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Article

Differences at Species Level and in Repertoires of Secondary Metabolite Biosynthetic Gene Clusters among Streptomyces coelicolor A3(2) and Type Strains of S. coelicolor and Its Taxonomic Neighbors

by
Hisayuki Komaki
* and
Tomohiko Tamura
Biological Resource Center, National Institute of Technology and Evaluation (NBRC), Chiba 292-0818, Japan
*
Author to whom correspondence should be addressed.
Appl. Microbiol. 2021, 1(3), 573-585; https://doi.org/10.3390/applmicrobiol1030037
Submission received: 26 October 2021 / Revised: 12 November 2021 / Accepted: 16 November 2021 / Published: 18 November 2021
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Abstract

:
Streptomyces coelicolor A3(2) is used worldwide for genetic studies, and its complete genome sequence was published in 2002. However, as the whole genome of the type strain of S. coelicolor has not been analyzed, the relationship between S. coelicolor A3(2) and the type strain is not yet well known. To clarify differences in their biosynthetic potential, as well as their taxonomic positions, we sequenced whole genomes of S. coelicolor NBRC 12854T and type strains of its closely related species—such as Streptomyces daghestanicus, Streptomyces hydrogenans, and Streptomyces violascens—via PacBio. Biosynthetic gene clusters for polyketides and non-ribosomal peptides were surveyed by antiSMASH, followed by bioinformatic analyses. Type strains of Streptomyces albidoflavus, S. coelicolor, S. daghestanicus, S. hydrogenans, and S. violascens shared the same 16S rDNA sequence, but S. coelicolor A3(2) did not. S. coelicolor A3(2) and S. coelicolor NBRC 12854T can be classified as Streptomyces anthocyanicus and S. albidoflavus, respectively. In contrast, S. daghestanicus, S. hydrogenans, and S. violascens are independent species, despite their identical 16S rDNA sequences. S. coelicolor A3(2), S. coelicolor NBRC 12854T, S. daghestanicus NBRC 12762T, S. hydrogenans NBRC 13475T, and S. violascens NBRC 12920T each harbor specific polyketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS) gene clusters in their genomes, whereas PKS and NRPS gene clusters are well conserved between S. coelicolor A3(2) and S. anthocyanicus JCM 5058T, and between S. coelicolor NBRC 12854T and S. albidoflavus DSM 40455T, belonging to the same species. These results support our hypothesis that the repertoires of PKS and NRPS gene clusters are different between different species.

1. Introduction

Actinomycetes are Gram-positive filamentous bacteria that are attracting attention as a source of bioactive secondary metabolites. Many pharmaceuticals, such as antibiotics, have been developed from these metabolites. The genus Streptomyces is a representative actinomycete, and includes approximately 673 species with validly published names at present. These members are a promising source of diverse bioactive compounds. In 1908, “Streptothrix coelicolor” (the former genus name for Streptomyces), which was characterized by its production of a blue pigment, was isolated by Müller [1,2]. The species name Streptomyces coelicolor was effectively published by Waksman and Henrici in 1948 [3], and validly approved in 1980 [4]. The type strain is Müller’s strain, and has been added to the NBRC culture collection as NBRC 12854T. On the other hand, Streptomyces coelicolor A3(2) is derived from Waksman’s strain 3443. Stanier obtained several cultures from Waksman, which were classified as “Actinomyces coelicolor” based on cultural characteristics. Erikson obtained Waksman’s strain 3443 from Stanier through van Niel, isolated a single spore, and designated it Streptomyces coelicolor A3(2) according to the current systematics for actinomycetes. Hopwood obtained this strain from Erikson as a starting strain for use in genetic work [1]. Today, S. coelicolor A3(2) is used worldwide for genetic studies, and as a host for gene cloning experiments of streptomycetes [5,6,7]. According to a PubMed search, more than 3000 papers in which S. coelicolor A3(2) is used have been published to date. In 2002, the whole genome of the strain was sequenced, which revealed that it harbors a few dozen secondary metabolite biosynthetic gene clusters (smBGCs) in its genome. This number is more than that discovered by previous experiments based on activity-based screening for novel secondary metabolites. [8] Recent genome analyses have introduced a new approach called “genome mining” in the field of research for untapped secondary metabolites [9]. As the complete genome sequencing of S. coelicolor A3(2) had been published earlier, subsequent genome analyses of the genus Streptomyces have been targeted at strains belonging to species other than S. coelicolor [10]. Consequently, even the type strain of S. coelicolor has not been genome sequenced, although extensive whole-genome sequencing projects are ongoing [11]. The present study aims to provide the whole-genome sequence of the type strain, clarify the taxonomic relationship between S. coelicolor A3(2) and type strains of S. coelicolor and its closely related species, and reveal their potential to synthesize secondary metabolites such as polyketides and non-ribosomal peptides; it also aims to broaden knowledge about the potential of each strain as a source of diverse secondary metabolites, since these compounds are representative secondary metabolites in actinomycetes [10], diverse in bioactivities and structures, and often studied for evaluation as sources of new secondary metabolites [12,13,14,15,16,17]. This study posits that correct classification is significant in the pursuit of knowledge about the relationships between each species and their biosynthetic potential for secondary metabolites.

2. Materials and Methods

EzBioCloud [18] was used to search for taxonomic neighbors based on 16S rDNA sequences. Multilocus sequence analysis (MLSA) was conducted using DNA sequences of five housekeeping genes—atpD, gyrB, recA, rpoB, and trpB—as established in the genus Streptomyces [19]. The accession numbers of used gene sequences for MLSA are listed in Table 1. The phylogenetic trees were reconstructed using ClustalX 2.1 [20]. S. coelicolor NBRC 12854T, Streptomyces daghestanicus NBRC 12762T, Streptomyces hydrogenans NBRC 13475T, and Streptomyces violascens NBRC 12920T were distributed from the NBRC Culture Collection; their genomic DNA was prepared from cultured cells via the method of Saito and Kimura [21]. Subsequently, library preparation and whole-genome de novo sequencing were performed by the Kazusa DNA Research Institute using a single-molecule real-time (SMRT) strategy. Sequencing was performed using the BluePippin system (Sage Science) with a SMRTbell Template Prep Kit 1.0 and a SMRTbell Damage Repair Kit (Pacific Bioscience), via the Sequel system with Sequel SMRT cell 1M versions 2 and 3, Sequel Sequencing Kits 2.1 and 3.0, a Sequel Binding Kit 2.0, and a Sequel Binding and Internal Ctrl Kit 3.0 (Pacific Biosciences). The resulting reads for each strain were assembled using SMRT Link version 6.0 (Pacific Bioscience) and Prokka 1.13.3. The assembled genome sequences were deposited to DDBJ under the following accession numbers: S. coelicolor NBRC 12854T, BNDZ00000000.1; S. daghestanicus NBRC 12762T, BNDX00000000.1; S. hydrogenans NBRC 13475T, BNDW00000000.1; and S. violascens NBRC 12920T, BNDY00000000.1. DNA–DNA relatedness was digitally calculated using Formula 2 of the Genome-to-Genome Distance Calculator (GGDC) [22]. Polyketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS) gene clusters in the genomes were surveyed using antiSMASH [23], and then manually analyzed as reported previously [15].

3. Results

3.1. Taxnomic Positions of S. coelicolor and Related Strains

S. coelicolor NBRC 12854T shares the same 16S rDNA sequences as those of the type strains of Streptomyces albidoflavus, S. daghestanicus, S. hydrogenans, and S. violascens, but the similarity between S. coelicolor strains NBRC 12854T and A3(2) is only 97.8%. However, S. coelicolor A3(2) showed sequence similarities of 100% to the type strains of Streptomyces anthocyanicus, Streptomyces violaceoruber, and Streptomyces tricolor. These two S. coelicolor strains are phylogenetically distant, as shown in Figure 1.
We also reconstructed a phylogenetic tree based on MLSA because it is often used to elucidate more precise phylogenetic relationships in the genus Streptomyces [19]. As shown in Figure 2, S. coelicolor NBRC 12854T formed a clade with S. albidoflavus, but the clade did not include S. daghestanicus, S. hydrogenans, or S. violascens. In contrast, S. coelicolor A3(2) formed a clade with S. anthocyanicus, S. violaceoruber, and S. tricolor. These results also support the hypothesis that the two S. coelicolor strains are phylogenetically distant.
To identify species, we conducted digital DNA–DNA hybridization (DDH). DNA–DNA relatedness of 70% is recognized to be the cutoff of species delineation [22,24]. The relatedness of strain A3(2) to the type strains of S. coelicolor and S. anthocyanicus was 23.1% and 94.2%, respectively, suggesting that strain A3(2) is not S. coelicolor but S. anthocyanicus. In contrast, as DNA–DNA relatedness between the type strains of S. coelicolor and S. albidoflavus was 91.8%; thus, these two species are synonymous, as reported in [25]. The type strains of S. coelicolor/S. albidoflavus S. daghestanicus, S. hydrogenans, and S. violascens did not show DNA–DNA relatedness of > 70% with one another, suggesting each to be an independent species (Table 2).

3.2. PKS and NRPS Gene Clusters in Genomes

As shown in Figure 3, S. coelicolor A3(2) possessed eight PKS and four NRPS gene clusters, [8] whereas S. anthocyanicus JCM 5058T harbored six PKS and four NRPS gene clusters. Ten gene clusters (closed circle)—excluding the PKS gene clusters for coelimycin and arsono-polyketide (open circle)—were conserved between S. coelicolor A3(2) and S. anthocyanicus JCM 5058T, which were classified as the same species, as stated in the previous section. S. coelicolor NBRC 12854T had three PKS, six NRPS, and four hybrid PKS/NRPS gene clusters, whereas S. albidoflavus DSM 40455T had two PKS, six NRPS, and four hybrid PKS/NRPS gene clusters. Twelve (closed circle) gene clusters—excluding fdm (fredericamycin) (open circle) [26]—were conserved between S. coelicolor NBRC 12854T and S. albidoflavus DSM 40455T, since S. coelicolor and S. albidoflavus are synonymous species. In contrast, among the twelve gene clusters of S. coelicolor A3(2), seven PKS and four NRPS gene clusters—excluding rpp [27,28]—were not present in the genome of S. coelicolor NBRC 12854T. S. daghestanicus NBRC 12762T encoded four PKS, one NRPS, and four hybrid PKS/NRPS gene clusters in its genome. Six gene clusters—excluding pfa (polyunsaturated fatty acid), ant (antimycin) [29], and rpp—were specific to this strain among the strains studied here. S. hydrogenans NBRC 13475T possessed seven PKS, two NRPS, and three hybrid PKS/NRPS gene clusters. Ten gene clusters—excluding pfa and whi (spore pigment) [8,30]—were specific to this strain. S. violascens NBRC 12920T harbored six PKS, six NRPS, and one hybrid PKS/NRPS gene clusters. Twelve gene clusters—excluding the NRPS gene cluster for coelichelin—were specific to this strain. Although S. coelicolor NBRC 12854T, S. daghestanicus NBRC 12762T, S. hydrogenans NBRC 13475T, and S. violascens NBRC 12920T are phylogenetically close (Figure 1), most of their PKS and NRPS gene clusters were not conserved between the different species. In the seven strains, t1pks-1 to -5, one t2pks named tjh, one t3pks named plh, nrps-1 to -10, and pks/nrps-1 to -7 were orphan, and their products have not been experimentally clarified and, thus, could not be identified by our bioinformatic analysis.

3.3. Prediction of Products Synthesized by Orphan PKS and NRPS Gene Clusters

According to the co-linearity of the assembly lines [31], the backbones of polyketides and non-ribosomal peptides can be bioinformatically predicted from the sequences of the PKS and NRPS gene clusters. Based on the module numbers, substrates of adenylation (A) domains, and domain organizations [15], we predicted the products of orphan PKS and NRPS gene clusters in S. coelicolor A3(2), S. coelicolor NBRC 12854T, S. daghestanicus NBRC 12762T, S. hydrogenans NBRC 13475T, and S. violascens NBRC 12920T. Each strain possesses 1–9 orphan PKS and/or NRPS gene clusters. These products are diverse, as shown in Table 3, although some products could not be predicted because they are not multimodular. In addition to the known secondary metabolites shown in Figure 3, these strains show the potential to produce novel polyketides and non-ribosomal peptides.

4. Discussion

S. coelicolor A3(2) is the best studied strain as a model microorganism of actinomycetes. It has been extensively used for elucidating mechanisms in morphological differentiation [32], physiological features [33,34], metabolisms [35,36], and genetic regulation [37,38,39] in the genus Streptomyces. The genetics of actinomycetes were especially advanced with the strain [7]. Its wild strain and derived strains have contributed to various biotechnological fields. It is notable that these strains are used as the hosts for heterogeneous secondary metabolite production [40,41,42,43,44]. In contrast to these applications, the classification of S. coelicolor A3(2) has been paid less attention. Hatano et al. [1] reclassified strain A3(2) from S. coelicolor to S. violaceoruber; however, this reclassification is not widely known. In addition to many recent reports [45,46,47,48], even GenBank still classifies strain A3(2) as S. coelicolor [49,50]. In this study, we showed that strain A3(2) can be reclassified to S. anthocyanicus based on DNA–DNA relatedness, because the whole-genome sequence of the type strain of S. violaceoruber has not yet been published. Very recently, Komaki proposed that S. anthocyanicus and Streptomyces tricolor are later heterotypic synonyms of S. violaceoruber, in a paper submitted to the International Journal of Systematic and Evolutionary Microbiology that is now under review. Therefore, there is no contradiction between the report by Hatano et al. and our present results.
Rong et al. reclassified S. coelicolor to S. albidoflavus based on multilocus sequence analysis, DDH experiments, and phenotypic comparisons [25]; our digital DDH supported this. Even if it is recognized that strain A3(2) and the type strain of S. coelicolor belong to different species, many researchers may think that S. coelicolor A3(2) and the type strain of S. coelicolor harbor a similar set of smBGCs, because they believe that there is no correlation between taxonomic species and secondary metabolites. Our present study provides the evidence to deny this possibility, and rather supports our hypothesis that strains belonging to different species harbor different repertoires of PKS and NRPS gene clusters—even if they are phylogenetically close [15,51,52,53,54]. S. coelicolor A3(2) and the type strains of S. anthocyanicus, S. violaceoruber, and S. tricolor share the same 16S rDNA sequence, and these four strains can be reclassified to the same species. In contrast, the type strains of S. albidoflavus/S. coelicolor, S. daghestanicus, S. hydrogenans, and S. violascens also share the same 16S rDNA sequence, but these four are independent species. It is often reported that the resolution of 16S rDNA sequences is so low that we are unable to classify Streptomyces members at the species level by only analyzing 16S rDNA sequences [15,55,56]. The present study suggests that each species harbors specific smBGCs. These gene clusters might have moved via repeated and/or complicated horizontal gene transfers (HGTs) between various Streptomyces strains. On the other hand, HGTs between strains belonging to the same species may not be as frequent, because strains within the same species—such as strains A3(2) and JCM 5058T of S. anthocyanicus, or strains NBRC 12854 and DSM 40455T of S. albidoflavus—harbor a similar set of PKS and NRPS gene clusters. In contrast, it has been reported that a part of the secondary metabolism is related more to strain ecology than to the phylogeny of a strain [57]. It is still unclear whether the presence of PKS and NRPS gene clusters in genomes indeed changes based on the ecology of strains. Our genome analysis of the type strains of the four species revealed the presence of many orphan PKS and NRPS pathways whose metabolites have not yet been identified; their presence suggests the potential for producing novel polyketides and non-ribosomal peptides through further research. Appropriate classification at the species level is significant in the search for bioactive secondary metabolites in the post-genomic era, and to deepen our understanding of the relationship between taxonomical species and smBGCs.

5. Conclusions

We examined the taxonomic relationships between S. coelicolor A3(2) and the type strains of S. coelicolor and its phylogenetically close species. We suggest that S. coelicolor A3(2) should be reclassified to S. anthocyanicus, which is a synonym of S. violaceoruber, whereas S. coelicolor is a synonym of S. albidoflavus, as reported by Rong et al. [25]. Analysis of PKS and NRPS gene clusters in the genomes revealed that the repertoires of these gene clusters are quite different between S. coelicolor A3(2) and S. coelicolor NBRC 12854T, although these strains were once classified as S. coelicolor. Although the type strains of S. albidoflavus/S. coelicolor, S. daghestanicus, S. hydrogenans, and S. violascens share the same 16S rDNA sequence, they are independent species, and most of their PKS and NRPS gene clusters differ between the species. This is the first report on a genomic study for the type strains of S. coelicolor and its closely related species.

Author Contributions

Conceptualization, H.K. and T.T.; methodology, H.K. and T.T.; formal analysis, H.K.; investigation, H.K.; resources, T.T.; data curation, H.K.; writing—original draft preparation, H.K.; writing—review and editing, T.T.; funding acquisition, T.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported in part by a commissioned project from the Japan Patent Office.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The whole genome shotgun project of S. coelicolor NBRC 12854T, S. daghestanicus NBRC 12762T, S. hydrogenans NBRC 13475T and S. violascens NBRC 12920T have been deposited at GenBank under the accession numbers BNDZ00000000, BNDX00000000, BNDW00000000 and BNDY00000000, respectively. BioProject accession numbers are PRJDB9785, PRJDB9783, PRJDB9782 and PRJDB9784. BioSample accession numbers are SAMD00228000, SAMD00227998, SAMD00227997 and SAMD00227999.

Acknowledgments

We thank Shinpei Ino and Takahiro Matsuyama for genome DNA preparation, and Aya Uohara for registering the genome sequences in the DDBJ.

Conflicts of Interest

The authors declare no conflict of interest.

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Applmicrobiol 01 00037 g001 550
Figure 1. Phylogenetic tree based on the 16S rDNA sequences. Numbers on the branches represent the confidence limits estimated by a bootstrap analysis with 1000 replicates; values above 50% are at the branching points. Streptomyces albus NBRC 13014T (AB184257) was used as an outgroup.
Figure 1. Phylogenetic tree based on the 16S rDNA sequences. Numbers on the branches represent the confidence limits estimated by a bootstrap analysis with 1000 replicates; values above 50% are at the branching points. Streptomyces albus NBRC 13014T (AB184257) was used as an outgroup.
Applmicrobiol 01 00037 g001
Applmicrobiol 01 00037 g002 550
Figure 2. Phylogenetic tree based on MLSA. Numbers on the branches represent the confidence limits estimated by a bootstrap analysis with 1000 replicates; values above 50% are at the branching points. S. albus NBRC 13014T was used as an outgroup.
Figure 2. Phylogenetic tree based on MLSA. Numbers on the branches represent the confidence limits estimated by a bootstrap analysis with 1000 replicates; values above 50% are at the branching points. S. albus NBRC 13014T was used as an outgroup.
Applmicrobiol 01 00037 g002
Applmicrobiol 01 00037 g003 550
Figure 3. PKS and NRPS gene clusters in genomes. Only chromosome or scaffold sequences encoding these gene clusters are indicated by black and bold horizontal lines. Alignments and directions of the scaffold sequences in six strains—excluding S. coelicolor A3(2)—are unclear, because their whole-genome sequences are incomplete drafts. The parts that look like gaps, where no PKS and NRPS gene clusters are present, are equally spaced in the figures of S. daghestanicus NBRC 12762T, S. hydrogenans NBRC 13475T, and S. violascens NBRC 12920T, because the lengths are unpredictable; however, the parts of S. anthocyanicus JCM 5058T and S. albidoflavus DSM 40455T are not, because they are aligned according to locations of PKS and NRPS gene clusters in the S. coelicolor A3(2) chromosome and S. coelicolor NBRC 12854T draft genome sequences, respectively. Light-gray horizontal dashed lines under the black and bold lines indicate putative whole genomes, such as chromosomes. Red: PKS gene cluster; blue: NRPS gene cluster; green: hybrid PKS/NRPS gene cluster; CDA: calcium-dependent antibiotics; THN: 1,3,6,8-tetrahydroxynaphthalene; ptm: polycyclic tetramate macrolactam biosynthetic gene cluster; t1pks: type-I PKS gene cluster; t2pks: type-II PKS gene cluster; t3pks: type-III PKS gene cluster. Gene clusters are shown as the products and/or gene names. As t1pks-1 to -5, tjh, phl, nrps-1 to -9, and pks/nrps-1 to -7 are orphan, their products are unclear. Gene clusters shown as closed circles are present in other strain(s) studied in this study, as connected by dashed lines. Gene clusters specific to each strain are shown by open circles. rppA, gcs, and phl are t3pks; act, whi, fdm, arx, lug, and tjh are t2pks; the other named PKS gene clusters are t1pks. All of the gene clusters shown here are completely sequenced in these draft genome sequences. →, S. coelicolor A3(2) is reclassified to S. anthocyanicus; =, S. coelicolor is a synonym of S. albidoflavus.
Figure 3. PKS and NRPS gene clusters in genomes. Only chromosome or scaffold sequences encoding these gene clusters are indicated by black and bold horizontal lines. Alignments and directions of the scaffold sequences in six strains—excluding S. coelicolor A3(2)—are unclear, because their whole-genome sequences are incomplete drafts. The parts that look like gaps, where no PKS and NRPS gene clusters are present, are equally spaced in the figures of S. daghestanicus NBRC 12762T, S. hydrogenans NBRC 13475T, and S. violascens NBRC 12920T, because the lengths are unpredictable; however, the parts of S. anthocyanicus JCM 5058T and S. albidoflavus DSM 40455T are not, because they are aligned according to locations of PKS and NRPS gene clusters in the S. coelicolor A3(2) chromosome and S. coelicolor NBRC 12854T draft genome sequences, respectively. Light-gray horizontal dashed lines under the black and bold lines indicate putative whole genomes, such as chromosomes. Red: PKS gene cluster; blue: NRPS gene cluster; green: hybrid PKS/NRPS gene cluster; CDA: calcium-dependent antibiotics; THN: 1,3,6,8-tetrahydroxynaphthalene; ptm: polycyclic tetramate macrolactam biosynthetic gene cluster; t1pks: type-I PKS gene cluster; t2pks: type-II PKS gene cluster; t3pks: type-III PKS gene cluster. Gene clusters are shown as the products and/or gene names. As t1pks-1 to -5, tjh, phl, nrps-1 to -9, and pks/nrps-1 to -7 are orphan, their products are unclear. Gene clusters shown as closed circles are present in other strain(s) studied in this study, as connected by dashed lines. Gene clusters specific to each strain are shown by open circles. rppA, gcs, and phl are t3pks; act, whi, fdm, arx, lug, and tjh are t2pks; the other named PKS gene clusters are t1pks. All of the gene clusters shown here are completely sequenced in these draft genome sequences. →, S. coelicolor A3(2) is reclassified to S. anthocyanicus; =, S. coelicolor is a synonym of S. albidoflavus.
Applmicrobiol 01 00037 g003
Table
Table 1. Accession numbers of housekeeping gene sequences used in MLSA.
Table 1. Accession numbers of housekeeping gene sequences used in MLSA.
StrainatpDgyrBrecArpoBtrpB
S. albus NBRC 13014TBBQG01000033BBQG01000007BBQG01000035BBQG01000012BBQG01000017
“S. abyssomicinicus” CHI39TBBZI01000006BBZI01000009BBZI01000014BBZI01000006BBZI01000008
S. albidoflavus DSM 40455TFJ406416FJ406427FJ406438FJ406449FJ406460
S. althioticus NRRL B-3981TKT384460KT384809KT385157KT388779KT389129
S. ambofaciens NRRL B-2516TKT384462KT384811KT385159KT388781KT389131
S. anthocyanicus NRRL B-24292TKT384465KT384814KT385162KT388784KT389134
S. ardesiacus NRRL B-1773TKT384534KT384883KT385231KT388853KT389203
S. arenae NRRL ISP 5293TKT384470KT384819KT385167KT388789KT389139
S. cadmiisoli ZFG47TCP030073CP030073CP030073CP030073CP030073
S. carpinensis NRRL B-16921TKT384503KT384852KT385200KT388822KT389172
S. cinerochromogenes NRRL B-16928TKT384514KT384863KT385211KT388833KT389183
S. coelicoflavus NRRL B-16363TKT384524KT384873KT385221KT388843KT389193
S. coelicolor NBRC 12854TBNDZ01000005BNDZ01000005BNDZ01000003BNDZ01000005BNDZ01000005
S. coelicolor A3(2)AL939123AL939118AL939125AL939121AL939121
S. coeruleorubidus NRRL B-2569TKT384528KT384877KT385225KT388847KT389197
S. collinus NRRL B-5412TKT384529KT384878KT385226KT388848KT389198
S. daghestanicus NRRL B-5418TKJ137021KJ137038KJ137055KJ996779KJ137089
S. diastaticus NBRC 13412TBLLN01000005BLLN01000002_BLLN01000005BLLN01000002BLLN01000003
S. eurythermus NRRL ISP-5014TKT384544KT384893KT385242KT388863KT389213
S. flaveolus NRRL B-1334TKT384550KT384899KT385248KT388869KT389219
S. flavofungini JCM 4753TJAEKOZ01000002JAEKOZ01000001JAEKOZ010000015JAEKOZ010000008JAEKOZ010000005
S. fragilis NBRC 12862TBEVZ01000004BEVZ01000008BEVZ01000002BEVZ01000004BEVZ01000003
S. griseoflavus NRRL B-5312TKT384578KT384927KT385276KT388897KT389247
S. griseoincarnatus NRRL B-5313TKT384580KT384929KT385278KT388899KT389249
S. griseorubens NRRL B-3982TKT384583KT384932KT385281KT388903KT389252
S. hawaiiensis NRRL B-1988TKT384592KT384941KT385290KT388912KT389261
S. hyderabadensis JCM 17657TJAIOJZ010000004JAIOJZ010000004JAIOJZ010000060JAIOJZ010000079JAIOJZ010000001
S. hydrogenans NBRC 13475TBNDW01000004BNDW01000040BNDW01000004BNDW01000004BNDW01000019
S. iakyrus NRRL B-3317TKT384600KT384949KT385298KT388920KT389269
S. indiaensis NRRL B-24311TKT384601KT384950KT385300KT388921KT389270
S. intermedius NRRL B-2670TKT384602KT384951KT385301KT388922KT389271
S. janthinus NRRL B-3365TKT384604KT384953KT385303KT388924KT389273
S. koyangensis JCM 14915TLC381971LC381972LC381973LC381974LC413709
S. lavenduligriseus NRRL ISP-5487TJOBD01000030JOBD01000019JOBD01000017JOBD01000005JOBD01000013
S. levis NRRL B-16370TKT384621KT384970KT385320KT388941KT389290
S. lienomycini NRRL B-16371TKT384622KT384971KT385321KT388942KT389291
S. lomondensis NRRL 3252TKT384626KT384975KT385326KT388946KT389295
S. luteogriseus NRRL B-12422TKT384632KT384981KT385332KT388952KT389301
S. massasporeus NRRL B-3300TKT384636KT384985KT385336KT388956KT389305
S. mutabilis NRRL ISP-5169TKT384652KT385002KT385353KT388972KT389321
S. nigra 452TCP029043CP029043CP029043CP029043CP029043
S. nogalater NRRL ISP-5546TKT384664KT385014KT385365KT388984KT389333
S. olivaceus NRRL B-1224TKT384667KT385017KT385368KT388987KT389336
S. pactum ATCC 27456TJACYXC010000001JACYXC010000001JACYXC010000001JACYXC010000001JACYXC010000001
S. paradoxus NRRL B-3457TKT384674KT385024KT385375KT388994KT389343
S. parvulus NRRL B-1628TKJ196367KJ196369KJ196371KJ196373KJ196375
S. purpurascens NRRL B-12230TKT384696KT385046KT385397KT389017KT389365
S. rochei NRRL B-2410TKT384704KT385054KT385405KT389025KT389373
S. roseoviolaceus NRRL B-12177TKT384710KT385060KT385411KT389031KT389379
S. rubrogriseus NRRL B-24295TKT384715KT385065KT385416KT389036KT389384
S. spinoverrucosus NRRL B-16932TKT384725KT385074KT385426KT844525 *KT389394
S. tendae NRRL B-2313TKT384733KT385082KT385434KT389053KT389402
S. tibetensis XZ 46TSZVR01000021SZVR01000021SZVR01000011SZVR01000023SZVR01000005
S. tricolor NBRC 103112TLC634004LC634005LC634006LC634007LC634008
S. tuirus NRRL B-3631TKT384742KT385090KT385444KT389062KT389411
S. venetus CMU-AB225TLC381976LC381977LC381978LC381979LC381980
S. violaceochromogenes NRRL B-5427TKT384748KT385096KT385450KT389068KT389417
S. violaceoruber NBRC 12826TLC634009LC634010LC634011LC634012LC634013
S. violaceorubidus NRRL B-16381TJODM01000021JODM01000004JODM01000011JODM01000001JODM01000015
S. violaceus JCM 4533TLC381981LC381982LC381983LC381984LC381985
S. violarus JCM 4534TBMUP01000003BMUP01000013BMUP01000001BMUP01000012BMUP01000009
S. violascens NRRL B-2700TKT384752KT385100KT385454KT389072KT389421
S. viridochromogenes NRRL B-1511TKT384756KT385104KT385458KT389076KT389425
S. viridodiastaticus NRRL B-5622TKT384757KT385105KT385459KT389077KT389426
* As the sequence of S. spinoverrucosus NRRL B-16932T is not published in GenBank, that of S. spinoverrucosus DSM 41648T is alternatively used.
Table
Table 2. DNA–DNA relatedness.
Table 2. DNA–DNA relatedness.
StrainDDH Estimate (%)
1234567
1. 
S. coelicolor NBRC 12854T
-91.823.223.222.722.723.1
2. 
S. albidoflavus DSM 40455T (1)
 -23.023.122.722.722.7
3. 
S. daghestanicus NBRC 12762T
 -23.022.728.028.1
4. 
S. hydrogenans NBRC 13475T
 -23.422.822.9
5. 
S. violascens NBRC 12920T
 -22.622.8
6. 
S. anthocyanicus JCM 5058T (2)
 -94.2
7. 
S. coelicolor A3(2) (3)
 -
The accession numbers of the used genome sequences are as follows: (1) PKLO00000000.1; (2) BMWI00000000.1; (3) AL645882. The other accession numbers are shown in the Materials and Methods.
Table
Table 3. PKSs and NRPSs in the orphan gene clusters and the predicted products.
Table 3. PKSs and NRPSs in the orphan gene clusters and the predicted products.
StrainGene ClusterORF (Locus Tag)Domain OrganizationPredicted Product
S. coelicolor A3(2)nrps-1SCO6431
SCO6432		A/T-C/T
C/Acys/T-Te		Tripeptide (x-y-cys)
S. coelicolor NBRC 12854Tnrps-2ScoT_42860A/T/E-TDUnknown
nrps-3ScoT_34810C/A/T-C/A/T-C/A/T-TeTripeptide
nrps-4ScoT_12950
ScoT_12970		Aphe/T-C/A/T/E-C/Aval/T
C/A/T/E-C/Athr/T-C/Athr/T/E		Hexapeptide (phe-x-val-x-thr-thr)
pks/nrps-1ScoT_62740
ScoT_62750
ScoT_62760
ScoT_62780		Agly/T-KS/DH/ACP-KS/ATm
DH/KR/ACP-KS/ACP-KS/KR/ACP
KS/DH/ACP-KS/ATm
DH/KR/ACP-AmT		Hexaketide including gly
pks/nrps-2ScoT_02700
ScoT_02710
ScoT_02720		A/T
KS/ACP-C/Aala/T/C-Te
C/Athr/T-C/T/E-C/Aval/T-C		Pentapeptide with polyketide moiety (thr-y-val-x-pk-ala)
S. daghestanicus NBRC 12762Tt1pks-1Sdagh_09690
Sdagh_09680
Sdagh_09670		CoL/KR/ACP-KS/ATmm/KR/ACP-KS/ATmm/DH/KR/ACP
KS/ATm/DH/KR/ACP
KS/ATm/ACP		Tetraketide with a starter
pks/nrps-3Sdagh_50890
Sdagh_50900
Sdagh_50940
Sdagh_50980		C
A/KR/ACP
A
T		Unknown
pks/nrps-4Sdagh_52260
Sdagh_52060
Sdagh_51920
Sdagh_51910
Sdagh_51900		T-C/Acys/MT/T
KS (type-III PKS)
A/T/E-C/A/T/E-C/A/T/E-C/A/T/E-C/Athr/T/E
C/A/T/E
C/A/T-C/A/T-C/A/T-X/A-Te		Undecapeptide including cys, thr, and a polyketide moiety
S. hydrogenans NBRC 13475Tt1pks-2Shyd_35460KS/ATmm/ACP-
KS/ATmm/DH/ER/KR/ACP		Unknown
nrps-5Shyd_62130
Shyd_62150
Shyd_62160		Aphe/MT/T
C/Aval/T-C/Agly/T/E
C/A/T-Te		Tetrapeptide (methyl phe-val-gly-x)
nrps-6Shyd_62460
Shyd_62450		A/MT/T-C/A/T-C/Aval/T
C/A/T-C/Athr/T-Te		Pentapeptide (methyl x-x-val-x-thr)
pks/nrps-5Shyd_13440
Shyd_13450
Shyd_13460
Shyd_13470
Shyd_13490
Shyd_13520
Shyd_13530		Aval/T
C/T-C
T
KS/ACP-TD
T
FkbH
A		Dipeptide with a polyketide moiety
pks/nrps-6Shyd_48540
Shyd_48670
Shyd_48680		Aval/T-C
Atyr/T
KS/ATm/ACP		Dipeptide with a polyketide moiety (val-tyr-pk)
S. violascens NBRC 12920Tt1pks-3Sviol_48010
Sviol_48000
Sviol_47990		KS/ATm/ACP-KR
KS/ATm
ACP		Unknown
t1pls-4Sviol_60680KS/AT/DH/MT/ER/KR/ACPUnknown
t1pks-5Sviol_68600KS/AT/DH/KR/ACPUnknown
tjh (t2pks)Sviol_35480
Sviol_35470
Sviol_35460
Sviol_35440		KSα
KSβ (CLF)
ACP
KR		Unidentified aromatic polyketide
phlDSviol_40150KS (type-III PKS)Unidentified polyketide
nrps-7Sviol_61030C/Athr/T-TeUnknown including thr
nrps-8Sviol_25110C/Aphe/T/E-C/Aphe/T-C/A/T/T-TeTripeptide (phe-phe-x)
nrps-9Sviol_35280
Sviol_35230
Sviol_35220		A/T-C
T
A		Dipeptide
nrps-10Sviol_76120
Sviol_76140
Sviol_76160		A/KR/ACP
Acys/T-C/A/T
C/Aala/T/E-C/A/T-C/A/T/E-C/A/T-Te		Heptapeptide including cys and ala
pks/nrps-7Sviol_68100
Sviol_68090
Sviol_68080
Sviol_68070
Sviol_68030
Sviol_68020
Sviol_67990
Sviol_67980		A/T
C/A/T-C/T
KS/DH/ACP-TD
A
ATm
TE
ACP
KS		Tripeptide with a polyketide moiety
A: adenylation; ACP: acyl carrier protein; AmT: aminotransferase; AT: acyltransferase; ATm: AT for malonyl-CoA: ATmm: AT for methyl malonyl-CoA; C: condensation; CLF: chain length factor; CoL: CoA ligase; DH: dehydratase; E: epimerization; ER: enoyl reductase; KR: ketoreductase; KS: ketosynthase; MT: methyltransferase; pk: polyketide; T: thiolation; TD: termination; Te: thioesterase: x: unidentified amino acid residue; X: unknown domain: y: unknown unit by lack of A domain in the module. Amino acids incorporated by A domains are indicated as three-letter abbreviations in subscripts just after A.
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Komaki, H.; Tamura, T. Differences at Species Level and in Repertoires of Secondary Metabolite Biosynthetic Gene Clusters among Streptomyces coelicolor A3(2) and Type Strains of S. coelicolor and Its Taxonomic Neighbors. Appl. Microbiol. 2021, 1, 573-585. https://doi.org/10.3390/applmicrobiol1030037

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Komaki H, Tamura T. Differences at Species Level and in Repertoires of Secondary Metabolite Biosynthetic Gene Clusters among Streptomyces coelicolor A3(2) and Type Strains of S. coelicolor and Its Taxonomic Neighbors. Applied Microbiology. 2021; 1(3):573-585. https://doi.org/10.3390/applmicrobiol1030037

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Komaki, Hisayuki, and Tomohiko Tamura. 2021. "Differences at Species Level and in Repertoires of Secondary Metabolite Biosynthetic Gene Clusters among Streptomyces coelicolor A3(2) and Type Strains of S. coelicolor and Its Taxonomic Neighbors" Applied Microbiology 1, no. 3: 573-585. https://doi.org/10.3390/applmicrobiol1030037

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