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1.
Chem Pharm Bull (Tokyo) ; 72(5): 475-479, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38749722

RESUMO

Heterologous expression of natural compound biosynthetic gene clusters (BGCs) is a robust approach for not only revealing the biosynthetic mechanisms leading to the compounds, but also for discovering new products from uncharacterized BGCs. We established a heterologous expression technique applicable to huge biosynthetic gene clusters for generating large molecular secondary metabolites such as type-I polyketides. As an example, we targeted concanamycin BGC from Streptomyces neyagawaensis IFO13477 (the cluster size of 99 kbp), and obtained a bacterial artificial chromosome (BAC) clone with an insert size of 211 kbp that contains the entire concanamycin BGC. Interestingly, heterologous expression for this BAC clone resulted in two additional aromatic polyketides, ent-gephyromycin, and a new compound designated as JBIR-157, together with the expected concanamycin. Bioinformatic and biochemical analyses revealed that a cryptic biosynthetic gene cluster in this BAC clone was responsible for the production of these type-II polyketide synthases (PKS) compounds. Here, we describe the production, isolation, and structure elucidation of JBIR-157, determined primarily by a series of NMR spectral analyses.


Assuntos
Família Multigênica , Policetídeos , Streptomyces , Policetídeos/química , Policetídeos/metabolismo , Policetídeos/isolamento & purificação , Streptomyces/genética , Streptomyces/metabolismo , Streptomyces/química , Estrutura Molecular , Policetídeo Sintases/genética , Policetídeo Sintases/metabolismo , Conformação Molecular
2.
Biosci Biotechnol Biochem ; 84(8): 1570-1575, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32338185

RESUMO

Chemical screening of culture medium from the soil fungus Stachybotrys sp. resulted in the isolation of the three new phenylspirodrimanes MBJ-0030 (1), MBJ-0031 (2) and MBJ-0032 (3). Their structures were determined by detailed analysis of spectroscopic data. The absolute configurations of 1-3 were determined by modified Mosher's and Marfey's methods. In addition, cytotoxic and antimicrobial evaluations of the compounds were conducted.


Assuntos
Sesquiterpenos Policíclicos/química , Compostos de Espiro/química , Stachybotrys/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Micrococcus luteus/efeitos dos fármacos , Micrococcus luteus/crescimento & desenvolvimento , Sesquiterpenos Policíclicos/isolamento & purificação , Microbiologia do Solo , Compostos de Espiro/isolamento & purificação , Stachybotrys/isolamento & purificação
3.
J Am Chem Soc ; 140(21): 6631-6639, 2018 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-29716187

RESUMO

Benzastatins have unique structures probably derived from geranylated p-aminobenzoic acids. The indoline and tetrahydroquinoline scaffolds are presumably formed by cyclization of the geranyl moiety, but the cyclization mechanism was unknown. We studied the benzastatin biosynthetic gene cluster of Streptomyces sp. RI18; functions of the six enzymes encoded by it were analyzed by gene disruption in a heterologous host and in vitro enzyme assays. We propose the biosynthetic pathway for benzastatins in which a cytochrome P450 (BezE) is responsible for the cyclization of geranylated p-acetoxyaminobenzoic acids; BezE catalyzes elimination of acetic acid to form an iron nitrenoid, nitrene transfer to form an aziridine ring, and nucleophilic addition of hydroxide ion to C-10 and chloride ion to C-9 to generate the indoline and tetrahydroquinoline scaffolds, respectively. Discovery of this enzyme, which should be termed cytochrome P450 nitrene transferase, provides an important insight into the functional diversity of cytochrome P450.


Assuntos
Produtos Biológicos/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Quinolinas/metabolismo , Biocatálise , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Ciclização , Estrutura Molecular , Quinolinas/química , Streptomyces/química , Streptomyces/metabolismo
4.
Bioorg Med Chem ; 26(23-24): 6023-6034, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30455074

RESUMO

The synthesis and biological evaluation of thielocin B1 analogues have been demonstrated. Fourteen analogues modified in the central core and terminal carboxylic acid moiety were concisely synthesized by simple esterification or etherification reaction. The evaluation of synthetic analogues as inhibitors of proteasome assembling chaperone (PAC) complexes (the PAC3 homodimer and PAC1/PAC2) revealed that the natural product-like bending structure and terminal carboxylic acid groups were crucial for its biological activity. Moreover, SAR and in silico docking studies indicated that all methyl groups on the diphenyl ether moiety of thielocin B1 contribute to the potent and selective inhibition of the PAC3 homodimer via hydrophobic interactions.


Assuntos
Benzoatos/farmacologia , Ácidos Carboxílicos/farmacologia , Ésteres/farmacologia , Chaperonas Moleculares/antagonistas & inibidores , Complexo de Endopeptidases do Proteassoma/metabolismo , Benzoatos/síntese química , Benzoatos/química , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Dimerização , Relação Dose-Resposta a Droga , Ésteres/síntese química , Ésteres/química , Interações Hidrofóbicas e Hidrofílicas , Chaperonas Moleculares/metabolismo , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
5.
J Nat Prod ; 81(2): 264-269, 2018 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-29381067

RESUMO

During genome mining for thioviridamide-like biosynthetic gene clusters that could produce polythioamide RiPP (ribosomally synthesized and post-translationally modified peptides), we discovered a novel cryptic biosynthetic gene cluster. During efforts to express this biosynthetic gene using heterologous expression of this biosynthetic gene cluster, a novel compound designated as neothioviridamide was produced. We report herein the cloning and heterologous expression of the neothioviridamide biosynthetic gene cluster and the isolation, structure determination, and cytotoxic activity of neothioviridamide.


Assuntos
Família Multigênica/genética , Peptídeos Cíclicos/genética , Streptomyces/genética , Tioamidas/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Humanos , Células Jurkat , Estrutura Molecular , Peptídeos/genética
6.
Fungal Genet Biol ; 86: 58-70, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26703898

RESUMO

Ustiloxins were found recently to be the first example of cyclic peptidyl secondary metabolites that are ribosomally synthesized in filamentous fungi. In this work, two function-unknown genes (ustYa/ustYb) in the gene cluster for ustiloxins from Aspergillus flavus were found experimentally to be involved in cyclization of the peptide. Their homologous genes are observed mainly in filamentous fungi and mushrooms. They have two "HXXHC" motifs that might form active sites. Computational genome analyses showed that these genes are frequently located near candidate genes for ribosomal peptide precursors, which have signal peptides at the N-termini and repeated sequences with core peptides for the cyclic portions, in the genomes of filamentous fungi, particularly Aspergilli, as observed in the ustiloxin gene cluster. Based on the combination of the ustYa/ustYb homologous genes and the nearby ribosomal peptide precursor candidate genes, 94 ribosomal peptide precursor candidates that were identified computationally from Aspergilli genome sequences were classified into more than 40 types including a wide variety of core peptide sequences. A set of the predicted ribosomal peptide biosynthetic genes was experimentally verified to synthesize a new cyclic peptide compound, designated as asperipin-2a, which comprises the amino acid sequence in the corresponding precursor gene, distinct from the ustiloxin precursors.


Assuntos
Aspergillus flavus/genética , Genes Fúngicos , Genes Sintéticos , Peptídeos Cíclicos/genética , Sequência de Aminoácidos , Genoma Fúngico , Dados de Sequência Molecular , Família Multigênica , Peptídeos Cíclicos/química , Ribossomos/metabolismo
7.
Chembiochem ; 17(11): 1021-8, 2016 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-27158812

RESUMO

JBIR-76 and -77 are isofuranonaphthoquinones (IFNQs) isolated from Streptomyces sp. RI-77. Draft genome sequencing and gene disruption analysis of Streptomyces sp. RI-77 showed that a type II polyketide synthase (PKS) gene cluster (ifn cluster) was responsible for the biosynthesis of JBIR-76 and -77. It was envisaged that an octaketide intermediate (C16 ) could be synthesized by the minimal PKS (IfnANO) and that formation of the IFNQ scaffold (C13 ) would therefore require a C-C bond cleavage reaction. An ifnQ disruptant accumulated some shunt products (C15 ), which were presumably produced by spontaneous cyclization of the decarboxylated octaketide intermediate. Recombinant IfnQ catalyzed the Baeyer-Villiger oxidation of 1-(2-naphthyl)acetone, an analogue of the bicyclic octaketide intermediate. Based on these results, we propose a pathway for the biosynthesis of JBIR-76 and -77, involving IfnQ-catalyzed C-C bond cleavage as a key step in the formation of the IFNQ scaffold.


Assuntos
Proteínas de Bactérias/metabolismo , Oxigenases de Função Mista/metabolismo , Naftoquinonas/metabolismo , Streptomyces/química , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Família Multigênica , Naftoquinonas/química , Policetídeo Sintases/genética , Policetídeo Sintases/metabolismo , Streptomyces/metabolismo
8.
Appl Environ Microbiol ; 82(12): 3640-8, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27084005

RESUMO

UNLABELLED: The antibiotic streptothricin (ST) possesses an amino sugar bound to an l-ß-lysine (ß-Lys) residue via a peptide bond. The peptide bond formation has been shown to be catalyzed by a nonribosomal peptide synthetase (NRPS) during ST biosynthesis. The focus of this study is the closely related ST analogue BD-12, which carries a glycine-derived side chain rather than a ß-Lys residue. Here, in Streptomyces luteocolor NBRC13826, we describe our biosynthetic studies of BD-12, which revealed that the peptide bond between the amino sugar and the glycine residue is catalyzed by a Fem-like enzyme (Orf11) in a tRNA-dependent manner rather than by an NRPS. Although there have been several reports of peptide bond-forming tRNA-dependent enzymes, to our knowledge, Orf11 is the first enzyme that can accept an amino sugar as a substrate. Our findings clearly demonstrate that the structural diversity of the side chains of ST-type compounds in nature is generated in an unusual manner via two distinct peptide bond-forming mechanisms. Moreover, the identification and functional analysis of Orf11 resulted in not only the production of new ST-related compounds, but also the provision of new insights into the structure-activity relationship of the ST-related antibiotics. IMPORTANCE: The antibiotic streptothricin (ST) possesses an amino sugar bound to an l-ß-lysine (ß-Lys) side chain via a peptide bond formed by a nonribosomal peptide synthetase (NRPS). BD-12, an analogue of ST, carries a glycine-derived side chain rather than ß-Lys, and here, we describe the BD-12-biosynthetic gene cluster from Streptomyces luteocolor NBRC13826, which contains the orf11 gene encoding a novel tRNA-dependent peptide bond-forming enzyme. The unique Fem-like enzyme (Orf11) accepts the amino sugar as a substrate and mediates the peptide formation between the amino sugar intermediate and glycine. Our studies demonstrate that the structural diversity of the side chains of ST-related compounds in nature is generated via two distinct peptide bond-forming mechanisms.


Assuntos
Amino Açúcares/metabolismo , Antibacterianos/biossíntese , RNA de Transferência/metabolismo , Streptomyces/metabolismo , Estreptotricinas/biossíntese , Aminoacilação , Redes e Vias Metabólicas , Streptomyces/enzimologia
9.
Angew Chem Int Ed Engl ; 55(28): 8072-5, 2016 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-27166860

RESUMO

The biosynthetic machinery of the first fungal ribosomally synthesized and post-translationally modified peptide (RiPP) ustiloxin B was elucidated through a series of gene inactivation and heterologous expression studies. The results confirmed an essential requirement for novel oxidases possessing the DUF3328 motif for macrocyclization, and highly unique side-chain modifications by three oxidases (UstCF1F2) and a pyridoxal 5'-phosphate (PLP)-dependent enzyme (UstD). These findings provide new insight into the expression of the RiPP gene clusters found in various fungi.


Assuntos
Vias Biossintéticas , Fungos/metabolismo , Peptídeos Cíclicos/metabolismo , Fungos/enzimologia , Fungos/genética , Família Multigênica , Oxirredutases/genética , Oxirredutases/metabolismo , Peptídeos Cíclicos/genética , Processamento de Proteína Pós-Traducional , Ribossomos/genética , Ribossomos/metabolismo
10.
Chembiochem ; 16(16): 2385-91, 2015 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-26403163

RESUMO

Streptazone derivatives isolated from Streptomyces species are piperidine alkaloids with a cyclopenta[b]pyridine scaffold. Previous studies indicated that these compounds are polyketides, but the biosynthetic enzymes responsible for their synthesis are unknown. Here, we have identified the streptazone E biosynthetic gene cluster in Streptomyces sp. MSC090213JE08, which encodes a modular type I PKS and tailoring enzymes that include an aminotransferase, three oxidoreductases, and two putative cyclases. The functions of the six tailoring enzymes were analyzed by gene disruption, and two putative biosynthetic intermediates that accumulated in particular mutants were structurally elucidated. On the basis of these results, we propose a pathway for the biosynthesis of streptazone E in which the two putative cyclases of the nuclear transport factor 2-like superfamily are responsible for C-C bond formation coupled with epoxide ring opening to give the five-membered ring of streptazone E.


Assuntos
Família Multigênica , Piperidinas/metabolismo , Streptomyces/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Liases/genética , Liases/metabolismo , Espectroscopia de Ressonância Magnética , Conformação Molecular , Oxirredutases/genética , Oxirredutases/metabolismo , Piperidinas/química , Piperidinas/isolamento & purificação , Policetídeo Sintases/metabolismo , Policetídeos/química , Policetídeos/metabolismo , Streptomyces/enzimologia , Streptomyces/genética , Transaminases/genética , Transaminases/metabolismo
11.
Chemistry ; 21(7): 3031-41, 2015 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-25524716

RESUMO

The total synthesis and stereochemical structural elucidation of JBIR-39, containing four nonproteinogenic piperazic acid (Piz) residues, is reported. The synthesis includes Sc(OTf)3 -catalyzed acylation of a Piz(γ-OTBS) derivative with piperazic acid chloride, providing the desired Piz-Piz(γ-OTBS) dipeptide in high yield without epimerization. After assembling two additional Piz moieties and (S)-isoleucic acid at the N-terminus, amidation with the (R)-α-methylserine ester at the C-terminus, and deprotection afforded the desired (2R,8S)-hexapeptide, which is the assumed structure of JBIR-39. Although the spectral data of the (2R,8S)-hexapeptide was not identical to JBIR-39, further synthesis of three stereoisomers confirmed the stereochemical structure of JBIR-39 to be (2S,6S,8S,11R,16S,21R,26S,27S).


Assuntos
Piridazinas/química , Acilação , Produtos Biológicos , Estrutura Molecular , Estereoisomerismo
12.
Chemistry ; 21(26): 9454-60, 2015 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-26014374

RESUMO

An asymmetric total synthesis of ent-pyripyropene A was achieved by a convergent synthetic route. We used our originally developed Ti(III) -catalyzed radical cyclization to construct an AB-ring portion that consisted of a trans-decalin skeleton with five contiguous stereogenic centers. The coupling between the AB-ring and the DE-ring portions, and a subsequent C-ring cyclization, led to the total synthesis of ent-pyripyropene A. An evaluation of the insecticidal activity of ent-pyripyropene A against two aphid species revealed that ent-pyripyropene A was 35-175 times less active than naturally occurring pyripyropene A. This result indicated that the biological target of pyripyropene A recognizes the absolute configuration of pyripyropene A.


Assuntos
Piridinas/síntese química , Sesquiterpenos/síntese química , Catálise , Estrutura Molecular , Piridinas/química , Sesquiterpenos/química , Estereoisomerismo , Titânio/química
13.
J Org Chem ; 80(1): 114-32, 2015 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-25437251

RESUMO

The planar and stereostructures of JBIR-108 isolated from Streptomyces gramineus IR087Pi-4 were determined partly by spectral analysis, and these structural assignments were confirmed and completed by the total synthesis of both 1-epimers. The key stereocenters in JBIR-108 were constructed via a Corey-Bakshi-Shibata (CBS) reduction (C-1), vinylogous Mukaiyama aldol reaction (C-7), and Brown crotylation (C-14 and C-15). Although it was difficult to determine the stereochemistries at the C-1 and C-7 positions in the natural product using the modified Mosher's method, the synthesis of two possible C-1 diastereomers enabled the identification of the configurations at the hitherto unknown stereocenters.


Assuntos
Furanos/síntese química , Furanos/isolamento & purificação , Streptomyces/química , Furanos/química , Conformação Molecular , Estrutura Molecular
14.
Angew Chem Int Ed Engl ; 54(13): 4046-50, 2015 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-25650886

RESUMO

Recent reports have highlighted the biological activity associated with a subfamily of the tetramic acid class of natural products. Despite the fact that members of this subfamily act as protein-protein interaction inhibitors that are of relevance to proteasome assembly, no synthetic work has been reported. This may be due to the fact that this subfamily contains an unnatural 4,4-disubstitued glutamic acid, the synthesis of which provides a key challenge. A highly stereoselective route to a masked form of this unnatural amino acid now enabled the synthesis of two of the possible diastereomers of JBIR-22 and allowed the assignment of its relative and absolute stereochemistry.


Assuntos
Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Pirrolidinonas/síntese química , Tetra-Hidronaftalenos/síntese química , Aminoácidos/química , Produtos Biológicos/química , Glutamatos/síntese química , Glutamatos/química , Conformação Molecular , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Estereoisomerismo , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacologia
15.
J Am Chem Soc ; 136(34): 12011-7, 2014 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-25078546

RESUMO

Development of efficient methods for preparation of bioactive nonribosomal peptides, containing densely functionalized nonproteinogenic amino acids, is an important task in organic synthesis. We have employed a concise synthesis for such amino acids by asymmetric aldol addition coupled with an isomeric resolution via diastereoselective cyclization. This approach is successfully applied to the first total synthesis of the cyclic hexapeptide aglycone of the mannopeptimycins, a group of glycopeptides known for potent activity against drug-resistant bacteria. The facile preparation of the key amino acids and the synthesis of the aglycone pave the way for further studies on this class of antibiotics and the development of new lead compounds with therapeutic potential. In addition, our studies have led to the revision of the stereochemistry of the ß-methylphenylalanine residue in the mannopeptimycin aglycone.


Assuntos
Antibacterianos/síntese química , Glicopeptídeos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Ciclização , Glicopeptídeos/química , Glicopeptídeos/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Staphylococcus aureus/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade
16.
Chembiochem ; 15(4): 527-32, 2014 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-24474719

RESUMO

Two new acyloin compounds were isolated from the thermophilic bacterium Thermosporothrix hazakensis SK20-1(T) . Genome sequencing of the bacterium and biochemical studies identified the thiamine diphosphate (TPP)-dependent enzyme Thzk0150, which is involved in the formation of acyloin. Through extensive analysis of the Thzk0150-catalyzed reaction products, we propose a putative reaction mechanism involving two substrates: 4-methyl-2-oxovalerate as an acyl donor and phenyl pyruvate as an acyl acceptor.


Assuntos
Chloroflexi/química , Álcoois Graxos/metabolismo , Proteínas de Bactérias/metabolismo , Biocatálise , Candida albicans/efeitos dos fármacos , Chloroflexi/metabolismo , Álcoois Graxos/química , Álcoois Graxos/farmacologia , Hexanonas/química , Hexanonas/metabolismo , Hexanonas/farmacologia , Cetoácidos/química , Cetoácidos/metabolismo , Ácidos Fenilpirúvicos/química , Ácidos Fenilpirúvicos/metabolismo
17.
Nat Chem Biol ; 8(9): 791-7, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22820420

RESUMO

The streptothricin (ST) antibiotics, produced by Streptomyces bacteria, contain L-ß-lysine ((3S)-3,6-diaminohexanoic acid) oligopeptides as pendant chains. Here we describe three unusual nonribosomal peptide synthetases (NRPSs) involved in ST biosynthesis: ORF 5 (a stand-alone adenylation (A) domain), ORF 18 (containing thiolation (T) and condensation (C) domains) and ORF 19 (a stand-alone A domain). We demonstrate that ST biosynthesis begins with adenylation of L-ß-lysine by ORF 5, followed by transfer to the T domain of ORF 18. In contrast, L-ß-lysine molecules adenylated by ORF 19 are used to elongate an L-ß-lysine peptide chain on ORF 18, a reaction unexpectedly catalyzed by ORF 19 itself. Finally, the C domain of ORF 18 catalyzes the condensation of L-ß-lysine oligopeptides covalently bound to ORF 18 with a freely diffusible intermediate to release the ST products. These results highlight an unusual activity for an A domain and unique mechanisms of crosstalk within NRPS machinery.


Assuntos
Monofosfato de Adenosina/metabolismo , Amidas/metabolismo , Estreptotricinas/biossíntese , Cromatografia Líquida de Alta Pressão , Clonagem Molecular , Família Multigênica , Fases de Leitura Aberta , Espectrometria de Massas por Ionização por Electrospray
18.
J Antibiot (Tokyo) ; 77(5): 288-298, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38438499

RESUMO

The biosynthetic gene clusters (BGCs) for the macrocyclic lactone-based polyketide compounds are extremely large-sized because the polyketide synthases that generate the polyketide chains of the basic backbone are of very high molecular weight. In developing a heterologous expression system for the large BGCs amenable to the production of such natural products, we selected concanamycin as an appropriate target. We obtained a bacterial artificial chromosome (BAC) clone with a 211-kb insert harboring the entire BGC responsible for the biosynthesis of concanamycin. Heterologous expression of this clone in a host strain, Streptomyces avermitilis SUKA32, permitted the production of concanamycin, as well as that of two additional aromatic polyketides. Structural elucidation identified these additional products as ent-gephyromycin and a novel compound that was designated JBIR-157. We describe herein sequencing and expression studies performed on these BGCs, demonstrating the utility of large BAC clones for the heterologous expression of cryptic or near-silent loci.


Assuntos
Cromossomos Artificiais Bacterianos , Família Multigênica , Streptomyces , Streptomyces/genética , Streptomyces/metabolismo , Cromossomos Artificiais Bacterianos/genética , Clonagem Molecular , Policetídeo Sintases/genética , Policetídeo Sintases/metabolismo , Policetídeos/metabolismo , Produtos Biológicos/metabolismo
19.
Biosci Biotechnol Biochem ; 77(3): 663-5, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23470743

RESUMO

As part of our chemical screening program for new microbial secondary metabolites, we discovered a new compound, JBIR-107 (1), from the culture of Streptomyces tateyamensis NBRC 105047 isolated from a marine sponge sample. Extensive NMR and MS spectroscopic data enabled the structure of 1 to be determined as 5-acetamido-6-(4-(methyl(2-oxo-3-phenylpropyl)amino)phenyl)-4-oxohexanoic acid.


Assuntos
Acetamidas/isolamento & purificação , Acetamidas/metabolismo , Organismos Aquáticos/microbiologia , Caproatos/isolamento & purificação , Caproatos/metabolismo , Poríferos/microbiologia , Streptomyces/metabolismo , Acetamidas/química , Animais , Caproatos/química , Fermentação , Streptomyces/isolamento & purificação
20.
Appl Environ Microbiol ; 78(22): 8015-24, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22961899

RESUMO

The γ-butyrolactone autoregulator signaling cascades have been shown to control secondary metabolism and/or morphological development among many Streptomyces species. However, the conservation and variation of the regulatory systems among actinomycetes remain to be clarified. The genome sequence of Kitasatospora setae, which also belongs to the family Streptomycetaceae containing the genus Streptomyces, has revealed the presence of three homologues of the autoregulator receptor: KsbA, which has previously been confirmed to be involved only in secondary metabolism; KsbB; and KsbC. We describe here the characterization of ksbC, whose regulatory cluster closely resembles the Streptomyces virginiae barA locus responsible for the autoregulator signaling cascade. Deletion of the gene ksbC resulted in lowered production of bafilomycin and a defect of aerial mycelium formation, together with the early and enhanced production of a novel ß-carboline alkaloid named kitasetaline. A putative kitasetaline biosynthetic gene cluster was identified, and its expression in a heterologous host led to the production of kitasetaline together with JBIR-133, the production of which is also detected in the ksbC disruptant, and JBIR-134 as novel ß-carboline alkaloids, indicating that these genes were biosynthetic genes for ß-carboline alkaloid and thus are the first such genes to be discovered in bacteria.


Assuntos
4-Butirolactona/metabolismo , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Redes e Vias Metabólicas/genética , Transdução de Sinais , Streptomycetaceae/citologia , Streptomycetaceae/genética , Proteínas de Bactérias/genética , Carbolinas/metabolismo , Deleção de Genes , Hifas/citologia , Hifas/crescimento & desenvolvimento , Macrolídeos/metabolismo , Streptomycetaceae/crescimento & desenvolvimento , Streptomycetaceae/metabolismo
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