries into the evolution of this fascinating biosynthetic pathway.
en
A gene cluster for the biosynthesis of moenomycin family antibiotics in the genome of teicoplanin producer Actinoplanes teichomyceticus.
Article
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oai:repository.helmholtz-hzi.de:10033/6209372019-08-30T11:34:22Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Tokovenko, Bogdan
author
Rückert, Christian
author
Kalinowski, Jörn
author
Mohammadipanah, Fatemeh
author
Wink, Joachim
author
Rosenkränzer, Birgit
author
Myronovskyi, Maksym
author
Luzhetskyy, Andriy N
department
Helmholtz Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-06-09T09:46:10Z
2017-05-18
Complete Draft Genome Sequence of the Actinobacterium Nocardiopsis sinuspersici UTMC102 (DSM 45277(T)), Which Produces Serine Protease. 2017, 5 (20) Genome Announc
28522715
10.1128/genomeA.00362-17
http://hdl.handle.net/10033/620937
Genome announcements
The genome sequence of alkalohalophilic actinobacterium Nocardiopsis sinuspersici UTMC102 is provided. N. sinuspersici UTMC102 produces a highly active serine alkaline protease, and contains at least 11 gene clusters encoding the biosynthesis of secondary metabolites. The N. sinuspersici UTMC102 genome was assembled into a single chromosomal scaffold.
en
Complete Draft Genome Sequence of the Actinobacterium Nocardiopsis sinuspersici UTMC102 (DSM 45277(T)), Which Produces Serine Protease.
Article
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oai:repository.helmholtz-hzi.de:10033/6209642019-08-30T11:33:57Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Axenov-Gribanov, Denis V
author
Tokovenko, Bogdan T
author
Rebets, Yuriy V
author
Voytsekhovskaya, Irina V
author
Shatilina, Zhanna M
author
Protasov, Eugenii S
author
Luzhetskyy, Andriy N
author
Timofeyev, Maxim A
department
Helmholtz Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-06-21T08:03:29Z
2017-04-27
Draft Genome Sequence of Streptomyces sp. Strain IB2014011-1, Isolated from Trichoptera sp. Larvae of Lake Baikal. 2017, 5 (17) Genome Announc
28450500
10.1128/genomeA.00062-17
http://hdl.handle.net/10033/620964
Genome announcements
Unique ecosystems with specific environmental conditions have been proven to be a promising source for isolation of new actinobacterial strains. Ancient Lake Baikal is one of the greatest examples of an ecosystem with high species biodiversity and endemicity caused by long-lasting isolated evolution and stable environmental conditions. Herein we report the draft genome sequence of Streptomyces sp. strain IB2014011-1, which was isolated from insect Trichoptera sp. larvae collected at the bottom of Lake Baikal.
en
Draft Genome Sequence of Streptomyces sp. Strain IB2014011-1, Isolated from Trichoptera sp. Larvae of Lake Baikal.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6209672019-08-30T11:34:22Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Koshla, Oksana
author
Lopatniuk, Maria
author
Rokytskyy, Ihor
author
Yushchuk, Oleksandr
author
Dacyuk, Yuriy
author
Fedorenko, Victor
author
Luzhetskyy, Andriy N
author
Ostash, Bohdan
department
Helmholtz Institut für phsarmazeutische Forschung Saarland (HIPS), Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-06-21T11:37:08Z
2017-05-20
Properties of Streptomyces albus J1074 mutant deficient in tRNA(Leu)UAA gene bldA. 2017 Arch. Microbiol.
1432-072X
28528473
10.1007/s00203-017-1389-7
http://hdl.handle.net/10033/620967
Archives of microbiology
Streptomyces albus J1074 is one of the most popular and convenient hosts for heterologous expression of gene clusters directing the biosynthesis of various natural metabolic products, such as antibiotics. This fuels interest in elucidation of genetic mechanisms that may limit secondary metabolism in J1074. Here, we report the generation and initial study of J1074 mutant, deficient in gene bldA for tRNA(Leu)UAA, the only tRNA capable of decoding rare leucyl TTA codon in Streptomyces. The bldA deletion in J1074 resulted in a highly conditional Bld phenotype, with depleted formation of aerial hyphae on certain solid media. In addition, bldA mutant of J1074 was unable to produce endogenous antibacterial compounds and two heterologous antibiotics, moenomycin and aranciamycin, whose biosynthesis is directed by TTA-containing genes. We have employed a new TTA codon-specific β-galactosidase reporter system to provide genetic evidence that J1074 bldA mutant is impaired in translation of TTA. In addition, we have discussed the possible reasons for differences in the phenotypes of bldA mutants described here and in previous studies, providing knowledge to study bldA-based regulation of antibiotic biosynthesis.
en
Properties of Streptomyces albus J1074 mutant deficient in tRNA(Leu)UAA gene bldA.
Article
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oai:repository.helmholtz-hzi.de:10033/6209992019-08-30T11:25:11Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Paulus, Constanze
author
Rebets, Yuriy
author
Tokovenko, Bogdan
author
Nadmid, Suvd
author
Terekhova, Larisa P
author
Myronovskyi, Maksym
author
Zotchev, Sergey B
author
Rückert, Christian
author
Braig, Simone
author
Zahler, Stefan
author
Kalinowski, Jörn
author
Luzhetskyy, Andriy N
department
Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-07-05T14:47:26Z
2017-02-10
New natural products identified by combined genomics-metabolomics profiling of marine Streptomyces sp. MP131-18. 2017, 7:42382 Sci Rep
2045-2322
28186197
10.1038/srep42382
http://hdl.handle.net/10033/620999
Scientific reports
Marine actinobacteria are drawing more and more attention as a promising source of new natural products. Here we report isolation, genome sequencing and metabolic profiling of new strain Streptomyces sp. MP131-18 isolated from marine sediment sample collected in the Trondheim Fjord, Norway. The 16S rRNA and multilocus phylogenetic analysis showed that MP131-18 belongs to the genus Streptomyces. The genome of MP131-18 isolate was sequenced, and 36 gene clusters involved in the biosynthesis of 18 different types of secondary metabolites were predicted using antiSMASH analysis. The combined genomics-metabolics profiling of the strain led to the identification of several new biologically active compounds. As a result, the family of bisindole pyrroles spiroindimicins was extended with two new members, spiroindimicins E and F. Furthermore, prediction of the biosynthetic pathway for unusual α-pyrone lagunapyrone isolated from MP131-18 resulted in foresight and identification of two new compounds of this family - lagunapyrones D and E. The diversity of identified and predicted compounds from Streptomyces sp. MP131-18 demonstrates that marine-derived actinomycetes are not only a promising source of new natural products, but also represent a valuable pool of genes for combinatorial biosynthesis of secondary metabolites.
en
New natural products identified by combined genomics-metabolomics profiling of marine Streptomyces sp. MP131-18.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/620999/1/Paulus%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6211182019-08-30T11:37:24Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Bilyk, Bohdan
author
Horbal, Liliya
author
Luzhetskyy, Andriy N
department
Helmholz-Institut für pharmazeutische Forschung , Josef-Schneider-Straße2,97080 Würzburg, Germany.
2017-09-25T12:13:33Z
2017-01-04
Chromosomal position effect influences the heterologous expression of genes and biosynthetic gene clusters in Streptomyces albus J1074. 2017, 16 (1):5 Microb. Cell Fact.
1475-2859
28052753
10.1186/s12934-016-0619-z
http://hdl.handle.net/10033/621118
Microbial cell factories
Efforts to construct the Streptomyces host strain with enhanced yields of heterologous product have focussed mostly on engineering of primary metabolism and/or the deletion of endogenous biosynthetic gene clusters. However, other factors, such as chromosome compactization, have been shown to have a significant influence on gene expression levels in bacteria and fungi. The expression of genes and biosynthetic gene clusters may vary significantly depending on their location within the chromosome. Little is known about the position effect in actinomycetes, which are important producers of various industrially relevant bioactive molecules.
en
Chromosomal position effect influences the heterologous expression of genes and biosynthetic gene clusters in Streptomyces albus J1074.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6211212019-08-30T11:27:16Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Ahmed, Yousra
author
Rebets, Yuriy
author
Tokovenko, Bogdan
author
Brötz, Elke
author
Luzhetskyy, Andriy N
department
Helmholtz-Institut für pharmazeutische Forschung Saarland,Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2017-09-26T09:34:57Z
2017-08-29
Identification of butenolide regulatory system controlling secondary metabolism in Streptomyces albus J1074. 2017, 7 (1):9784 Sci Rep
2045-2322
28852167
10.1038/s41598-017-10316-y
http://hdl.handle.net/10033/621121
Scientific reports
A large majority of genome-encrypted chemical diversity in actinobacteria remains to be discovered, which is related to the low level of secondary metabolism genes expression. Here, we report the application of a reporter-guided screening strategy to activate cryptic polycyclic tetramate macrolactam gene clusters in Streptomyces albus J1074. The analysis of the S. albus transcriptome revealed an overall low level of secondary metabolism genes transcription. Combined with transposon mutagenesis, reporter-guided screening resulted in the selection of two S. albus strains with altered secondary metabolites production. Transposon insertion in the most prominent strain, S. albus ATGSal2P2::TN14, was mapped to the XNR_3174 gene encoding an unclassified transcriptional regulator. The mutant strain was found to produce the avenolide-like compound butenolide 4. The deletion of the gene encoding a putative acyl-CoA oxidase, an orthologue of the Streptomyces avermitilis avenolide biosynthesis enzyme, in the S. albus XNR_3174 mutant caused silencing of secondary metabolism. The homologues of XNR_3174 and the butenolide biosynthesis genes were found in the genomes of multiple Streptomyces species. This result leads us to believe that the discovered regulatory elements comprise a new condition-dependent system that controls secondary metabolism in actinobacteria and can be manipulated to activate cryptic biosynthetic pathways.
en
openAccess
Identification of butenolide regulatory system controlling secondary metabolism in Streptomyces albus J1074.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/621121/1/Ahmed%20and%20Luzhetskyy.pdf
File
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URL
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oai:repository.helmholtz-hzi.de:10033/6213112019-08-30T11:26:13Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Horbal, Lilya
author
Siegl, Theresa
author
Luzhetskyy, Andriy N
department
HIPS, Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus 8.1, 66123 Saarbrücken, Germany.
2018-03-07T15:01:40Z
2018-01-11
A set of synthetic versatile genetic control elements for the efficient expression of genes in Actinobacteria. 2018, 8 (1):491 Sci Rep
2045-2322
29323285
10.1038/s41598-017-18846-1
http://hdl.handle.net/10033/621311
Scientific reports
The design and engineering of secondary metabolite gene clusters that are characterized by complicated genetic organization, require the development of collections of well-characterized genetic control elements that can be reused reliably. Although a few intrinsic terminators and RBSs are used routinely, their translation and termination efficiencies have not been systematically studied in Actinobacteria. Here, we analyzed the influence of the regions surrounding RBSs on gene expression in these bacteria. We demonstrated that inappropriate RBSs can reduce the expression efficiency of a gene to zero. We developed a genetic device - an in vivo RBS-selector - that allows selection of an optimal RBS for any gene of interest, enabling rational control of the protein expression level. In addition, a genetic tool that provides the opportunity for measurement of termination efficiency was developed. Using this tool, we found strong terminators that lead to a 17-100-fold reduction in downstream expression and are characterized by sufficient sequence diversity to reduce homologous recombination when used with other elements. For the first time, a C-terminal degradation tag was employed for the control of protein stability in Streptomyces. Finally, we describe a collection of regulatory elements that can be used to control metabolic pathways in Actinobacteria.
en
A set of synthetic versatile genetic control elements for the efficient expression of genes in Actinobacteria.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/621311/1/Horbal%20et%20al.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/6214132019-08-30T11:32:37Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Busche, Tobias
author
Tsolis, Konstantinos C
author
Koepff, Joachim
author
Rebets, Yuriy
author
Rückert, Christian
author
Hamed, Mohamed B
author
Bleidt, Arne
author
Wiechert, Wolfgang
author
Lopatniuk, Mariia
author
Yousra, Ahmed
author
Anné, Jozef
author
Karamanou, Spyridoula
author
Oldiges, Marco
author
Kalinowski, Jörn
author
Luzhetskyy, Andriy N
author
Economou, Anastassios
department
HIPS, Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus 8.1, 66123 Saarbrücken, Germany.
2018-06-27T13:27:06Z
2018-01-01
1664-302X
29915569
10.3389/fmicb.2018.01174
http://hdl.handle.net/10033/621413
Gram-positive
Attribution-NonCommercial-ShareAlike 3.0 United States
FtsH
RNAseq
Streptomyces lividans
expression levels
mRFP
multi-omics
proteases
protein secretion
Multi-Omics and Targeted Approaches to Determine the Role of Cellular Proteases in Protein Secretion.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/621413/1/Busche%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6215222019-08-30T11:29:16Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Paulus, Constanze
author
Rebets, Yuriy
author
Zapp, Josef
author
Rückert, Christian
author
Kalinowski, Jörn
author
Luzhetskyy, Andriy N
department
HIPS, Helmholtz-Institut füt Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2018-10-23T09:11:11Z
2018-01-01
1664-302X
30186270
10.3389/fmicb.2018.01959
http://hdl.handle.net/10033/621522
he environment of Lake Baikal is a well-known source of microbial diversity. The strain
Streptomyces sp. IB2014/011-12, isolated from samples collected at Lake Baikal, was
found to exhibit potent activity against Gram-positive bacteria. Here, we report isolation
and characterization of linear polyketide alpiniamide A (1) and its new derivatives
B–D (2–5). The structures of alpiniamides A–D were established and their relative
configuration was determined by combination of partial Murata’s method and ROESY
experiment. The absolute configuration of alpiniamide A was established through
Mosher’s method. The gene cluster, responsible for the biosynthesis of alpiniamides
(alp) has been identified by genome mining and gene deletion experiments. The
successful expression of the cloned alp gene cluster in a heterologous host supports
these findings. Analysis of the architecture of the alp gene cluster and the feeding of
labeled precursors elucidated the alpiniamide biosynthetic pathway. The biosynthesis
of alpiniamides is an example of a rather simple polyketide assembly line generating
unusual chemical diversity through the combination of domain/module skipping and
double bond migration events.
Attribution-NonCommercial-ShareAlike 3.0 United States
NRPS-trans-AT-polyketide synthase
Streptomyces
bioactivity
secondary metabolites
stereochemistry
New Alpiniamides From sp. IB2014/011-12 Assembled by an Unusual Hybrid Non-ribosomal Peptide Synthetase -AT Polyketide Synthase Enzyme.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/621522/1/Paulus%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6216082019-08-30T11:30:27Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Amin, Rafat
author
Franz-Wachtel, Mirita
author
Tiffert, Yvonne
author
Heberer, Martin
author
Meky, Mohamed
author
Ahmed, Yousra
author
Matthews, Arne
author
Krysenko, Sergii
author
Jakobi, Marco
author
Hinder, Markus
author
Moore, Jane
author
Okoniewski, Nicole
author
Maček, Boris
author
Wohlleben, Wolfgang
author
Bera, Agnieszka
department
HIPS, Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2018-12-06T15:38:01Z
2016-01-01
2296-889X
27556027
10.3389/fmolb.2016.00038
http://hdl.handle.net/10033/621608
Soil-dwelling Streptomyces bacteria such as S.coelicolor have to constantly adapt to the nitrogen (N) availability in their habitat. Thus, strict transcriptional and post-translational control of the N-assimilation is fundamental for survival of this species. GlnR is a global response regulator that controls transcription of the genes related to the N-assimilation in S. coelicolor and other members of the Actinomycetales. GlnR represents an atypical orphan response regulator that is not activated by the phosphorylation of the conserved aspartate residue (Asp 50). We have applied transcriptional analysis, LC-MS/MS analysis and electrophoretic mobility shift assays (EMSAs) to understand the regulation of GlnR in S. coelicolor M145. The expression of glnR and GlnR-target genes was revisited under four different N-defined conditions and a complex N-rich condition. Although, the expression of selected GlnR-target genes was strongly responsive to changing N-concentrations, the glnR expression itself was independent of the N-availability. Using LC-MS/MSanalysis we demonstrated that GlnR was post-translationally modified. The post-translational modifications of GlnR comprise phosphorylation of the serine/threonine residues and acetylation of lysine residues. In the complex N-rich medium GlnR was phosphorylated on six serine/threonine residues and acetylated on one lysine residue. Under defined N-excess conditions only two phosphorylated residues were detected whereas under defined N-limiting conditions no phosphorylation was observed. GlnR phosphorylation is thus clearly correlated with N-rich conditions. Furthermore, GlnR was acetylated on four lysine residues independently of the N-concentration in the defined media and on only one lysine residue in the complex N-rich medium. Using EMSAs we demonstrated that phosphorylation inhibited the binding of GlnR to its targets genes, whereas acetylation had little influence on the formation of GlnR-DNA complex. This study clearly demonstrated that GlnR DNA-binding affinity is modulated by post-translational modifications in response to changing N-conditions in order to elicit a proper transcriptional response to the latter.
en
Attribution-NonCommercial-ShareAlike 4.0 International
GlnR
Streptomyces coelicolor
acetylation
nitrogen assimilation
phosphorylation
post-translational modifications
regulation
Post-translational Serine/Threonine Phosphorylation and Lysine Acetylation: A Novel Regulatory Aspect of the Global Nitrogen Response Regulator GlnR in S. coelicolor M145.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/621608/1/Amin%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6216092019-11-21T11:59:00Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Rodríguez Estévez, Marta
author
Myronovskyi, Maksym
author
Gummerlich, Nils
author
Nadmid, Suvd
author
Luzhetskyy, Andriy N
department
HIPS, Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
2018-12-06T16:22:51Z
2018-11-04
1660-3397
30400361
10.3390/md16110435
http://hdl.handle.net/10033/621609
Streptomycetes represent an important reservoir of active secondary metabolites with potential applications in the pharmaceutical industry. The gene clusters responsible for their production are often cryptic under laboratory growth conditions. Characterization of these clusters is therefore essential for the discovery of new microbial pharmaceutical drugs. Here, we report the identification of the previously uncharacterized nybomycin gene cluster from the marine actinomycete
en
Attribution-NonCommercial-ShareAlike 4.0 International
heterologous expression
nybomycin biosynthesis
nybomycin gene cluster
secondary metabolites
streptomycetes
Heterologous Expression of the Nybomycin Gene Cluster from the Marine StrainStreptomyces albus subsp. NRRL B-24108.
Article
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oai:repository.helmholtz-hzi.de:10033/6216302019-08-30T11:29:13Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Hamed, Mohamed Belal
author
Vrancken, Kristof
author
Bilyk, Bohdan
author
Koepff, Joachim
author
Novakova, Renata
author
van Mellaert, Lieve
author
Oldiges, Marco
author
Luzhetskyy, Andriy N
author
Kormanec, Jan
author
Anné, Jozef
author
Karamanou, Spyridoula
author
Economou, Anastassios
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2019-01-04T13:55:21Z
2018-12-07
1664-302X
30581427
10.3389/fmicb.2018.03019
http://hdl.handle.net/10033/621630
Fluorescent proteins are a major cell biology tool to analyze protein sub-cellular topology. Here we have applied this technology to study protein secretion in the Gram-positive bacterium Streptomyces lividans TK24, a widely used host for heterologous protein secretion biotechnology. Green and monomeric red fluorescent proteins were fused behind Sec (SPSec) or Tat (SPTat) signal peptides to direct them through the respective export pathway. Significant secretion of fluorescent eGFP and mRFP was observed exclusively through the Tat and Sec pathways, respectively. Plasmid over-expression was compared to a chromosomally integrated spSec-mRFP gene to allow monitoring secretion under high and low level synthesis in various media. Fluorimetric detection of SPSec-mRFP recorded folded states, while immuno-staining detected even non-folded topological intermediates. Secretion of SPSec-mRFP is unexpectedly complex, is regulated independently of cell growth phase and is influenced by the growth regime. At low level synthesis, highly efficient secretion occurs until it is turned off and secretory preforms accumulate. At high level synthesis, the secretory pathway overflows and proteins are driven to folding and subsequent degradation. High-level synthesis of heterologous secretory proteins, whether secretion competent or not, has a drastic effect on the endogenous secretome, depending on their secretion efficiency. These findings lay the foundations of dissecting how protein targeting and secretion are regulated by the interplay between the metabolome, secretion factors and stress responses in the S. lividans model.
en
Attribution-NonCommercial-ShareAlike 4.0 International
Streptomyces lividans
eGFP
mRFP
protein secretion
protein secretion biotechnology
signal peptide
Monitoring Protein Secretion in Using Fluorescent Proteins.
Article
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oai:repository.helmholtz-hzi.de:10033/6216412019-08-30T11:33:27Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Kuzhyk, Yuriy
author
Lopatniuk, Maria
author
Luzhetskyy, Andriy N
author
Fedorenko, Victor
author
Ostash, Bohdan
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2019-01-10T13:21:57Z
2018-09-25
0046-8991
10.1007/s12088-018-0761-x
http://hdl.handle.net/10033/621641
Indian Journal of Microbiology
Here we describe our efforts to improve the levels of phosphoglycolipid antibiotic nosokomycin A production by Streptomyces ghanaensis ATCC14672 via genome engineering approaches. Introduction of two extra copies of leucyl tRNA (UUA) gene bldA and one copy of moenomycin biosynthesis gene cluster led, on average, to threefold increase in nosokomycin A titers (up to 1.5 mg/L). Our results validate genome engineering approach as a viable strategy to improve moenomycin production.
Attribution-NonCommercial-ShareAlike 4.0 International
Streptomyces ghanaensis
Moenomycins
Genome engineering
ntegrative vectors
Genome Engineering Approaches to Improve Nosokomycin A Production by Streptomyces ghanaensis B38.3
Article
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oai:repository.helmholtz-hzi.de:10033/6216502019-01-21T14:57:25Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Hamed, Mohamed Belal
author
Vrancken, Kristof
author
Bilyk, Bohdan
author
Koepff, Joachim
author
Novakova, Renata
author
van Mellaert, Lieve
author
Oldiges, Marco
author
Luzhetskyy, Andriy
author
Kormanec, Jan
author
Anné, Jozef
author
Karamanou, Spyridoula
author
Economou, Anastassios
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2019-01-15T14:29:24Z
2018-01-01
Front Microbiol. 2018 Dec 7;9:3019. doi: 10.3389/fmicb.2018.03019. eCollection 2018.
1664-302X
30581427
10.3389/fmicb.2018.03019
http://hdl.handle.net/10033/621650
Fluorescent proteins are a major cell biology tool to analyze protein sub-cellular topology. Here we have applied this technology to study protein secretion in the Gram-positive bacterium Streptomyces lividans TK24, a widely used host for heterologous protein secretion biotechnology. Green and monomeric red fluorescent proteins were fused behind Sec (SPSec) or Tat (SPTat) signal peptides to direct them through the respective export pathway. Significant secretion of fluorescent eGFP and mRFP was observed exclusively through the Tat and Sec pathways, respectively. Plasmid over-expression was compared to a chromosomally integrated spSec-mRFP gene to allow monitoring secretion under high and low level synthesis in various media. Fluorimetric detection of SPSec-mRFP recorded folded states, while immuno-staining detected even non-folded topological intermediates. Secretion of SPSec-mRFP is unexpectedly complex, is regulated independently of cell growth phase and is influenced by the growth regime. At low level synthesis, highly efficient secretion occurs until it is turned off and secretory preforms accumulate. At high level synthesis, the secretory pathway overflows and proteins are driven to folding and subsequent degradation. High-level synthesis of heterologous secretory proteins, whether secretion competent or not, has a drastic effect on the endogenous secretome, depending on their secretion efficiency. These findings lay the foundations of dissecting how protein targeting and secretion are regulated by the interplay between the metabolome, secretion factors and stress responses in the S. lividans model.
Attribution-NonCommercial-ShareAlike 4.0 International
Streptomyces lividans
eGFP
mRFP
protein secretion
protein secretion biotechnology
signal peptide
Monitoring Protein Secretion in streptomyces Using Fluorescent Proteins.
Article
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oai:repository.helmholtz-hzi.de:10033/6216612019-08-30T11:33:55Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Rebets, Yuriy
author
Tsolis, Konstantinos C
author
Guðmundsdóttir, Elísabet Eik
author
Koepff, Joachim
author
Wawiernia, Beata
author
Busche, Tobias
author
Bleidt, Arne
author
Horbal, Liliya
author
Myronovskyi, Maksym
author
Ahmed, Yousra
author
Wiechert, Wolfgang
author
Rückert, Christian
author
Hamed, Mohamed B
author
Bilyk, Bohdan
author
Anné, Jozef
author
Friðjónsson, Ólafur
author
Kalinowski, Jörn
author
Oldiges, Marco
author
Economou, Anastassios
author
Luzhetskyy, Andriy N
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2019-01-18T13:35:08Z
2018-01-01
Front Microbiol. 2018 Dec 10;9:3033. doi: 10.3389/fmicb.2018.03033. eCollection 2018.
1664-302X
30619125
10.3389/fmicb.2018.03033
http://hdl.handle.net/10033/621661
Frontiers in Microbiology
Alternative sigma factors control numerous aspects of bacterial life, including adaptation to physiological stresses, morphological development, persistence states and virulence. This is especially true for the physiologically complex actinobacteria. Here we report the development of a robust gene deletions system for Streptomyces lividans TK24 based on a BAC library combined with the λ-Red recombination technique. The developed system was validated by systematically deleting the most highly expressed genes encoding alternative sigma factors and several other regulatory genes within the chromosome of S. lividans TK24. To demonstrate the possibility of large scale genomic manipulations, the major part of the undecylprodigiosin gene cluster was deleted as well. The resulting mutant strains were characterized in terms of morphology, growth parameters, secondary metabolites production and response to thiol-oxidation and cell-wall stresses. Deletion of SLIV_12645 gene encoding S. coelicolor SigR1 ortholog has the most prominent phenotypic effect, resulted in overproduction of actinorhodin and coelichelin P1 and increased sensitivity to diamide. The secreted proteome analysis of SLIV_12645 mutant revealed SigR1 influence on trafficking of proteins involved in cell wall biogenesis and refactoring. The reported here gene deletion system will further facilitate work on S. lividans strain improvement as a host for either secondary metabolites or protein production and will contribute to basic research in streptomycetes physiology, morphological development, secondary metabolism. On the other hand, the systematic deletion of sigma factors encoding genes demonstrates the complexity and conservation of regulatory processes conducted by sigma factors in streptomycetes
en
Attribution-NonCommercial-ShareAlike 4.0 International
Streptomyces lividans
genomic library
secretomics
strain phenotyping
transcriptomics
σ-factor
Characterization of Sigma Factor Genes in streptomyces lividans TK24 Using a Genomic Library-Based Approach for Multiple Gene Deletions.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/621661/1/Rebets%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6217612019-08-30T11:33:00Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Sun, Yi-Qian
author
Busche, Tobias
author
Rückert, Christian
author
Paulus, Constanze
author
Rebets, Yuriy
author
Novakova, Renata
author
Kalinowski, Jörn
author
Luzhetskyy, Andriy N
author
Kormanec, Jan
author
Sekurova, Olga N
author
Zotchev, Sergey B
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2019-05-07T08:28:13Z
2017-06-16
ACS Synth Biol. 2017 Jun 16;6(6):1026-1033. doi: 10.1021/acssynbio.6b00353. Epub 2017 Mar 3.
2161-5063
28221784
10.1021/acssynbio.6b00353
http://hdl.handle.net/10033/621761
ACS Synthetic Biology
Genome mining of actinomycete bacteria aims at the discovery of novel bioactive secondary metabolites that can be developed into drugs. A new repressor-based biosensor to detect activated secondary metabolite biosynthesis gene clusters in Streptomyces was developed. Biosynthetic gene clusters for undecylprodigiosin and coelimycin in the genome of Streptomyces lividans TK24, which encoded TetR-like repressors and appeared to be almost “silent” based on the RNA-seq data, were chosen for the proof-of-principle studies. The bpsA reporter gene for indigoidine synthetase was placed under control of the promotor/operator regions presumed to be controlled by the cluster-associated TetR-like repressors. While the biosensor for undecylprodigiosin turned out to be nonfunctional, the coelimycin biosensor was shown to perform as expected, turning on biosynthesis of indigoidine in response to the concomitant production of coelimycin. The developed reporter system concept can be applied to those cryptic gene clusters that encode metabolite-sensing repressors to speed up discovery of novel bioactive compounds in Streptomyces.
Attribution-NonCommercial-ShareAlike 4.0 International
Streptomyces
TetR repressor
biosensor
orphan gene clusters
secondary metabolite biosynthesis
Development of a Biosensor Concept to Detect the Production of Cluster-Specific Secondary Metabolites.
Article
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URL
https://hzi.openrepository.com/bitstream/10033/621761/1/Sun%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6220882020-01-18T02:08:47Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Ahmed, Yousra
author
Rebets, Yuriy
author
Estévez, Marta Rodríguez
author
Zapp, Josef
author
Myronovskyi, Maksym
author
Luzhetskyy, Andriy
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2020-01-17T10:39:34Z
2020-01-09
Microb Cell Fact. 2020 Jan 9;19(1):5. doi: 10.1186/s12934-020-1277-8.
1475-2859
31918711
10.1186/s12934-020-1277-8
http://hdl.handle.net/10033/622088
Microbial Cell Factories
BACKGROUND:
Heterologous expression of secondary metabolite gene clusters is used to achieve increased production of desired compounds, activate cryptic gene clusters, manipulate clusters from genetically unamenable strains, obtain natural products from uncultivable species, create new unnatural pathways, etc. Several Streptomyces species are genetically engineered for use as hosts for heterologous expression of gene clusters. S. lividans TK24 is one of the most studied and genetically tractable actinobacteria, which remain untapped. It was therefore important to generate S. lividans chassis strains with clean metabolic backgrounds.
RESULTS:
In this study, we generated a set of S. lividans chassis strains by deleting endogenous gene clusters and introducing additional φC31 attB loci for site-specific integration of foreign DNA. In addition to the simplified metabolic background, the engineered S. lividans strains had better growth characteristics than the parental strain in liquid production medium. The utility of the developed strains was validated by expressing four secondary metabolite gene clusters responsible for the production of different classes of natural products. Engineered strains were found to be superior to the parental strain in production of heterologous natural products. Furthermore, S. lividans-based strains were better producers of amino acid-based natural products than other tested common hosts. Expression of a Streptomyces albus subsp. chlorinus NRRL B-24108 genomic library in the modified S. lividans ΔYA9 and S. albus Del14 strains resulted in the production of 7 potentially new compounds, only one of which was produced in both strains.
CONCLUSION:
The constructed S. lividans-based strains are a great complement to the panel of heterologous hosts for actinobacterial secondary metabolite gene expression. The expansion of the number of such engineered strains will contribute to an increased success rate in isolation of new natural products originating from the expression of genomic and metagenomic libraries, thus raising the chance to obtain novel biologically active compounds.
en
Attribution-NonCommercial-ShareAlike 4.0 International
Gene cluster
Heterologous expression
Heterologous host
Natural product
Streptomyces
Engineering of Streptomyces lividans for heterologous expression of secondary metabolite gene clusters.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6221432020-03-12T03:27:41Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Rodríguez Estévez, Marta
author
Gummerlich, Nils
author
Myronovskyi, Maksym
author
Zapp, Josef
author
Luzhetskyy, Andriy
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2020-02-17T14:48:49Z
2019-01-01
Front Chem. 2020 Jan 10;7:896. doi: 10.3389/fchem.2019.00896. eCollection 2019.
2296-2646
31998688
10.3389/fchem.2019.00896
http://hdl.handle.net/10033/622143
Frontiers in Chemistry
Streptomycetes constitute a diverse bacterial group able to produce a wide variety of secondary metabolites with potential applications in the pharmacy industry. However, the genes responsible for the biosynthesis of these compounds are very frequently inactive or expressed at very low levels under standard laboratory cultivation conditions. Therefore, the activation or upregulation of secondary metabolite biosynthesis genes is a crucial step for the discovery of new bioactive natural products. We have recently reported the discovery of the biosynthetic genes for the antibiotic nybomycin (nyb genes) in Streptomyces albus subsp. chlorinus. The nyb genes were expressed in the heterologous host Streptomyces albus Del14, which produces not only nybomycin, but also a novel compound. In this study, we describe the isolation, purification, and structure elucidation of the new substance named benzanthric acid.
Attribution-NonCommercial-ShareAlike 4.0 International
Streptomyces
benzanthric acid
biosynthetic gene cluster
heterologous expression
nybomycin
secondary metabolite
Benzanthric Acid, a Novel Metabolite From Del14 Expressing the Nybomycin Gene Cluster.
Article
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URL
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URL
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oai:repository.helmholtz-hzi.de:10033/6221772020-03-12T03:29:15Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Myronovskyi, Maksym
author
Rosenkränzer, Birgit
author
Stierhof, Marc
author
Petzke, Lutz
author
Seiser, Tobias
author
Luzhetskyy, Andriy
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2020-02-26T14:12:48Z
2020-02-10
Microorganisms. 2020 Feb 10;8(2). pii: microorganisms8020237. doi: 10.3390/microorganisms8020237.
2076-2607
32050690
10.3390/microorganisms8020237
http://hdl.handle.net/10033/622177
Microorganisms
Herbicides with new modes of action and safer toxicological and environmental profiles are needed to manage the evolution of weeds that are resistant to commercial herbicides. The unparalleled structural diversity of natural products makes these compounds a promising source for new herbicides. In 2009, a novel nucleoside phytotoxin, albucidin, with broad activity against grass and broadleaf weeds was isolated from a strain of Streptomyces albus subsp. chlorinus NRRL B-24108. Here, we report the identification and heterologous expression of the previously uncharacterized albucidin gene cluster. Through a series of gene inactivation experiments, a minimal set of albucidin biosynthetic genes was determined. Based on gene annotation and sequence homology, a model for albucidin biosynthesis was suggested. The presented results enable the construction of producer strains for a sustainable supply of albucidin for biological activity studies.
en
Attribution-NonCommercial-ShareAlike 4.0 International
Streptomyces albus Del14
albucidin
biosynthetic gene cluster
herbicide
heterologous expression
nucleoside
Identification and Heterologous Expression of the Albucidin Gene Cluster from the Marine Strain Subsp. NRRL B-24108.
Article
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URL
https://repository.helmholtz-hzi.de/bitstream/10033/622177/1/Myronovskyi%20et%20al.pdf
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URL
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URL
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URL
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oai:repository.helmholtz-hzi.de:10033/6223022020-06-18T01:40:02Zcom_10033_620618col_10033_620619col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Dahlem, Charlotte
author
Siow, Wei Xiong
author
Lopatniuk, Maria
author
Tse, William K F
author
Kessler, Sonja M
author
Kirsch, Susanne H
author
Hoppstädter, Jessica
author
Vollmar, Angelika M
author
Müller, Rolf
author
Luzhetskyy, Andriy
author
Bartel, Karin
author
Kiemer, Alexandra K
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2020-06-17T13:31:30Z
2020-05-19
Cancers (Basel). 2020;12(5):1288. Published 2020 May 19. doi:10.3390/cancers12051288.
2072-6694
32438733
10.3390/cancers12051288
http://hdl.handle.net/10033/622302
Cancers
Natural products represent powerful tools searching for novel anticancer drugs. Thioholgamide A (thioA) is a ribosomally synthesized and post-translationally modified peptide, which has been identified as a product of Streptomyces sp. MUSC 136T. In this study, we provide a comprehensive biological profile of thioA, elucidating its effects on different hallmarks of cancer in tumor cells as well as in macrophages as crucial players of the tumor microenvironment. In 2D and 3D in vitro cell culture models thioA showed potent anti-proliferative activities in cancer cells at nanomolar concentrations. Anti-proliferative actions were confirmed in vivo in zebrafish embryos. Cytotoxicity was only induced at several-fold higher concentrations, as assessed by live-cell microscopy and biochemical analyses. ThioA exhibited a potent modulation of cell metabolism by inhibiting oxidative phosphorylation, as determined in a live-cell metabolic assay platform. The metabolic modulation caused a repolarization of in vitro differentiated and polarized tumor-promoting human monocyte-derived macrophages: ThioA-treated macrophages showed an altered morphology and a modulated expression of genes and surface markers. Taken together, the metabolic regulator thioA revealed low activities in non-tumorigenic cells and an interesting anti-cancer profile by orchestrating different hallmarks of cancer, both in tumor cells as well as in macrophages as part of the tumor microenvironment.
en
Attribution-NonCommercial-ShareAlike 4.0 International
HUVEC
M2 macrophages
OXPHOS
RiPPs
TAM-like macrophages
flow cytometry
migration
mitochondria
phagocytosis
qPCR
scratch assay
thioviridamide-like compounds
Thioholgamide A, a New Anti-Proliferative Anti-Tumor Agent, Modulates Macrophage Polarization and Metabolism.
Article
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oai:repository.helmholtz-hzi.de:10033/6224212020-09-08T01:34:12Zcom_10033_620618col_10033_620620col_10033_620649col_10033_621520
Helmholtz Zentrum für Infektionsforschung Repository
author
Sikandar, Asfandyar
author
Franz, Laura
author
Adam, Sebastian
author
Santos-Aberturas, Javier
author
Horbal, Liliya
author
Luzhetskyy, Andriy
author
Truman, Andrew W
author
Kalinina, Olga V
author
Koehnke, Jesko
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2020-08-31T14:13:30Z
2020-06-29
Nat Chem Biol. 2020 Jul 15;:]. Nat Chem Biol. 2020;16(9):1013-1018. doi:10.1038/s41589-020-0569-y.
32601484
10.1038/s41589-020-0569-y
http://hdl.handle.net/10033/622421
1552-4469
Nature chemical biology
d-amino acids endow peptides with diverse, desirable properties, but the post-translational and site-specific epimerization of l-amino acids into their d-counterparts is rare and chemically challenging. Bottromycins are ribosomally synthesized and post-translationally modified peptides that have overcome this challenge and feature a d-aspartate (d-Asp), which was proposed to arise spontaneously during biosynthesis. We have identified the highly unusual α/β-hydrolase (ABH) fold enzyme BotH as a peptide epimerase responsible for the post-translational epimerization of l-Asp to d-Asp during bottromycin biosynthesis. The biochemical characterization of BotH combined with the structures of BotH and the BotH–substrate complex allowed us to propose a mechanism for this reaction. Bioinformatic analyses of BotH homologs show that similar ABH enzymes are found in diverse biosynthetic gene clusters. This places BotH as the founding member of a group of atypical ABH enzymes that may be able to epimerize non-Asp stereocenters across different families of secondary metabolites.
en
Attribution-NonCommercial-ShareAlike 4.0 International
The bottromycin epimerase BotH defines a group of atypical α/β-hydrolase-fold enzymes.
Article
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oai:repository.helmholtz-hzi.de:10033/6224392020-09-12T02:03:48Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Shuai, Hui
author
Myronovskyi, Maksym
author
Nadmid, Suvd
author
Luzhetskyy, Andriy
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2020-09-11T09:36:26Z
2020-07-18
Biomolecules. 2020;10(7):E1074. Published 2020 Jul 18. doi:10.3390/biom10071074.
32708402
10.3390/biom10071074
http://hdl.handle.net/10033/622439
2218-273X
Biomolecules
Pyrrolopyrimidines are an important class of natural products with a broad spectrum of biological activities, including antibacterial, antifungal, antiviral, anticancer or anti-inflammatory. Here, we present the identification of a biosynthetic gene cluster from the rare actinomycete strain Kutzneria albida DSM 43870, which leads to the production of huimycin, a new member of the pyrrolopyrimidine family of compounds. The huimycin gene cluster was successfully expressed in the heterologous host strain Streptomyces albus Del14. The compound was purified, and its structure was elucidated by means of nuclear magnetic resonance spectroscopy. The minimal huimycin gene cluster was identified through sequence analysis and a series of gene deletion experiments. A model for huimycin biosynthesis is also proposed in this paper.
en
Attribution-NonCommercial-ShareAlike 4.0 International
heterologous expression
kutzneria
nucleoside
pyrrolopyrimidines
secondary metabolites
Identification of a Biosynthetic Gene Cluster Responsible for the Production of a New Pyrrolopyrimidine Natural Product-Huimycin.
Article
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https://repository.helmholtz-hzi.de/bitstream/10033/622439/1/Shuai%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6225662020-11-11T03:34:32Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Marques, Filipe
author
Luzhetskyy, Andriy
author
Mendes, Marta V
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2020-11-10T09:46:57Z
2020-08-20
Metab Eng. 2020 Aug 20;62:221-234. doi: 10.1016/j.ymben.2020.08.007. Epub ahead of print.
32827704
10.1016/j.ymben.2020.08.007
http://hdl.handle.net/10033/622566
1096-7184
Metabolic engineering
The Gram-positive bacterium Corynebacterium glutamicum sustains the industrial production of chiral molecules such as L-amino acids. Through heterologous gene expression, C. glutamicum is becoming a sustainable source of small organic molecules and added-value chemicals. The current methods to implement heterologous genes in C. glutamicum rely on replicative vectors requiring lasting selection or chromosomal integration using homologous recombination. Here, we present a set of dedicated and transversal tools for genome editing and gene delivery into C. glutamicum. We generated a cosmid-based library suitable for efficient double allelic exchange, covering more than 94% of the chromosome with an average 5.1x coverage. We employed the library and an iterative marker excision system to generate the carotenoid-free C. glutamicum BT1-C31-Albino (BCA) host, featuring the attachment sites for actinophages ϕC31 and ϕBT1 for one-step chromosomal integration. As a proof-of-principle, we employed a ϕC31-based integration and a Cre system for the markerless expression of the type III polyketide synthase RppA, and a ϕBT1-based integration system for the expression of the phosphopantetheinylation-dependent non-ribosomal peptide synthetase BpsA in the C. glutamicum BCA host. The developed genomic library and microbial host, and the characterized molecular tools will contribute to the study of the physiology and the rise of C. glutamicum as a leading host for drug discovery.
en
Attribution-NonCommercial-NoDerivatives 4.0 International
Actinobacteria
Genome editing
Heterologous expression
Natural products
Engineering Corynebacterium glutamicum with a comprehensive genomic library and phage-based vectors.
Article
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oai:repository.helmholtz-hzi.de:10033/6225822020-11-16T09:35:26Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Lasch, Constanze
author
Gummerlich, Nils
author
Myronovskyi, Maksym
author
Palusczak, Anja
author
Zapp, Josef
author
Luzhetskyy, Andriy
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2020-11-13T15:03:59Z
2020-10-09
Molecules. 2020 Oct 9;25(20):4594. doi: 10.3390/molecules25204594.
33050154
10.3390/molecules25204594
http://hdl.handle.net/10033/622582
1420-3049
Molecules (Basel, Switzerland)
Natural products are a valuable source of biologically active compounds with potential applications in medicine and agriculture. Unprecedented scaffold diversity of natural products and biocatalysts from their biosynthetic pathways are of fundamental importance. Heterologous expression and refactoring of natural product biosynthetic pathways are generally regarded as a promising approach to discover new secondary metabolites of microbial origin. Here, we present the identification of a new group of alkylresorcinols after transcriptional activation and heterologous expression of the type III polyketide synthase of Micromonospora endolithica. The most abundant compounds loseolamycins A1 and A2 have been purified and their structures were elucidated by NMR. Loseolamycins contain an unusual branched hydroxylated aliphatic chain which is provided by the host metabolism and is incorporated as a starter fatty acid unit. The isolated loseolamycins show activity against gram-positive bacteria and inhibit the growth of the monocot weed Agrostis stolonifera in a germination assay. The biosynthetic pathway leading to the production of loseolamycins is proposed in this paper.
en
Attribution-NonCommercial-ShareAlike 4.0 International
Micromonospora endolithica
Streptomyces albus Del14
alkylresorcinol
biosynthetic gene
heterologous expression
type III polyketide synthase
Loseolamycins: A Group of New Bioactive Alkylresorcinols Produced after Heterologous Expression of a Type III PKS from micromonospora endolithica.
Article
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URL
https://repository.helmholtz-hzi.de/bitstream/10033/622582/1/Lasch%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6225842020-11-17T01:36:51Zcom_10033_620618col_10033_620620col_10033_620649
Helmholtz Zentrum für Infektionsforschung Repository
author
Sikandar, Asfandyar
author
Lopatniuk, Maria
author
Luzhetskyy, Andriy
author
Koehnke, Jesko
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2020-11-16T10:45:03Z
2020-10-01
ACS Chem Biol. 2020 Oct 16;15(10):2815-2819. doi: 10.1021/acschembio.0c00637. Epub 2020 Oct 1.
32965102
10.1021/acschembio.0c00637
http://hdl.handle.net/10033/622584
1554-8937
ACS chemical biology
Thioviridamide-like compounds, including thioholgamides, are ribosomally synthesized and post-translationally modified peptide natural products with potent anticancer cell activity and an unprecedented structure. Very little is known about their biosynthesis, and we were intrigued by the β-hydroxy-N1, N3-dimethylhistidinium moiety found in these compounds. Here we report the construction of a heterologous host capable of producing thioholgamide with a 15-fold increased yield compared to the wild-type strain. A knockout of thoJ, encoding a predicted nonheme monooxygenase, shows that ThoJ is essential for thioholgamide β-hydroxylation. The crystal structure of ThoJ exhibits a typical mono/dioxygenase fold with conserved key active-site residues. Yet, ThoJ possesses a very large substrate binding pocket that appears suitable to receive a cyclic thioholgamide intermediate for hydroxylation. The improved production of the heterologous host will enable the dissection of the individual biosynthetic steps involved in biosynthesis of this exciting RiPP family.
en
Attribution-NonCommercial-ShareAlike 4.0 International
Non-Heme Monooxygenase ThoJ Catalyzes Thioholgamide β-Hydroxylation.
Article
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URL
https://repository.helmholtz-hzi.de/bitstream/10033/622584/1/Sikandar%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6226492020-12-15T01:34:41Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Lasch, Constanze
author
Stierhof, Marc
author
Estévez, Marta Rodríguez
author
Myronovskyi, Maksym
author
Zapp, Josef
author
Luzhetskyy, Andriy
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2020-12-14T13:27:15Z
2020-11-16
Microorganisms. 2020 Nov 16;8(11):1800. doi: 10.3390/microorganisms8111800.
2076-2607
33207845
10.3390/microorganisms8111800
http://hdl.handle.net/10033/622649
Microorganisms
Since the 1950s, natural products of bacterial origin were systematically developed to be used as drugs with a wide range of medical applications. The available treatment options for many diseases are still not satisfying, wherefore, the discovery of new structures has not lost any of its importance. Beyond the great variety of already isolated and characterized metabolites, Streptomycetes still harbor uninvestigated gene clusters whose products can be accessed using heterologous expression in host organisms. This works presents the discovery of a set of structurally novel secondary metabolites, dudomycins A to D, through the expression of a cryptic NRPS cluster from Streptomyces albus ssp. Chlorinus NRRL B-24108 in the heterologous host strain Streptomyces albus Del14. A minimal set of genes, required for the production of dudomycins, was defined through gene inactivation experiments. This paper also proposes a model for dudomycin biosynthesis.
en
Attribution 4.0 International
NRPS
Streptomyces
heterologous expression
Dudomycins: New Secondary Metabolites Produced After Heterologous Expression of an Nrps Cluster from ssp. Nrrl B-24108.
Article
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URL
https://repository.helmholtz-hzi.de/bitstream/10033/622649/1/Lasch%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6226772021-01-14T01:42:09Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Gummerlich, Nils
author
Rebets, Yuriy
author
Paulus, Constanze
author
Zapp, Josef
author
Luzhetskyy, Andriy
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2021-01-13T15:12:49Z
2020-12-19
Microorganisms. 2020 Dec 19;8(12):2034. doi: 10.3390/microorganisms8122034.
2076-2607
33352664
10.3390/microorganisms8122034
http://hdl.handle.net/10033/622677
Microorganisms
Natural products are an important source of novel investigational compounds in drug discovery. Especially in the field of antibiotics, Actinobacteria have been proven to be a reliable source for lead structures. The discovery of these natural products with activity- and structure-guided screenings has been impeded by the constant rediscovery of previously identified compounds. Additionally, a large discrepancy between produced natural products and biosynthetic potential in Actinobacteria, including representatives of the order Pseudonocardiales, has been revealed using genome sequencing. To turn this genomic potential into novel natural products, we used an approach including the in-silico pre-selection of unique biosynthetic gene clusters followed by their systematic heterologous expression. As a proof of concept, fifteen Saccharothrixespanaensis genomic library clones covering predicted biosynthetic gene clusters were chosen for expression in two heterologous hosts, Streptomyceslividans and Streptomycesalbus. As a result, two novel natural products, an unusual angucyclinone pentangumycin and a new type II polyketide synthase shunt product SEK90, were identified. After purification and structure elucidation, the biosynthetic pathways leading to the formation of pentangumycin and SEK90 were deduced using mutational analysis of the biosynthetic gene cluster and feeding experiments with 13C-labelled precursors.
en
Attribution 4.0 International
Actinobacteria
angucyclinone
biosynthesis
heterologous expression
natural products
Targeted Genome Mining-From Compound Discovery to Biosynthetic Pathway Elucidation.
Article
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URL
https://repository.helmholtz-hzi.de/bitstream/10033/622677/1/Gummerlich%20et%20al.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/6226872021-01-19T03:37:24Zcom_10033_620618col_10033_620619col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Rebets, Yuriy
author
Nadmid, Suvd
author
Paulus, Constanze
author
Dahlem, Charlotte
author
Herrmann, Jennifer
author
Hübner, Harald
author
Rückert, Christian
author
Kiemer, Alexandra K
author
Gmeiner, Peter
author
Kalinowski, Jörn
author
Müller, Rolf
author
Luzhetskyy, Andriy
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2021-01-18T15:43:47Z
2019-08-21
Angew Chem Int Ed Engl. 2019 Sep 9;58(37):12930-12934. doi: 10.1002/anie.201905538. Epub 2019 Aug 21.
31310031
10.1002/anie.201905538
http://hdl.handle.net/10033/622687
1521-3773
Angewandte Chemie (International ed. in English)
Autophagy, a membrane-dependent catabolic process, ensures survival of aging cells and depends on the cellular energetic status. Acetyl-CoA carboxylase 1 (Acc1) connects central energy metabolism to lipid biosynthesis and is rate-limiting for the de novo synthesis of lipids. However, it is unclear how de novo lipogenesis and its metabolic consequences affect autophagic activity. Here, we show that in aging yeast, autophagy levels highly depend on the activity of Acc1. Constitutively active Acc1 (acc1S/A ) or a deletion of the Acc1 negative regulator, Snf1 (yeast AMPK), shows elevated autophagy levels, which can be reversed by the Acc1 inhibitor soraphen A. Vice versa, pharmacological inhibition of Acc1 drastically reduces cell survival and results in the accumulation of Atg8-positive structures at the vacuolar membrane, suggesting late defects in the autophagic cascade. As expected, acc1S/A cells exhibit a reduction in acetate/acetyl-CoA availability along with elevated cellular lipid content. However, concomitant administration of acetate fails to fully revert the increase in autophagy exerted by acc1S/A Instead, administration of oleate, while mimicking constitutively active Acc1 in WT cells, alleviates the vacuolar fusion defects induced by Acc1 inhibition. Our results argue for a largely lipid-dependent process of autophagy regulation downstream of Acc1. We present a versatile genetic model to investigate the complex relationship between acetate metabolism, lipid homeostasis, and autophagy and propose Acc1-dependent lipogenesis as a fundamental metabolic path downstream of Snf1 to maintain autophagy and survival during cellular aging.
en
Attribution 4.0 International
8-amino-7-oxononanoate synthase
Streptomyces
biosynthesis
natural product
tetrahydroisoquinoline
Perquinolines A-C: Unprecedented Bacterial Tetrahydroisoquinolines Involving an Intriguing Biosynthesis.
Article
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
URL
https://repository.helmholtz-hzi.de/bitstream/10033/622687/1/Rebets%20et%20al.pdf
File
MD5
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URL
https://repository.helmholtz-hzi.de/bitstream/10033/622687/4/Rebets%20et%20al.pdf.txt
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oai:repository.helmholtz-hzi.de:10033/6227822021-03-23T01:31:19Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Pikl, Špela
author
Carrillo Rincón, Andrés Felipe
author
Slemc, Lucija
author
Goranovič, Dušan
author
Avbelj, Martina
author
Gjuračić, Krešimir
author
Sucipto, Hilda
author
Stare, Katja
author
Baebler, Špela
author
Šala, Martin
author
Guo, Meijin
author
Luzhetskyy, Andriy
author
Petković, Hrvoje
author
Magdevska, Vasilka
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2021-03-22T14:47:20Z
2021-02-17
Microb Cell Fact. 2021 Feb 17;20(1):47. doi: 10.1186/s12934-021-01522-5.
33596911
10.1186/s12934-021-01522-5
http://hdl.handle.net/10033/622782
1475-2859
Microbial cell factories
Background: Natural products are a valuable source of biologically active compounds that have applications in medicine and agriculture. One disadvantage with natural products is the slow, time-consuming strain improvement regimes that are necessary to ensure sufficient quantities of target compounds for commercial production. Although great efforts have been invested in strain selection methods, many of these technologies have not been improved in decades, which might pose a serious threat to the economic and industrial viability of such important bioprocesses.
Results: In recent years, introduction of extra copies of an entire biosynthetic pathway that encodes a target product in a single microbial host has become a technically feasible approach. However, this often results in minor to moderate increases in target titers. Strain stability and process reproducibility are the other critical factors in the industrial setting. Industrial Streptomyces rimosus strains for production of oxytetracycline are one of the most economically efficient strains ever developed, and thus these represent a very good industrial case. To evaluate the applicability of amplification of an entire gene cluster in a single host strain, we developed and evaluated various gene tools to introduce multiple copies of the entire oxytetracycline gene cluster into three different Streptomyces rimosus strains: wild-type, and medium and high oxytetracycline-producing strains. We evaluated the production levels of these engineered S. rimosus strains with extra copies of the oxytetracycline gene cluster and their stability, and the oxytetracycline gene cluster expression profiles; we also identified the chromosomal integration sites.
Conclusions: This study shows that stable and reproducible increases in target secondary metabolite titers can be achieved in wild-type and in high oxytetracycline-producing strains, which always reflects the metabolic background of each independent S. rimosus strain. Although this approach is technically very demanding and requires systematic effort, when combined with modern strain selection methods, it might constitute a very valuable approach in industrial process development.
en
Attribution 4.0 International
Biosynthesis
Biosynthetic gene cluster
Oxytetracycline
Streptomyces rimosus
ΦC31
Multiple copies of the oxytetracycline gene cluster in selected Streptomyces rimosus strains can provide significantly increased titers.
Article
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URL
https://repository.helmholtz-hzi.de/bitstream/10033/622782/1/Pikl%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6228862021-05-28T02:13:13Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Voitsekhovskaia, Irina
author
Paulus, Constanze
author
Dahlem, Charlotte
author
Rebets, Yuriy
author
Nadmid, Suvd
author
Zapp, Josef
author
Axenov-Gribanov, Denis
author
Rückert, Christian
author
Timofeyev, Maxim
author
Kalinowski, Jörn
author
Kiemer, Alexandra K
author
Luzhetskyy, Andriy
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2021-05-27T13:34:34Z
2020-05-07
Microorganisms. 2020 May 7;8(5):680. doi: 10.3390/microorganisms8050680.
2076-2607
32392775
10.3390/microorganisms8050680
http://hdl.handle.net/10033/622886
Microorganisms
Natural products produced by bacteria found in unusual and poorly studied ecosystems, such as Lake Baikal, represent a promising source of new valuable drug leads. Here we report the isolation of a new Streptomyces sp. strain IB201691-2A from the Lake Baikal endemic mollusk Benedictia baicalensis. In the course of an activity guided screening three new angucyclines, named baikalomycins A-C, were isolated and characterized, highlighting the potential of poorly investigated ecological niches. Besides that, the strain was found to accumulate large quantities of rabelomycin and 5-hydroxy-rabelomycin, known shunt products in angucyclines biosynthesis. Baikalomycins A-C demonstrated varying degrees of anticancer activity. Rabelomycin and 5-hydroxy-rabelomycin further demonstrated antiproliferative activities. The structure elucidation showed that baikalomycin A is a modified aquayamycin with β-d-amicetose and two additional hydroxyl groups at unusual positions (6a and 12a) of aglycone. Baikalomycins B and C have alternating second sugars attached, α-l-amicetose and α-l-aculose, respectively. The gene cluster for baikalomycins biosynthesis was identified by genome mining, cloned using a transformation-associated recombination technique and successfully expressed in S. albus J1074. It contains a typical set of genes responsible for an angucycline core assembly, all necessary genes for the deoxy sugars biosynthesis, and three genes coding for the glycosyltransferase enzymes. Heterologous expression and deletion experiments allowed to assign the function of glycosyltransferases involved in the decoration of baikalomycins aglycone.
en
Attribution 4.0 International
Lake Baikal
Streptomyces
angucycline
aquayamycin
glycosyltransferase
natural products
Baikalomycins A-C, New Aquayamycin-Type Angucyclines Isolated from Lake Baikal Derived sp. IB201691-2A.
Article
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URL
https://repository.helmholtz-hzi.de/bitstream/10033/622886/1/Voitsekhovskaia%20et%20al.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/6229702021-08-07T03:28:24Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Stierhof, Marc
author
Myronovskyi, Maksym
author
Zapp, Josef
author
Luzhetskyy, Andriy N
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2021-07-29T14:12:32Z
2021-06-28
Microorganisms. 2021 Jun 28;9(7):1396. doi: 10.3390/microorganisms9071396.
2076-2607
34203385
10.3390/microorganisms9071396
http://hdl.handle.net/10033/622970
Microorganisms
Streptomyces are producers of valuable secondary metabolites with unique scaffolds that perform a plethora of biological functions. Nonribosomal peptides are of special interest due to their variety and complexity. They are synthesized by nonribosomal peptide synthetases, large biosynthetic machineries that are encoded in the genome of many Streptomyces species. The identification of new peptides and the corresponding biosynthetic gene clusters is of major interest since knowledge can be used to facilitate combinatorial biosynthesis and chemical semisynthesis of natural products. The recently discovered bosamycins are linear octapeptides with an interesting 5-OMe tyrosine moiety and various modifications at the N-terminus. In this study, the new cyclic depsibosamycins B, C, and D from Streptomyces aurantiacus LU19075 were discovered. In comparison to the linear bosamycins B, C, and D, which were also produced by the strain, the cyclic depsibosamycins showed a side-chain-to-tail lactonization of serine and glycine, leading to a ring of four amino acids. In silico identification and heterologous expression of the depsibosamycin (dbm) gene cluster indicated that the cyclic peptides, rather than the linear derivatives, are the main products of the cluster.
en
Attribution 4.0 International
NRPS
Streptomyces
bosamycin
cyclic peptide
heterologous expression
Discovery and Heterologous Production of New Cyclic Depsibosamycins.
Article
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URL
https://repository.helmholtz-hzi.de/bitstream/10033/622970/1/Stierhof%20et%20al.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/6229822021-08-07T03:27:57Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Rodríguez Estévez, Marta
author
Myronovskyi, Maksym
author
Rosenkränzer, Birgit
author
Paululat, Thomas
author
Petzke, Lutz
author
Ristau, Jeanette
author
Luzhetskyy, Andriy
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2021-08-06T09:57:28Z
2020-05-28
Mar Drugs. 2020 May 28;18(6):284. doi: 10.3390/md18060284.
32481766
10.3390/md18060284
http://hdl.handle.net/10033/622982
1660-3397
Marine drugs
Streptomycetes are an important source of natural products potentially applicable in the pharmaceutical industry. Many of these drugs are secondary metabolites whose biosynthetic genes are very often poorly expressed under laboratory cultivation conditions. In many cases, antibiotic-resistant mutants exhibit increased production of natural drugs, which facilitates the identification and isolation of new substances. In this study, we report the induction of a type II polyketide synthase gene cluster in the marine strain Streptomyces albus subsp. chlorinus through the selection of streptomycin-resistant mutants, resulting in overproduction of the novel compound fredericamycin C2 (1). Fredericamycin C2 (1) is structurally related to the potent antitumor drug lead fredericamycin A.
en
Attribution 4.0 International
antitumor
fredericamycin
overproduction
secondary metabolites
streptomycetes
streptomycin-resistant
type II PKS
Novel Fredericamycin Variant Overproduced by a Streptomycin-resistant subsp. Strain.
Article
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URL
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oai:repository.helmholtz-hzi.de:10033/6230062021-08-31T01:50:28Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Horbal, Liliya
author
Stierhof, Marc
author
Palusczak, Anja
author
Eckert, Nikolas
author
Zapp, Josef
author
Luzhetskyy, Andriy N
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2021-08-30T12:26:53Z
2021-07-28
Microorganisms. 2021 Jul 28;9(8):1609. doi: 10.3390/microorganisms9081609.
2076-2607
34442689
10.3390/microorganisms9081609
http://hdl.handle.net/10033/623006
Microorganisms
Targeted genome mining is an efficient method of biosynthetic gene cluster prioritization within constantly growing genome databases. Using two capreomycidine biosynthesis genes, alpha-ketoglutarate-dependent arginine beta-hydroxylase and pyridoxal-phosphate-dependent aminotransferase, we identified two types of clusters: one type containing both genes involved in the biosynthesis of the abovementioned moiety, and other clusters including only arginine hydroxylase. Detailed analysis of one of the clusters, the flk cluster from Streptomyces albus, led to the identification of a cyclic peptide that contains a rare D-capreomycidine moiety for the first time. The absence of the pyridoxal-phosphate-dependent aminotransferase gene in the flk cluster is compensated by the XNR_1347 gene in the S. albus genome, whose product is responsible for biosynthesis of the abovementioned nonproteinogenic amino acid. Herein, we report the structure of cyclofaulknamycin and the characteristics of its biosynthetic gene cluster, biosynthesis and bioactivity profile.
en
Attribution 4.0 International
D-capreomycidine
Streptomyces
cyclofaulknamycin
cyclopeptide
Cyclofaulknamycin with the Rare Amino Acid D-capreomycidine Isolated from a Well-Characterized Strain.
Article
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URL
https://repository.helmholtz-hzi.de/bitstream/10033/623006/1/Horbal%20et%20al.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/6230052021-08-31T10:58:50Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Lasch, Constanze
author
Stierhof, Marc
author
Estévez, Marta Rodríguez
author
Myronovskyi, Maksym
author
Zapp, Josef
author
Luzhetskyy, Andriy N
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2021-08-30T12:20:40Z
2021-07-31
Microorganisms. 2021 Jul 31;9(8):1640. doi: 10.3390/microorganisms9081640.
2076-2607
34442719
10.3390/microorganisms9081640
http://hdl.handle.net/10033/623005
Microorganisms
The intriguing structural complexity of molecules produced by natural organisms is uncontested. Natural scaffolds serve as an important basis for the development of molecules with broad applications, e.g., therapeutics or agrochemicals. Research in recent decades has demonstrated that by means of classic metabolite extraction from microbes only a small portion of natural products can be accessed. The use of genome mining and heterologous expression approaches represents a promising way to discover new natural compounds. In this paper we report the discovery of a novel cyclic pentapeptide called bonsecamin through the heterologous expression of a cryptic NRPS gene cluster from Streptomyces albus ssp. chlorinus NRRL B-24108 in Streptomyces albus Del14. The new compound was successfully isolated and structurally characterized using NMR. The minimal set of genes required for bonsecamin production was determined through bioinformatic analysis and gene deletion experiments. A biosynthetic route leading to the production of bonsecamin is proposed in this paper.
en
Attribution 4.0 International
NRPS
Streptomyces
cyclic peptide
heterologous expression
Bonsecamin: A New Cyclic Pentapeptide Discovered through Heterologous Expression of a Cryptic Gene Cluster.
Article
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URL
https://repository.helmholtz-hzi.de/bitstream/10033/623005/1/Lasch%20et%20al.pdf
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oai:repository.helmholtz-hzi.de:10033/6230732021-10-19T01:51:19Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Tistechok, Stepan
author
Skvortsova, Maryna
author
Mytsyk, Yuliia
author
Fedorenko, Victor
author
Parnikoza, Ivan
author
Luzhetskyy, Andriy
author
Gromyko, Oleksandr
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2021-10-18T12:25:18Z
2021-09-01
Polar Biol 44, 1859–1868 (2021). https://doi.org/10.1007/s00300-021-02924-2.
07224060
10.1007/s00300-021-02924-2
http://hdl.handle.net/10033/623073
14322056
Polar Biology
2-s2.0-85112193855
SCOPUS_ID:85112193855
Antarctic actinobacteria, which can be isolated from both soils and marine sediments, demonstrate a wide range of antimicrobial activities as well as significant biosynthetic potential as the producers of biologically active compounds. However, the actinobacterial diversity of the Antarctic region has not yet been sufficiently studied. The present study sought to examine the diversity and antibacterial activity of culturable actinobacteria isolated from the rhizosphere soil of Deschampsia antarctica (É. Desv.), which was collected from Galindez Island, Maritime Antarctic. Among the actinobacteria isolated using a 16S rRNA gene sequence-based phylogenetic analysis process, five genera, namely Streptomyces, Micromonospora, Umezawaea, Kribbella and Micrococcus, were identified. To the best of our knowledge, this is the first report to describe the isolation and initial characterisation of members of the genus Umezawaea from the Antarctic. The isolated actinobacteria were assayed to determine their activity against Gram-positive bacteria, Gram-negative bacteria and yeast. Among the isolated strains, only 30.2% were able to inhibit the growth of at least one of the tested pathogens. The polymerase chain reaction-based screening of the biosynthetic genes revealed the presence of type I polyketide synthases (65.1%), type II polyketide synthases (25.6%) and non-ribosomal peptide synthetases (9.3%) in the actinobacteria strains. The examination of the sensitivity/resistance to antibiotics profile of the actinobacteria strains revealed their high sensitivity in relation to the tested antibiotics. Taken together, the results showed that Antarctic actinobacteria demonstrate potential as the producers of natural bioactive compounds, which means that they represent a valuable prospect for further studies.
en
Attribution 4.0 International
Antarctic actinobacteria
Biosynthetic potential
Deschampsia antarctica
Galindez Island
Umezawaea sp
The diversity and antibacterial activity of culturable actinobacteria isolated from the rhizosphere soil of Deschampsia antarctica (Galindez Island, Maritime Antarctic)
Article
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oai:repository.helmholtz-hzi.de:10033/6231172021-12-11T01:52:21Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Kolling, Dominik
author
Stierhof, Marc
author
Lasch, Constanze
author
Myronovskyi, Maksym
author
Luzhetskyy, Andriy
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2021-12-10T14:31:22Z
2021-10-14
Molecules. 2021 Oct 14;26(20):6220. doi: 10.3390/molecules26206220.
34684801
10.3390/molecules26206220
http://hdl.handle.net/10033/623117
1420-3049
Molecules (Basel, Switzerland)
Halogenation often improves the bioactive properties of natural products and is used in pharmaceutical research for the generation of new potential drug leads. High regio- and stereospecificity, simple reaction conditions and straightforward downstream processing are the main advantages of halogenation using enzymatic biocatalysts compared to chemical synthetic approaches. The identification of new promiscuous halogenases for the modification of various natural products is of great interest in modern drug discovery. In this paper, we report the identification of a new promiscuous FAD-dependent halogenase, DklH, from Frankia alni ACN14a. The identified halogenase readily modifies various flavonoid compounds, including those with well-studied biological activities. This halogenase has been demonstrated to modify not only flavones and isoflavones, but also flavonols, flavanones and flavanonols. The structural requirements for DklH substrate recognition were determined using a feeding approach. The homology model of DklH and the mechanism of substrate recognition are also proposed in this paper.
en
Attribution 4.0 International
Frankia alni
Streptomyces albus Del14
flavonoid
halogenase
heterologous expression
A Promiscuous Halogenase for the Derivatization of Flavonoids.
Article
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oai:repository.helmholtz-hzi.de:10033/6231222021-12-18T03:46:30Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Paulus, Constanze
author
Gromyko, Oleksandr
author
Luzhetskyy, Andriy
department
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
2021-12-17T15:35:03Z
2021-11-12
Molecules. 2021 Nov 12;26(22):6834. doi: 10.3390/molecules26226834.
34833926
10.3390/molecules26226834
http://hdl.handle.net/10033/623122
1420-3049
Molecules (Basel, Switzerland)
In the course of screening new streptomycete strains, the strain Streptomyces sp. Cl 58-27 caught our attention due to its interesting secondary metabolite production profile. Here, we report the isolation and characterization of an ansamycin natural product that belongs structurally to the already known kendomycins. The structure of the new kendomycin E was elucidated using NMR spectroscopy, and the corresponding biosynthetic gene cluster was identified by sequencing the genome of Streptomyces sp. Cl 58-27 and conducting a detailed analysis of secondary metabolism gene clusters using bioinformatic tools.
en
Attribution 4.0 International
Streptomyces
ansamycins
polyketide synthases
New Kendomycin Derivative Isolated from sp. Cl 58-27.
Article
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URL
https://repository.helmholtz-hzi.de/bitstream/10033/623122/1/Paulus%20et%20al.pdf
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URL
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oai:repository.helmholtz-hzi.de:10033/6232282022-06-15T02:52:53Zcom_10033_620618col_10033_620620
Helmholtz Zentrum für Infektionsforschung Repository
author
Shtenikov, M.D.
author
Ostapchuk, A.M.
author
Vasylieva, N.Y.
author
Luzhetskyy, A.M.
author
Rückert, C.
author
Kalinowski, J.
author
Ivanytsia, V.О.
2022-06-14T14:11:33Z
2020-06-17
1028-0987
10.15407/microbiolj82.03.014
http://hdl.handle.net/10033/623228
2616-9258
Attribution 4.0 International
General Medicine
Characteristics of Genome of Bacillus velezensis ONU 553 Strain Isolated from the Bottom Sediments of the Black Sea
Article
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URL
https://repository.helmholtz-hzi.de/bitstream/10033/623228/1/ShtenikovMicrobiolJ2020.pdf
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ShtenikovMicrobiolJ2020.pdf
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https://repository.helmholtz-hzi.de/bitstream/10033/623228/4/ShtenikovMicrobiolJ2020.pdf.txt
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ShtenikovMicrobiolJ2020.pdf.txt