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Papers by Victor Fedorenko
3 Biotech
Streptomyces cyanogenus S136 is the only known producer of landomycin A (LaA), one of the foundin... more Streptomyces cyanogenus S136 is the only known producer of landomycin A (LaA), one of the founding members of angucycline family of aromatic polyketides. LaA displays potent anticancer activities which has made this natural product a target of numerous chemical and cell biological studies. Little is known about the potential of S136 strain to produce other secondary metabolites. Here we report complete genome sequence of LaA producer and how we used this sequence to evaluate for this species its phylogenetic position and diversity of gene clusters for natural product biosynthesis.
Folia Microbiologica, 2018
Low molecular weight signaling compounds (LMWC) are important players in regulating various aspec... more Low molecular weight signaling compounds (LMWC) are important players in regulating various aspects of Streptomyces biology. Their exact roles in certain strain will ultimately depend on overall configuration of regulatory network and thus cannot be predicted on basis of in silico studies. Here, we explored S. ghanaensis gene SSFG_07725 (afsAgh) presumably involved in initial steps of formation of γ-butyrolactone LMWC. Disruption of afsAgh impaired aerial mycelium formation and increased the transcription of pleiotropic regulatory gene adpAgh, whereas level of moenomycin production remained virtually unaffected. We provide evidence that morphogenetic deficiency of afsAgh-minus mutant was caused by inability to produce diffusible LMWC. Possible links between γ-butyrolactone signaling and various aspects of S. ghanaensis biology are discussed.
Applied Microbiology and Biotechnology
Teicoplanin (Tcp) is a clinically relevant glycopeptide antibiotic (GPA) that is produced by the ... more Teicoplanin (Tcp) is a clinically relevant glycopeptide antibiotic (GPA) that is produced by the actinobacterium Actinoplanes teichomyceticus. Tcp is a front-line therapy for treating severe infections caused by multidrug-resistant Gram-positive pathogens in adults and infants. In this review, we provide a detailed overview of how Tcp is produced by A. teichomyceticus by describing Tcp biosynthesis, regulation, and resistance. We summarize the knowledge gained from in vivo and in vitro studies to provide an integrated model of teicoplanin biosynthesis. Then, we discuss genetic and nutritional factors that contribute to the regulation of teicoplanin biosynthesis, focusing on those that have been successfully applied for improving teicoplanin production. A current view on teicoplanin self-resistance mechanisms in A. teichomyceticus is given, and we compare the Tcp biosynthetic gene cluster with other glycopeptide gene clusters from actinoplanetes and from unidentified isolates/metagenomics samples. Finally, we provide an outlook for further directions in studying Tcp biosynthesis and regulation.
BioMed Research International
Here we report functional characterization of the Streptomyces coelicolor M145 gene SCO1678, whic... more Here we report functional characterization of the Streptomyces coelicolor M145 gene SCO1678, which encodes a GntR-like regulator of the FadR subfamily. Bioinformatic analysis suggested that SCO1678 is part of putative operon (gnt) involved in gluconate metabolism. Combining the results of SCO1678 knockout, transcriptional analysis of gnt operon, and Sco1678 protein-DNA electromobility shift assays, we established that Sco1678 protein controls the gluconate operon. It does so via repression of its transcription from a single promoter located between genes SCO1678 and SCO1679. The knockout also influenced, in a medium-dependent manner, the production of secondary metabolites by S. coelicolor. In comparison to the wild type, on gluconate-containing minimal medium, the SCO1678 mutant produced much less actinorhodin and accumulated a yellow-colored pigment, likely to be the cryptic polyketide coelimycin. Possible links between gluconate metabolism and antibiotic production are discussed.
Folia Microbiologica
Streptomyces coelicolor genome carries two apparently paralogous genes, SCO4164 and SCO5854, that... more Streptomyces coelicolor genome carries two apparently paralogous genes, SCO4164 and SCO5854, that encode putative thiosulfate sulfurtransferases (rhodaneses). These genes (and their presumed translation products) are highly conserved and widely distributed across actinobacterial genomes. The SCO4164 knockout strain was unable to grow on minimal media with either sulfate or sulfite as the sole sulfur source. The SCO5854 mutant had no growth defects in the presence of various sulfur sources; however, it produced significantly less amounts of actinorhodin. Furthermore, we discuss possible links between basic interconversions of inorganic sulfur species and secondary metabolism in S. coelicolor.
Archives of microbiology, Jan 20, 2017
Streptomyces albus J1074 is one of the most popular and convenient hosts for heterologous express... more 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....
SpringerPlus, 2016
The gene bldA for leucyl [Formula: see text] is known for almost 30 years as a key regulator of m... more The gene bldA for leucyl [Formula: see text] is known for almost 30 years as a key regulator of morphogenesis and secondary metabolism in genus Streptomyces. Codon UUA is the rarest one in Streptomyces genomes and is present exclusively in genes with auxiliary functions. Delayed accumulation of translation-competent [Formula: see text] is believed to confine the expression of UUA-containing transcripts to stationary phase. Implicit to the regulatory function of UUA codon is the assumption about high accuracy of its translation, e.g. the latter should not occur in the absence of cognate [Formula: see text]. However, a growing body of facts points to the possibility of mistranslation of UUA-containing transcripts in the bldA-deficient mutants. It is not known what type of near-cognate tRNA(s) may decode UUA in the absence of cognate tRNA in Streptomyces, and whether UUA possesses certain inherent properties (such as increased/decreased accuracy of decoding) that would favor its use fo...
Applied Microbiology and Biotechnology, 2016
A gene cluster for the biosynthesis of moenomycin family antibiotics in the genome of teicoplanin... more 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.
Bacillus circulans Jordan 32352 was isolated from decaying organic matter in the New Jersey soil ... more Bacillus circulans Jordan 32352 was isolated from decaying organic matter in the New Jersey soil in the early 1930s. This soil-dwelling bacterium produced an enzyme capable of degrading the type 3 capsular polysaccharide (Pn3P) of Streptococcus pneumoniae (Spn). Early reports of this enzyme, Pn3Pase, demonstrated its inducibility by, and specificity for Pn3P. We set out to identify and clone this enzyme for its recombinant expression and characterization. We first sequenced the genome of this bacterial species, and reclassified the Pn3Pase producing bacterium as Paenibacillus species 32352. We identified the putative protein of Pn3Pase through mass spectrometry-based proteomics and cloned the gene for recombinant expression. We then characterized the oligosaccharide products generated upon the enzymatic depolymerization of Pn3P. Sequence analysis suggests that this glycoside hydrolase belongs to a new carbohydrate-active enzyme GH family. To our knowledge, this is the only enzyme to demonstrate Pn3P depolymerization activity.
ACS Chemical Biology, 2016
Antonie van Leeuwenhoek, Jan 7, 2016
The cell wall glycopolymers of three strains of Streptomyces albus and the type strain of Strepto... more The cell wall glycopolymers of three strains of Streptomyces albus and the type strain of Streptomyces pathocidini were investigated. The structures of the glycopolymers were established using a combination of chemical and NMR spectroscopic methods. The cell wall of S. albus subsp. albus VKM Ac-35(T) was found to be comprised of three glycopolymers, viz. unsubstituted 1,5-poly(ribitol phosphate), 1,3-poly(glycerol phosphate) substituted with β-D-glucopyranose, and the major polymer, a 3-deoxy-D-glycero-D-galacto-non-2-ulosonic acid (Kdn)-teichulosonic acid: β-D-Glcp-(1 → 8)-α-Kdnp-(2[(→6)-β-D-Glcp-(1 → 8)-α-Kdnp-(2 →] n 6)-β-D-Glcp-(1 → 8)-β-Kdnp-(2-OH, where n ≥ 3. The cell walls of 'S. albus' J1074 and 'S. albus' R1-100 were found to contain three glycopolymers of identical structures, viz. unsubstituted 1,3- and 2,3-poly(glycerol phosphates), and the major polymer, a Kdn-teichulosonic acid with an unusual structure that has not been previously described: β-D-Galp-...
T͡Sitologii͡a i genetika
Successful transfer of the studied plasmids into S. nogalater IMET43360 cells using bacterial con... more Successful transfer of the studied plasmids into S. nogalater IMET43360 cells using bacterial conjugation in the system E. coli--Streptomyces is an appropriate method for constructing this strain. Using DNA-DNA hybridization the character of integration of pVWB and pRT801 plasmids has been studied. The influence of these plasmids on nogalamycin biosynthesis has been investigated as well. The obtained results enable detailed study of nogalamycin gene functioning in S. nogalater IMET43360. The use of conjugation for substitution, destruction of genes, and heterological expression allows to get new "hybrid" antibiotics produced by this strain.
... Це свідчить про перспек-тивність використання DNRr-MyTaHTÍB для селекції штамів з високим рів... more ... Це свідчить про перспек-тивність використання DNRr-MyTaHTÍB для селекції штамів з високим рівнем синтезу DXR та здатних до утворення DXR з доданого DNR. LР Dubitska, VО Fedorenko Construction and selecthion strains Streptomyces peucetius subsp. ...
Antibiotiki i khimioterapii͡a = Antibiotics and chemoterapy [sic] / Ministerstvo meditsinskoĭ i mikrobiologicheskoĭ promyshlennosti SSSR
The growth of anthracycline producer Streptomices peucetius subsp. caesius ATCC 27952-2 was inhib... more The growth of anthracycline producer Streptomices peucetius subsp. caesius ATCC 27952-2 was inhibited by presence of glucose on complete media, containing alternative carbon sources. Amount of clones not producing antibiotic increased to 80.2 per cent along with elevation of glucose concentration in corn meal medium from 0.1 to 1.0 per cent. Mutants of S. peucetius subsp. caesius ATCC 27952-2 able to grow on complete media with 2 per cent of glucose (glr-mutants) were obtained. Glr-mutants had decreased antibiotic production in comparison with 27952-2 strain. 17 per cent of studied glr-mutants synthesized 1.6-3.1-fold quantities of anthracyclines in comparison with parental strain. Glr-mutants synthesized more biomass, although more slowly utilized glucose than strain 27952-2.
3 Biotech
Streptomyces cyanogenus S136 is the only known producer of landomycin A (LaA), one of the foundin... more Streptomyces cyanogenus S136 is the only known producer of landomycin A (LaA), one of the founding members of angucycline family of aromatic polyketides. LaA displays potent anticancer activities which has made this natural product a target of numerous chemical and cell biological studies. Little is known about the potential of S136 strain to produce other secondary metabolites. Here we report complete genome sequence of LaA producer and how we used this sequence to evaluate for this species its phylogenetic position and diversity of gene clusters for natural product biosynthesis.
Folia Microbiologica, 2018
Low molecular weight signaling compounds (LMWC) are important players in regulating various aspec... more Low molecular weight signaling compounds (LMWC) are important players in regulating various aspects of Streptomyces biology. Their exact roles in certain strain will ultimately depend on overall configuration of regulatory network and thus cannot be predicted on basis of in silico studies. Here, we explored S. ghanaensis gene SSFG_07725 (afsAgh) presumably involved in initial steps of formation of γ-butyrolactone LMWC. Disruption of afsAgh impaired aerial mycelium formation and increased the transcription of pleiotropic regulatory gene adpAgh, whereas level of moenomycin production remained virtually unaffected. We provide evidence that morphogenetic deficiency of afsAgh-minus mutant was caused by inability to produce diffusible LMWC. Possible links between γ-butyrolactone signaling and various aspects of S. ghanaensis biology are discussed.
Applied Microbiology and Biotechnology
Teicoplanin (Tcp) is a clinically relevant glycopeptide antibiotic (GPA) that is produced by the ... more Teicoplanin (Tcp) is a clinically relevant glycopeptide antibiotic (GPA) that is produced by the actinobacterium Actinoplanes teichomyceticus. Tcp is a front-line therapy for treating severe infections caused by multidrug-resistant Gram-positive pathogens in adults and infants. In this review, we provide a detailed overview of how Tcp is produced by A. teichomyceticus by describing Tcp biosynthesis, regulation, and resistance. We summarize the knowledge gained from in vivo and in vitro studies to provide an integrated model of teicoplanin biosynthesis. Then, we discuss genetic and nutritional factors that contribute to the regulation of teicoplanin biosynthesis, focusing on those that have been successfully applied for improving teicoplanin production. A current view on teicoplanin self-resistance mechanisms in A. teichomyceticus is given, and we compare the Tcp biosynthetic gene cluster with other glycopeptide gene clusters from actinoplanetes and from unidentified isolates/metagenomics samples. Finally, we provide an outlook for further directions in studying Tcp biosynthesis and regulation.
BioMed Research International
Here we report functional characterization of the Streptomyces coelicolor M145 gene SCO1678, whic... more Here we report functional characterization of the Streptomyces coelicolor M145 gene SCO1678, which encodes a GntR-like regulator of the FadR subfamily. Bioinformatic analysis suggested that SCO1678 is part of putative operon (gnt) involved in gluconate metabolism. Combining the results of SCO1678 knockout, transcriptional analysis of gnt operon, and Sco1678 protein-DNA electromobility shift assays, we established that Sco1678 protein controls the gluconate operon. It does so via repression of its transcription from a single promoter located between genes SCO1678 and SCO1679. The knockout also influenced, in a medium-dependent manner, the production of secondary metabolites by S. coelicolor. In comparison to the wild type, on gluconate-containing minimal medium, the SCO1678 mutant produced much less actinorhodin and accumulated a yellow-colored pigment, likely to be the cryptic polyketide coelimycin. Possible links between gluconate metabolism and antibiotic production are discussed.
Folia Microbiologica
Streptomyces coelicolor genome carries two apparently paralogous genes, SCO4164 and SCO5854, that... more Streptomyces coelicolor genome carries two apparently paralogous genes, SCO4164 and SCO5854, that encode putative thiosulfate sulfurtransferases (rhodaneses). These genes (and their presumed translation products) are highly conserved and widely distributed across actinobacterial genomes. The SCO4164 knockout strain was unable to grow on minimal media with either sulfate or sulfite as the sole sulfur source. The SCO5854 mutant had no growth defects in the presence of various sulfur sources; however, it produced significantly less amounts of actinorhodin. Furthermore, we discuss possible links between basic interconversions of inorganic sulfur species and secondary metabolism in S. coelicolor.
Archives of microbiology, Jan 20, 2017
Streptomyces albus J1074 is one of the most popular and convenient hosts for heterologous express... more 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....
SpringerPlus, 2016
The gene bldA for leucyl [Formula: see text] is known for almost 30 years as a key regulator of m... more The gene bldA for leucyl [Formula: see text] is known for almost 30 years as a key regulator of morphogenesis and secondary metabolism in genus Streptomyces. Codon UUA is the rarest one in Streptomyces genomes and is present exclusively in genes with auxiliary functions. Delayed accumulation of translation-competent [Formula: see text] is believed to confine the expression of UUA-containing transcripts to stationary phase. Implicit to the regulatory function of UUA codon is the assumption about high accuracy of its translation, e.g. the latter should not occur in the absence of cognate [Formula: see text]. However, a growing body of facts points to the possibility of mistranslation of UUA-containing transcripts in the bldA-deficient mutants. It is not known what type of near-cognate tRNA(s) may decode UUA in the absence of cognate tRNA in Streptomyces, and whether UUA possesses certain inherent properties (such as increased/decreased accuracy of decoding) that would favor its use fo...
Applied Microbiology and Biotechnology, 2016
A gene cluster for the biosynthesis of moenomycin family antibiotics in the genome of teicoplanin... more 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.
Bacillus circulans Jordan 32352 was isolated from decaying organic matter in the New Jersey soil ... more Bacillus circulans Jordan 32352 was isolated from decaying organic matter in the New Jersey soil in the early 1930s. This soil-dwelling bacterium produced an enzyme capable of degrading the type 3 capsular polysaccharide (Pn3P) of Streptococcus pneumoniae (Spn). Early reports of this enzyme, Pn3Pase, demonstrated its inducibility by, and specificity for Pn3P. We set out to identify and clone this enzyme for its recombinant expression and characterization. We first sequenced the genome of this bacterial species, and reclassified the Pn3Pase producing bacterium as Paenibacillus species 32352. We identified the putative protein of Pn3Pase through mass spectrometry-based proteomics and cloned the gene for recombinant expression. We then characterized the oligosaccharide products generated upon the enzymatic depolymerization of Pn3P. Sequence analysis suggests that this glycoside hydrolase belongs to a new carbohydrate-active enzyme GH family. To our knowledge, this is the only enzyme to demonstrate Pn3P depolymerization activity.
ACS Chemical Biology, 2016
Antonie van Leeuwenhoek, Jan 7, 2016
The cell wall glycopolymers of three strains of Streptomyces albus and the type strain of Strepto... more The cell wall glycopolymers of three strains of Streptomyces albus and the type strain of Streptomyces pathocidini were investigated. The structures of the glycopolymers were established using a combination of chemical and NMR spectroscopic methods. The cell wall of S. albus subsp. albus VKM Ac-35(T) was found to be comprised of three glycopolymers, viz. unsubstituted 1,5-poly(ribitol phosphate), 1,3-poly(glycerol phosphate) substituted with β-D-glucopyranose, and the major polymer, a 3-deoxy-D-glycero-D-galacto-non-2-ulosonic acid (Kdn)-teichulosonic acid: β-D-Glcp-(1 → 8)-α-Kdnp-(2[(→6)-β-D-Glcp-(1 → 8)-α-Kdnp-(2 →] n 6)-β-D-Glcp-(1 → 8)-β-Kdnp-(2-OH, where n ≥ 3. The cell walls of 'S. albus' J1074 and 'S. albus' R1-100 were found to contain three glycopolymers of identical structures, viz. unsubstituted 1,3- and 2,3-poly(glycerol phosphates), and the major polymer, a Kdn-teichulosonic acid with an unusual structure that has not been previously described: β-D-Galp-...
T͡Sitologii͡a i genetika
Successful transfer of the studied plasmids into S. nogalater IMET43360 cells using bacterial con... more Successful transfer of the studied plasmids into S. nogalater IMET43360 cells using bacterial conjugation in the system E. coli--Streptomyces is an appropriate method for constructing this strain. Using DNA-DNA hybridization the character of integration of pVWB and pRT801 plasmids has been studied. The influence of these plasmids on nogalamycin biosynthesis has been investigated as well. The obtained results enable detailed study of nogalamycin gene functioning in S. nogalater IMET43360. The use of conjugation for substitution, destruction of genes, and heterological expression allows to get new "hybrid" antibiotics produced by this strain.
... Це свідчить про перспек-тивність використання DNRr-MyTaHTÍB для селекції штамів з високим рів... more ... Це свідчить про перспек-тивність використання DNRr-MyTaHTÍB для селекції штамів з високим рівнем синтезу DXR та здатних до утворення DXR з доданого DNR. LР Dubitska, VО Fedorenko Construction and selecthion strains Streptomyces peucetius subsp. ...
Antibiotiki i khimioterapii͡a = Antibiotics and chemoterapy [sic] / Ministerstvo meditsinskoĭ i mikrobiologicheskoĭ promyshlennosti SSSR
The growth of anthracycline producer Streptomices peucetius subsp. caesius ATCC 27952-2 was inhib... more The growth of anthracycline producer Streptomices peucetius subsp. caesius ATCC 27952-2 was inhibited by presence of glucose on complete media, containing alternative carbon sources. Amount of clones not producing antibiotic increased to 80.2 per cent along with elevation of glucose concentration in corn meal medium from 0.1 to 1.0 per cent. Mutants of S. peucetius subsp. caesius ATCC 27952-2 able to grow on complete media with 2 per cent of glucose (glr-mutants) were obtained. Glr-mutants had decreased antibiotic production in comparison with 27952-2 strain. 17 per cent of studied glr-mutants synthesized 1.6-3.1-fold quantities of anthracyclines in comparison with parental strain. Glr-mutants synthesized more biomass, although more slowly utilized glucose than strain 27952-2.