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Draft genome sequence of Streptomyces hyaluromycini MB-PO13T, a hyaluromycin producer

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Abstract

Streptomyces hyaluromycini MB-PO13T (=NBRC 110483T = DSM 100105T) is type strain of the species, which produces a hyaluronidase inhibitor, hyaluromycin. Here, we report the draft genome sequence of this strain together with features of the organism and generation, annotation and analysis of the genome sequence. The 11.5 Mb genome of Streptomyces hyaluromycini MB-PO13T encoded 10,098 putative ORFs, of which 5317 were assigned with COG categories. The genome harbored at least six type I PKS clusters, three type II PKS gene clusters, two type III PKS gene clusters, six NRPS gene clusters, and one hybrid PKS/NRPS gene cluster. The type II PKS gene cluster including 2-amino-3-hydroxycyclopent-2-enone synthetic genes was identified to be responsible for hyaluromycin synthesis. We propose the biosynthetic pathway based on bioinformatic analysis.

Introduction

Hyaluromycin is a hyaluronidase inhibitor isolated from the culture broth of an actinomycete strain MB-PO13T of the genus Streptomyces [1]. The structure consists of a γ-rubromycin core possessing a C5N unit as an amide substituent of the carboxyl functionality. Rubromycins have inhibitory activities against human telomerase and the reverse transcriptase of human immunodeficiency virus-1 [2]. The core structure possesses a hexacyclic ring system and a 5,6-bisbenzannelated spiroketal structure. The most intriguing part of hyaluromycin is the C5N moiety, which is present only in a limited range of secondary metabolites of actinomycetes [3]. As for the rubromycin family biosynthesis, putative biosynthetic genes for griseorhodin A were reported [4], but there is no report on the rubromycins. Hence, the biosynthesis of rubromycin family remains unclear. In this study, we performed whole genome shotgun sequencing of the strain MB-PO13T to elucidate the biosynthetic mechanism of hyaluromycin. We herein present the draft genome sequence of Streptomyces hyaluromycini MB-PO13T, together with the taxonomical identification of the strain, description of its genome properties and annotation of the gene cluster for hyaluromycin synthesis. The biosynthetic pathway of hyaluromycin is also proposed on the basis of the bioinformatic prediction.

Organism information

Classification and features

During the course of screening for hyaluronidase inhibitors from actinomycetes, Streptomyces hyaluromycini MB-PO13T was isolated from a tunicate ( Molgula manhattensis ) collected in Tokyo Bay, Japan and found to produce hyaluromycin [1]. Colony appearance was examined after incubation at 28 °C for 14 days on an agar plate of ISP 4. Morphological features were observed under a light microscope (model BX-51; Olympus) and a scanning electron microscope (model JSM-6060; JEOL). The temperature range and optimum temperature for growth were determined by incubating the strain at 5, 10, 15, 20, 28, 37, 42, and 50 °C on ISP 2 agar plates for 14 days. The pH range for growth was determined at 28 °C in ISP 2 broth, of which pH was adjusted to 3 to 12 by 1 N HCl or 1 M Na2CO3. Tolerance to NaCl was tested on ISP 2 agar plates containing 2, 3, 5, 7, 9, and 12% (w/v) NaCl at 28 °C. Carbohydrate utilization was determined on ISP 9 supplemented with sterilized carbon sources [5]. The strain grow well on ISP 3, ISP 4 and yeast-starch agars but poor on ISP 2, ISP 5, ISP 6, ISP 7, glucose-asparagine, nutrient, sucrose-nitrate and skim milk agars. Soluble red pigments are produced on ISP 2, ISP 3, ISP 4, ISP 7, glucose-asparagine, nutrient and yeast-starch agars. Cells are aerobic and Gram-stain-positive. The aerial mycelia are branched and yellowish white in color, which become light grey at sporulation and the substrate mycelia are deep red on ISP 4 agar plate. Smooth surface spores (0.5–0.8 × 1.0–1.5 μm) in spiral chains are formed when cultured on nutritionally poor media. A scanning electron micrograph of the strain is shown in Fig. 1. Growth occurs at 10–37 °C (optimum 28 °C), at pH 4.0–9.0 (optimum pH 7.0) and in the presence of less than 2% NaCl (w/v). The strain utilizes L-arabinose, D-fructose, D-glucose, inositol, D-mannitol, rhamnose and D-xylose as sole carbon source for energy and growth, but not raffinose and sucrose (all at 1%, w/v). These results are summarized in Table 1. The genes encoding 16S rRNA were amplified by PCR using two universal primers, 27F (5′-AGAGTTTGATCMTGGCTCAG-3′) and 1492R (5′-TACGGYTACCTTGTTACGACTT-3′) [6]. GoTaq Green Master Mix (Promega) was used as described by the manufacture for the PCR. The reaction was started with denaturation at 94 °C for 5 min followed by a total 27 cycles that consisted of denaturation at 94 °C for 30 s, annealing at 57 °C for 30 s, and extension at 72 °C for 1.5 min, and extension at 72 °C for 7 min. The PCR product was purified by Wizard SV Gel and PCR Clean-Up System (Promega) and sequenced with a BigDye cycle sequencing ready reaction kit (Appled Biosystems) on an ABI PRISM 310 Genetic analyzer (Applied Biosystems). The sequence was deposited into DDBJ under the accession number AB184533. BLAST search of the sequence by the EzTaxon-e server [7] indicated the highest similarity to that of Streptomyces graminisoli JR-19T (HQ267975, 99.79%, 1440/1443). A phylogenetic tree was reconstructed on the basis of the 16S rRNA gene sequence together with taxonomically close Streptomyces type strains using CLUSTAL-W program [8] and by the neighbor-joining method [9] using the MEGA 6.0 program [10]. The resultant tree topologies were evaluated by bootstrap analysis [11] based on 1000 replicates. The phylogenetic tree is shown in Fig. 2. On the basis of these findings, strain MB-PO13T was proposed to be classified as a representative of a novel species of the genus Streptomyces , with the name Streptomyces hyaluromycini sp. nov. [12].

Fig. 1
figure1

Scanning electron micrograph of Streptomyces hyaluromycini MB-PO13T grown on 1/10 ISP 2 agar for 14 days at 28 °C. Bar, 5 μm

Table 1 Classification and general features of Streptomyces hyaluromycini MB-PO13T
Fig. 2
figure2

Neighbor-joining phylogenetic tree based on 16S rRNA gene sequences of strain MB-PO13T and its taxonomic neighbors. Kitasatospora setae KM-6054T (AB022868) was used as the outgroup. Bootstrap values (>70%) based on 1000 replicates are shown at branch nodes. Bar, 0.01 substitutions per nucleotide position

Chemotaxonomic data

The isomer of diaminopimelic acid in the whole-cell hydrolysate was analyzed according to the method described by Hasegawa et al. [13]. Isoprenoid quinones and cellular fatty acids were analyzed as described previously [14]. The whole-cell hydrolysate of strain MB-PO13T contained LL-A2pm, glucose and mannose. The detected menaquinones were identified as MK-9(H8), MK-9(H6), MK-9(H4) and MK-9(H10) (5:37:57:1). The principal polar lipids were diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylinositol. Six unidentified phospholipids were also detected. The major cellular fatty acids (>10%) were anteiso-C15:0 (24.9%), iso-C16:0 (23.4%), iso-C14:0 (15.0%) and C16:0 (10.7%). These chemotaxonomic features corresponded to those of the genus Streptomyces .

Genome sequencing information

Genome project history

In collaboration between Toyama Prefectural University and NBRC, the organism was selected for genome sequencing to elucidate the hyaluromycin biosynthetic pathway. We successfully accomplished the genome project of Streptomyces hyaluromycini MB-PO13T as reported in this paper. The draft genome sequences have been deposited in the INSDC database under the accession number BCFL01000001-BCFL01000052. The project information and its association with MIGS version 2.0 compliance are summarized in Table 2 [15].

Table 2 Project information

Growth conditions and genomic DNA preparation

Streptomyces hyaluromycini MB-PO13T was deposited in the NBRC culture collection with the registration number of NBRC 110483T. Its monoisolate was grown on polycarbonate membrane filter (Advantec) on 1/2 ISP 2 agar medium (0.2% yeast extract, 0.5% malt extract, 0.2% glucose, 2% agar, pH 7.3) at 28 °C. High quality genomic DNA for sequencing was isolated from the mycelia with an EZ1 DNA Tissue Kit and a Bio Robot EZ1 (Qiagen) according to the protocol for extraction of nucleic acid from Gram-positive bacteria. The size, purity, and double-strand DNA concentration of the genomic DNA were measured by pulsed-field gel electrophoresis, ratio of absorbance values at 260 nm and 280 nm, and Quant-iT PicoGreen dsDNA Assay Kit (Life Technologies), respectively, to assess the quality of genomic DNA.

Genome sequencing and assembly

Shotgun and paired-end libraries were prepared and subsequently sequenced using 454 pyrosequencing technology and HiSeq1000 (Illumina) paired-end technology, respectively (Table 2). The 77 Mb shotgun sequences and 881 Mb paired-end sequences were assembled using Newbler v2.8 and subsequently finished using GenoFinisher [16] to yield 52 scaffolds larger than 500 bp.

Genome annotation

Coding sequences were predicted by Prodigal [17] and tRNA-scanSE [18]. The gene functions were annotated using an in-house genome annotation pipeline, and PKS and NRPS-related domains were searched using the SMART and PFAM domain databases. PKS and NRPS gene clusters were determined as reported previously [19]. BLASTP search against the NCBI nr databases were also used for predicting function of proteins encoded in the hyaluromycin biosynthetic gene cluster.

Genome properties

The total size of the genome of Streptomyces hyaluromycini MB-PO13T is 11,525,033 bp and the GC content is 71.0% (Table 3), similar to other genome-sequenced Streptomyces members such as Streptomyces violaceoniger Tu4133, Streptomyces bingchenggensis BCW-1 [20] and Streptomyces rapamycinicus NRRL 5491T. Of the total 10,201 genes, 10,098 are protein-coding genes and 103 are RNA genes. The classification of genes into COGs functional categories is shown in Table 4. As for secondary metabolite pathways by PKSs and NRPSs, Streptomyces hyaluromycini MB-PO13T has at least six type I PKS gene clusters, three type II PKS gene clusters, two type III PKS gene clusters, six NRPS gene clusters, and one hybrid PKS/NRPS gene cluster.

Table 3 Genome statistics
Table 4 Number of genes associated with general COG functional categories

Insights from the genome sequence

Hyaluromycin biosynthetic pathway in Streptomyces hyaluromycini MB-PO13T

Hyarulomycin is a derivative of γ-rubromycin, possessing a C5N unit instead of a methoxy group as a side chain. The rubromycin-biosynthetic (rub) gene cluster is published in the GenBank (accession no. AF293355.2), but the biosynthetic mechanism has not been reported yet. Among the members of rubromycin family, only the griseorhodin-biosynthetic (grh) pathway has been extensively studied: griseorhodin A is synthesized by type II PKSs and modification enzymes [4, 21]. In the genome sequence of S. hyaluromycini MB-PO13T, three type II PKS gene clusters are present. Among them, the type II PKS gene cluster in scaffold000001 resembles those of rubromycin and griseorhodin as shown in Fig. 3 and Table 5. But, unlike rub and grh gene clusters, the cluster also encodes amide synthase (Orf1-763), 5-aminolevulinate synthase (Orf1-762) and AMP-dependent synthase (Orf1-761) essential for C5N unit synthesis [22]. Thus, we considered it to be the biosynthetic gene cluster for hyarulomycin. According to the proposed biosynthetic mechanisms of griseorhodin [4] and C5N [22, 23], we predicted the biosynthetic pathway of hyarulomycin as shown in Fig. 4. The polyketide chain is synthesized by the iterative condensation of an acyl-CoA starter and 12 malonyl-CoA units. This elongation cycle is catalyzed by KSα, KSβ (chain length factor) and acyl carrier protein. Since almost all the homologs of Grh enzymes are present in the putative hyarulomycin-biosynthetic gene cluster (Table 5, Fig. 3), the resulting polyketide chain is likely cyclized and modified to the polycyclic intermediate bearing a spiroketal moiety in the similar fashion to griseorhodin biosynthesis. Unlike griseorhodin A, the epoxide functionality is not present in the spiroketal moiety of rubromycin and hyaluromycin. This can be explained by the absence of  homolog of grhO4 encoding ferredoxin responsible for epoxide formation of griseorhodin A in rubromycin- and hyarulomycin-biosynthetic gene clusters. It was unable to predict a gene responsible for the removal of the hydroxyl group at the spiroketal only by this bioinformatic analysis. 5-Aminolevulinate synthase (Orf1-762), 5-aminolevulinate CoA ligase (Orf1-761) and amide synthase (Orf1-763) are involved in the formation of C5N unit and its coupling with the aromatic core.

Fig. 3
figure3

Gene organizations of rubromycin-, hyarulomycin- and griseorhodin-biosynthetic gene clusters. Homologs are linked by gray dotted lines. The rub, Orf1- and grh are rubromycin-, hyarulomycin- and griseorhodin-biosynthetic gene clusters, respectively. Hyarulomycin-biosynthetic genes are indicated with orf numbers as shown in Table 5

Table 5 Putative hyaluromycin biosynthetic gene cluster and the neighboring genes
Fig. 4
figure4

Putative biosynthetic pathways of hyarulomycin, rubromycin and griseorhodin. Each step is catalyzed by enzymes encoded following genes as proposed in griseorhodin biosynthesis [4]. 1grhA/rubA/orf1-742 (KSα), grhB/rubB/orf1-741 (KSβ) and grhC/rubC/orf1-740 (ACP); 2grhE/rubK?/orf1-769?, grhQ/rubE/orf1-744, grhS/rubD/orf1-743 and grhT/rubF/orf1-739, 3grhO8/rubO/orf1-750, grhO9/rubP/orf1-749 (monooxygenases), grhL/−/orf1-751 (MT), grhM/rubQ/orf1-748 (unknown) and grhP/rubR/orf1-746 (asparagine synthase); 4grhO5/rubL/orf1-755 (monooxygenase) and grhO1/rubI/orf1-758 (oxygenase)?; 5grhO6/rubN/orf1-753 (monooxygenase) and grhJ/−/orf1-756 (acetyltransferase)?; 6grhO10/rubG/orf1-738 (KR) or grhT/rubF/orf1-739 (cyclase/reductase); 7grhO3/rubU/orf1-735 (cytochrome P450), grhO4/−/− (ferredoxin) and grhO7/−/orf1-752 (oxidoreductase). Homologs are connected with slashes in order of rubromycin/griseorhodin/hyarulomycin. ACP, acyl carrier protein; CLF, chain length factor; Fd, ferredoxin; KS, ketosynthase; KR, ketoreductase; MT, methyltransferase; −, no homolog in the sequence

Conclusions

The 11.5 Mb draft genome of Streptomyces hyaluromycini MB-PO13T, a producer of hyaluromycin, isolated from tunicate ( Molgula manhattensis ) has been deposited at GenBank/ENA/DDBJ under the accession number BCFL00000000. We successfully identified the gene cluster for hyaluromycin synthesis and proposed the plausible biosynthetic pathway. These findings provide useful information for genetic engineering to synthesize more potential hyaluronidase inhibitors and discovering new bioactive aromatic polyketides possessing the C5N unit.

Abbreviations

A2pm:

Diaminopimelic acid

ABC:

ATP-binding cassette

ACP:

Acyl carrier protein

C5N:

2-amino-3-hydroxycyclopent-2-enone

CLF:

Chain length factor

CoA:

Coenzyme A

DDBJ:

DNA Data Bank of Japan

Fd:

Ferredoxin

ISP:

International Streptomyces project

KR:

Ketoreductase

KS:

Ketosynthase

MK:

Menaquinone

MT:

Methyltransferase

NBRC:

Biological Resource Center, National Institute of Technology and Evaluation

NRPS:

Nonribosomal peptide synthetase

PKS:

Polyketide synthase

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Acknowledgements

This research was supported by the Japan Society for the Promotion of Science (JSPS) for Young Scientists (15 K18692) and Institute for Fermentation, Osaka (IFO) for Young Scientists to E.H. We are grateful to Ms. Yuko Kitahashi for finishing the genome sequence and helping the search of secondary metabolite genes. We would like to thank Ms. Satomi Hirakata for technical assistance on whole genome sequencing. We also thank Ms. Mariko Ozu for registering the sequences on DDBJ.

Author information

EH performed chemotaxonomic experiments, examined features of the strain, and drafted the manuscript. KH elucidated the hyaluromycin-biosynthetic pathway. NI annotated the genome sequences. AH sequenced the genome. AK analysed secondary metabolite-biosynthetic genes. MH supervised taxonomic study of the strain. YI designed this study and edited the manuscript. All authors read and approved the final manuscript.

Correspondence to Yasuhiro Igarashi.

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Keywords

  • Biosynthesis
  • C5N
  • Polyketide synthase
  • Rubromycin
  • Streptomyces