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New Alpiniamides From Streptomyces sp. IB2014/011-12 Assembled by an Unusual Hybrid Non-ribosomal Peptide Synthetase Trans-AT Polyketide Synthase Enzyme.

ABSTRACT: The 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.

SUBMITTER: Paulus C

PROVIDER: S-EPMC6113372 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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New Alpiniamides From Streptomyces sp. IB2014/011-12 Assembled by an Unusual Hybrid Non-ribosomal Peptide Synthetase Trans-AT Polyketide Synthase Enzyme.

Paulus Constanze C Rebets Yuriy Y Zapp Josef J Rückert Christian C Kalinowski Jörn J Luzhetskyy Andriy A

Frontiers in microbiology 20180822

The 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 pa ...[more]

PMID: 30186270

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Project description:The improvement of genome sequencing techniques has brought to light the biosynthetic potential of actinomycetes due to the large number of gene clusters they present compared to the number of known compounds. Genome mining is a recent strategy in the search for novel bioactive compounds, which involves the analysis of sequenced genomes to identify uncharacterized natural product biosynthetic gene clusters, many of which are cryptic or silent under laboratory conditions, and to develop experimental approaches to identify their products. Owing to the importance of halogenation in terms of structural diversity, bioavailability, and bioactivity, searching for new halogenated bioactive compounds has become an interesting issue in the field of natural product discovery. Following this purpose, a screening for halogenase coding genes was performed on 12 Streptomyces strains isolated from fungus-growing ants of the Attini tribe. Using the bioinformatics tools antiSMASH and BLAST, six halogenase coding genes were identified. Some of these genes were located within biosynthetic gene clusters (BGCs), which were studied by construction of several mutants for the identification of the putative halogenated compounds produced. The comparison of the metabolite production profile of wild-type strains and their corresponding mutants by ultrahigh-performance liquid chromatography-UV and high-performance liquid chromatography-mass spectrometry allowed us the identification of a novel family of halogenated compounds in Streptomyces sp. strain CS147, designated colibrimycins. IMPORTANCE Genome mining has proven its usefulness in the search for novel bioactive compounds produced by microorganisms, and halogenases comprise an interesting starting point. In this work, we have identified a new halogenase coding gene that led to the discovery of novel lipopetide nonribosomal peptide synthetase/polyketide synthase (NRPS/PKS)-derived natural products, the colibrimycins, produced by Streptomyces sp. strain CS147, isolated from the Attini ant niche. Some colibrimycins display an unusual α-ketoamide moiety in the peptide structure. Although its biosynthetic origin remains unknown, its presence might be related to a hypothetical inhibition of virus proteases, and, together with the presence of the halogenase, it represents a feature to be incorporated in the arsenal of structural modifications available for combinatorial biosynthesis.

Project description:BackgroundThe genus Herbidospora comprises actinomycetes belonging to the family Streptosporangiaceae and currently contains five recognized species. Although other genera of this family often produce bioactive secondary metabolites, Herbidospora strains have not yet been reported to produce secondary metabolites. In the present study, to assess their potential as secondary metabolite producers, we sequenced the whole genomes of the five type strains and searched for the presence of their non-ribosomal peptide synthetase (NRPS) and type-I polyketide synthase (PKS) gene clusters. These clusters are involved in the major secondary metabolite-synthetic pathways in actinomycetes.ResultsThe genome sizes of Herbidospora cretacea NBRC 15474(T), Herbidospora mongoliensis NBRC 105882(T), Herbidospora yilanensis NBRC 106371(T), Herbidospora daliensis NBRC 106372(T) and Herbidospora sakaeratensis NBRC 102641(T) were 8.3, 9.0, 7.9, 8.5 and 8.6 Mb, respectively. They contained 15-18 modular NRPS and PKS gene clusters. Thirty-two NRPS and PKS pathways were identified, among which 9 pathways were conserved in all 5 strains, 8 were shared in 2-4 strains, and the remaining 15 were strain-specific. We predicted the chemical backbone structures of non-ribosomal peptides and polyketides synthesized by these gene clusters, based on module number and domain organization of NRPSs and PKSs. The relationship between 16S rRNA gene sequence-based phylogeny of the five strains and the distribution of their NRPS and PKS gene clusters were also discussed.ConclusionsThe genomes of Herbidospora strains carry as many NRPS and PKS gene clusters, whose products are yet to be isolated, as those of Streptomyces. Herbidospora members should synthesize large and diverse metabolites, many of whose chemical structures are yet to be reported. In addition to those conserved within this genus, each strain possesses many strain-specific gene clusters, suggesting the diversity of these pathways. This diversity could be accounted for by genus-level vertical inheritance and recent acquisition of these gene clusters during evolution. This genome analysis suggested that Herbidospora strains are an untapped and attractive source of novel secondary metabolites.

Dataset Information

New Alpiniamides From Streptomyces sp. IB2014/011-12 Assembled by an Unusual Hybrid Non-ribosomal Peptide Synthetase Trans-AT Polyketide Synthase Enzyme.

Publications

New Alpiniamides From <i>Streptomyces</i> sp. IB2014/011-12 Assembled by an Unusual Hybrid Non-ribosomal Peptide Synthetase <i>Trans</i>-AT Polyketide Synthase Enzyme.

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