Genome based analysis of type-I polyketide synthase and nonribosomal peptide synthetase gene clusters in seven strains of five representative Nocardia species
© Komaki et al.; licensee BioMed Central Ltd. 2014
Received: 11 October 2013
Accepted: 15 April 2014
Published: 30 April 2014
Actinobacteria of the genus Nocardia usually live in soil or water and play saprophytic roles, but they also opportunistically infect the respiratory system, skin, and other organs of humans and animals. Primarily because of the clinical importance of the strains, some Nocardia genomes have been sequenced, and genome sequences have accumulated. Genome sizes of Nocardia strains are similar to those of Streptomyces strains, the producers of most antibiotics. In the present work, we compared secondary metabolite biosynthesis gene clusters of type-I polyketide synthase (PKS-I) and nonribosomal peptide synthetase (NRPS) among genomes of representative Nocardia species/strains based on domain organization and amino acid sequence homology.
Draft genome sequences of Nocardia asteroides NBRC 15531T, Nocardia otitidiscaviarum IFM 11049, Nocardia brasiliensis NBRC 14402T, and N. brasiliensis IFM 10847 were read and compared with published complete genome sequences of Nocardia farcinica IFM 10152, Nocardia cyriacigeorgica GUH-2, and N. brasiliensis HUJEG-1. Genome sizes are as follows: N. farcinica, 6.0 Mb; N. cyriacigeorgica, 6.2 Mb; N. asteroides, 7.0 Mb; N. otitidiscaviarum, 7.8 Mb; and N. brasiliensis, 8.9 - 9.4 Mb. Predicted numbers of PKS-I, NRPS, and PKS-I/NRPS hybrid clusters ranged between 4–11, 7–13, and 1–6, respectively, depending on strains, and tended to increase with increasing genome size. Domain and module structures of representative or unique clusters are discussed in the text.
We conclude the following: 1) genomes of Nocardia strains carry as many PKS-I and NRPS gene clusters as those of Streptomyces strains, 2) the number of PKS-I and NRPS gene clusters in Nocardia strains varies substantially depending on species, and N. brasiliensis strains carry the largest numbers of clusters among the species studied, 3) the seven Nocardia strains studied in the present work have seven common PKS-I and/or NRPS clusters, some of whose products are yet to be studied, and 4) different N. brasiliensis strains have some different gene clusters of PKS-I/NRPS, although the rest of the clusters are common within the N. brasiliensis strains. Genome sequencing suggested that Nocardia strains are highly promising resources in the search of novel secondary metabolites.
KeywordsNocardia asteroides Nocardia otitidiscaviarum Nocardia brasiliensis Nocardia farcinica Nocardia cyriacigeorgica Genome sequence Type-I polyketide synthase Nonribosomal peptide synthetase
Actinomycetous strains of the genus Nocardia usually live in soil or water and play saprophytic roles in the environment, but also are opportunistic human pathogens, infecting the respiratory tract, skin, brain, and other organs of both immunocompromised and immunocompetent patients. To date, more than 80 species have been established in the genus Nocardia, and approximately one-third to one-half of the species have been reported as human pathogens [1–3]. Because of their medical importance, Nocardia strains have accumulated in microbial collections as a resource for clinical and scientific studies in the last few decades (e.g., [4–7]).
Although Nocardia strains belong to the Order Actinomycetales together with Streptomyces strains, the latter being known as a rich resource for discovery of secondary metabolites, few studies have been focused on secondary metabolites and their synthetic genes in Nocardia strains.
Type I polyketide synthase (PKS-I) and nonribosomal peptide synthetase (NRPS) gene clusters are two of the major secondary metabolite-producing clusters in bacteria and are involved in the biosynthesis of polyketide chains and nonribosomal peptides, respectively. It has been found that these clusters produce several medically and industrially important compounds, such as pathogenic factors, avermectin, erythromycin, and vancomycin.
In the present paper, we searched for PKS-I and NRPS genes in the genomes of representative Nocardia strains and analyzed their sequence similarities and differences in domain/module structures. While we were sequencing and analyzing Nocardia draft genomes, two new Nocardia genomes of N. cyriacigeorgica GUH-2 [8, 9] and N. brasiliensis HUJEG-1  were published. We included them in the present analysis together with N. farcinica genome, which our group has published previously .
N. otitidiscaviarum IFM 11049 and N. brasiliensis IFM 10847 were from the IFM culture collections of MMRC, Chiba University, Japan . N. asteroides NBRC 15531T and N. brasiliensis NBRC 14402T were from the NBRC culture collection . Cells were cultured in brain heart infusion liquid culture medium (Difco) in the conventional manner.
Acquisition of whole-genome sequences
Genomic DNA of N. otitidiscaviarum IFM 11049, N. brasiliensis (IFM 10847, NBRC 14402T), and N. asteroides NBRC 15531T was prepared as described previously . Genome sequences were read by the pyrosequencing method using genome sequencer GS FLX Instruments and GS FLX Titanium Kits (Roche Applied Science, Japan). The read redundancy for the four draft genomes ranged between 55 and 104. We assembled the sequence reads of N. otitidiscaviarum IFM 11049, N. brasiliensis IFM 10847, N. brasiliensis NBRC 14402T, and N. asteroides NBRC 15531T, and obtained 65, 223, 115, and 39 contigs, which were longer than 500 bp. The estimated genome sizes of N. otitidiscaviarum IFM 11049, N. brasiliensis IFM 10847, N. brasiliensis NBRC 14402T, and N. asteroides NBRC 15531T were 7.9 Mb, 9.2 Mb, 8.9 Mb, and 7.0 Mb, respectively. The draft genome sequences of N. otitidiscaviarum IFM 11049, N. brasiliensis (IFM 10847, NBRC 14402T), and N. asteroides NBRC 15531T are available at GenBank/EMBL/DDBJ under the accession numbers BATZ01000001–BATZ01000065, BAUA01000001–BAUA01000223, BAFT01000001–BAFT01000128, and BAFO01000001–BAFO01000049, respectively. The complete genome sequences of N. cyriacigeorgica GUH-2, N. brasiliensis HUJEG-1 (=ATCC 700358), and N. farcinica IFM 10152 were downloaded from DDBJ , with accession numbers FO082843, CP0033876, and AP006618, respectively.
Analysis of PKS-I and NRPS gene clusters
The assembled contig sequences were submitted to the auto-annotation pipeline MiGAP [15, 16] at DDBJ as described previously . Assigned ORFs were further searched for signature domains of PKS-I and NRPS genes using the InterPro domain database [18, 19]. ORFs having ketosynthase (KS) domain (IPR014030, IPR014031, IPR020841) or condensation (C) domain (IPR001242) were identified, and their adjacent genes were further analyzed as PKS-I and NRPS gene candidates. Module organizations were determined manually based on search results using InterPro database, results using PKS/NRPS analysis website , and signature sequences deduced using MOTIF search . We also used antiSMASH [22, 23], a website for antibiotics and secondary metabolite analysis, for finding orthologous clusters and predicting substrates for adenylation domains. PKS-I and NRPS gene clusters of N. farcinica IFM 10152, N. cyriacigeorgica GUH-2, and N. brasiliensis HUJEG-1 were also identified using the N. farcinica genomic database [11, 24]. We assumed that two or more PKS-I and/or NRPS genes that were adjacent to each other constitute one cluster for secondary metabolite production (See Additional file 1: Table S1, for details and exceptions). We also assumed that one multi-domain PKS-I or NRPS gene that was not accompanied by adjacent PKS-I/NRPS genes constitute one independent cluster. However, genes having only a single PKS-I or NRPS domain were excluded from the present analysis because we considered them atypical, and focused on multi-domain clusters. The contig sequences containing PKS-I and NRPS gene clusters are available at GenBank/EMBL/DDBJ under the following accession numbers: [AB700569 - AB700587] (N. otitidiscaviarum IFM 11049), [AB701575 - AB701605] (N. brasiliensis IFM 10847), [AB701607 – AB701636] (N. brasiliensis NBRC 14402T), and [AB685274], [AB700124 - AB700133], [AB700557 - AB700568] (N. asteroides NBRC 15531T).
Search for orthologous gene clusters among species and strains
BLASTP search was performed using the NCBI Protein BLAST program against the non-redundant protein sequence database [25, 26]. We considered Nocardia genes homologous to other genes when they have more than 70% sequence similarity in BLASTP search, and also when their domain organizations have high similarity. We also compared clusters with domain organizations that only partially match each other, as described in the text.
Results and discussion
Genome sizes and numbers of PKS-I, NRPS, and PKS-I/NRPS hybrid gene clusters in Nocardia strains
Genome size* (Mb)
State of sequence
Number of gene clusters (Average number of genes/modules per cluster)
Total number of clusters
N. farcinica IFM 10152 
Clinical (human sputum)
Clinical (human kidney)
Clinical (fatal brain abscess)
N. otitidiscaviarum IFM 11049 
Clinical (human sputum)
Clinical (leg lesion)
N. brasiliensis IFM 10847 
Clinical (human pus)
N. brasiliensis HUJEG-1 
Clinical (human mycetoma)
PKS-I, NRPS, and PKS-I/NRPS hybrid gene clusters from the Nocardia strains were predicted as described in Methods. Numbers of the three different types of clusters and the total number of clusters in each strain are listed in the four rightmost columns in Table 1. Among the seven strains, the numbers of PKS-I, NRPS, PKS-I/NRPS hybrid clusters, and their total number increased proportionally to the genome size, except for N. otitidiscaviarum and N. asteroides (Table 1) as reported in other genera . N. farcinica had the least while N. brasiliensis HUJEG-1 had the highest number of the gene clusters. The total number of clusters within the three N. brasiliensis genomes differed (27 to 30), suggesting that different strains of the same species potentially produce their own unique products (see below).
We also counted the numbers of type-II PKS, type-III PKS and terpene synthesis clusters in each genome. The numbers ranged between 0 and 3, except in N. otitidiscaviarum and N. brasiliensis strains, which have five and eight clusters for terpene synthesis per genome, respectively. In the present paper, however, we focused on PKS-I and NRPS secondary metabolite clusters because their products usually have larger molecular weights with more complex chemical structures than the others and have unique pharmacological activities.
Clusters common among the seven strains
Figure 2 suggests that seven presumable products (lines #1, #2, #4, #5, #25, #27, and #35) are common among the seven strains belonging to the five species. It is noteworthy that clusters #1, #2, #4, and #5 reside close to the original points of replication (ori.) in the three species whose completed genome sequences are known, in accordance with a report showing that conserved genes reside in the internal core region of actinomycete genomes .
Mycolic acid (pks13)
We predicted that the products of the PKS-I genes in line #1 were mycolic acids, cell wall components in members belonging to Corynebacterineae, because these PKS-Is showed the same domain organization as those of pks13 in Mycobacterium tuberculosis for the synthesis of mycolic acids , and also showed over 80% sequence similarities to PKS-Is of N. farcinica annotated for mycolic acid synthesis .
NRPS genes of line #2 were predicted to be for poly-lysine synthesis because their module organizations are the same as that of poly-lysine synthetase (Pls) in Streptomyces albulus. The corresponding gene, nfa3790, is also annotated as a Pls homolog in the N. farcinica database . The sequence identity between Pls in S. albulus and nfa3790 in N. farcinica was 55%.
Ser/The-rich nonribosomal peptides
NRPS gene clusters in line #4 were present in all strains examined, but only a partial sequence was found in N. otitidiscaviarum (Additional file 2: Figure S1A). Zoropogui et al.,  has suggested that #4 in N. cyriacigeorgica was for synthesis of 2-amino-9,10 epoxi-8-oxodecanoic acid, a component of HC-toxin, which is produced by a plant pathogen causing corn leaf spots (reviewed in ). However, we suggest two other possibilities based on the domain organization of the cluster. One is that the intact #4 cluster is for synthesis of a serine/threonine-rich peptide composed of 11 amino acids. The second possibility is that the same sequence consists of two different NRPS clusters, since two thioesterase domains are present within the sequence, and accordingly, produces two peptide chains. In the latter case, the products of cluster #4 in N. asteroides would be two peptides: one composed of four amino acids (NCAST_11_00880 & NCAST_11_00870) and the other composed of seven amino acids (NCAST_11_00860 & NCAST_11_00850). Likewise, in N. brasiliensis, the products of cluster #4 would also be two peptides: one composed of six amino acids (O3I_004080 & O3I_004085) and the other composed of five amino acids (O3I_004090) (Figure 2, #4, rightmost column).
A possible reason why N. otitidiscaviarum, unlike the other species, has only a partial #4 cluster is that this species is phylogenetically distant from the other strains, as shown in Figure 1. The relationships among the products of these gene clusters, the phylogenetic positions of the strains, and their pathogenicity to plants and animals are interesting issues to clarify.
NRPS genes in line #35 were also present in all the strains examined, although those of N. otitidiscaviarum and N. brasiliensis IFM 10847 were partial compared with those of the other strains (Additional file 2: Figure S1B). The genes in five strains, except for N. otitidiscaviarum and N. brasiliensis IFM 10847, have 12 modules, and many of their adenylation domains were predicted to select Ser as the substrate. Hence, we assumed the products would be Ser-rich 12 aa peptides. Besides the clusters common among the seven strains in line #35, similar NRPS clusters were also present in the adjacent clusters of line #36, but only in four species excluding N. brasiliensis strains. Interestingly, the predicted products are Ser-rich 13 aa peptides.
Although the conservation of Ser- (and Thr-) rich large peptides synthesized by clusters of #4, #35, and #36 in the Nocardia strains suggests that they have important roles, physiological roles of the products remain to be investigated.
Nocobactin (nbt)-like siderophore
Other common gene clusters
Two NRPS genes in lines #25 and #27 (Figure 2) were common in all the strains sequenced, having four and three modules, respectively. However, the amino-acid composition of the products could not be predicted in silico using antiSMASH. Chemical structures and physiological roles of the products remain to be investigated.
Clusters missing in a few strains but found in others
PKS-I clusters of line #13 (Figure 2) were present in the six strains except N. otitidiscaviarum. Other PKS-I clusters in line #30 were present in the four strains but not in N. asteroides and in the two N. brasiliensis strains (NBRC 14402T, IFM 10847). Nfa30250 (Figure 2 #13) has been predicted to be involved in mycocerosic acid synthesis in the N. farcinica genome project . On the other hand, O3I_032485 in N. brasiliensis HUJEG-1 (Figure 2 #30) has been putatively annotated as mycocerosate synthase . Both PKS-Is in N. farcinica (#13) and in N. brasiliensis (#30) showed approximately 47% amino acid similarities to Mycobacterium tuberculosis PKS-I [GenBank/EMBL/DDBJ accession number: CCP46654] for the synthesis of mycocerosic acid, a pathogenic factor [40, 41]. All the PKS-Is listed in line #13 and #30 showed sequence similarities ranging between 62 and 75%, having almost the same protein length (approximately 2200 aa) and identical domain organization (KS/AT/DH/KR/ER/ACP) (Additional file 1: Table S1).
It is possible that in N. otitidiscaviarum, cluster #30 is a substitute for cluster #13. Interestingly, N. farcinica and N. cyriacigeorgica possess both #13 and #30, which could be related to the strong pathogenicity of the two strains.
Polyunsaturated fatty acid (pfaA)
Orthologous genes of cluster #11 are found in N. asteroides, N. otitidiscaviarum, and N. brasiliensis IFM 10487 and HUJEG-1, but not in N. farcinica, N. cyriacigeorgica, and N. brasiliensis NBRC 14402 (Figure 2). The PKS-I sequence identities among N. asteroides, N. otitidiscaviarum, and N. brasiliensis ranged from 66 to 78%. The modular structures of PKS-Is in line #11 (KS/AT/ACP/ACP/KR) are unusual because they have two tandem ACP domains, and one KR domain is located after ACP (Additional file 3: Figure S2). These features have been known in polyunsaturated fatty acid (PUFA) synthase, PfaA, of marine bacteria, such as those belonging to the genus Shewanella[42, 43]. The module organizations are similar between #11 and PfaA (Figure S2), and their amino-acid sequence similarities are over 50%. Hence, we predict that the products of PKS-I in line #11 are polyunsaturated fatty acids, as already reported in N. brasiliensis HUJEG-1 genome . However, reports of production of polyunsaturated fatty acids have been limited only in some psychrophilic, piezophilic, or halophilic bacteria in prokaryotes [44, 45] and have not been found in Nocardia strains. Thus, future chemical and synthetic analysis are required to explore the potential of Nocardia strains as industrial producers of these pharmaceutically and nutraceutically valuable compounds.
The N. brasiliensis strains had the largest number of species-specific clusters among the strains studied in the present work: five to six PKS-I clusters (#15, #16, #19, #22, #26, #51, #52), six NRPS clusters (#3, #6, #17, #18, #21, #32), and two to four PKS-I/NRPS hybrid clusters (#9, #10, #12, #23), depending on the strains. Among them, three PKS-I clusters (#22, #51, #52) consisted of a single module, suggesting that their final or intermediate products may be small in accordance with the assembly line rule [46, 47], unless the modules are used iteratively, as has been reported in actinomycetes (e.g., [50, 51]). Interestingly, PKS-Is in #22 shows 61% sequence similarity to PksE of Streptomyces griseus [GenBank/EMBL/DDBJ accession number: AAO25858], whose product is an unusual polyketide compound including a 9-membered enediyne core .
The rest of the clusters with multiple modules may possibly produce large species-specific products. In particular, nonribosomal peptides produced by clusters #18 and #21 are, respectively, predicted to consist of nine and six (to eight) amino acids.
Intra-species variations of clusters
Strain-specific as well as species-specific PKS-I clusters were found in N. brasiliensis strains (#19, #30, #52), indicating different strains of the same species may potentially produce different products. Because there are large numbers of Nocardia strains stored in several bio-resource centers (e.g., [5–7]), and are rapidly accumulating , these Nocardia strains constitute a highly promising future resource for exploring secondary metabolites.
Other unique examples of clusters
Because the gene cluster of N. otitidiscaviarum #20 contains one PKS-I module and 19 NRPS modules, the product has been tentatively predicted to include one polyketide chain and 19 amino acids (Additional file 4: Figure S4). It should also be mentioned, however, that the two genes in cluster #20, NOTIT_47_07270 and NOTIT_47_07220, each contain thioesterase domains (Te) at their C-terminal ends, suggesting another possibility that the product may contain 12 amino acids instead of 19.
All cluster structures we analyzed in the present work are listed in (Additional file 1: Table S1).
We conclude the following: 1) genomes of Nocardia strains carry as many PKS-I and NRPS clusters as Streptomyces strains, 2) the number of PKS-I and NRPS gene clusters in Nocardia strains varies substantially depending on species, and N. brasiliensis strains carry the largest number of clusters among the species studied, 3) the seven Nocardia strains studied in the present work have six common PKS-I/NRPS clusters, some of whose products are yet to be studied, and 4) different N. brasiliensis strains have a few different clusters for secondary metabolite synthesis. Also, the following are suggested: 1) there is no clear relation between genome size and pathogenicity in Nocardia strains, e.g. N. farcinica and N. brasiliensis are both prevalent pathogens, but their genome sizes are 6.0 Mb and 9.4 Mb, respectively, the minimum and maximum among the strains studied, and 2) some genes (e.g. cluster #17 in Figure 2) are likely to have been horizontally transferred from (or to) other actinomycetous strains, such as Rhodococcus spp.
To summarize, in this study, we compared complete and draft genome sequences of seven strains from five representative Nocardia species. The sequences we obtained provided useful information for inferring numbers and molecular structures of secondary metabolites potentially produced by Nocardia strains. Genome sequencing revealed the possibility that Nocardia strains are as attractive resources as Streptomyces strains, the largest resource of natural compounds, in the search for new useful secondary metabolites.
HK: Senior Chief, Biological Resource Center, National Institute of Technology and Evaluation (NBRC).
NI: Chief, NBRC.
AH: Senior Chief, NBRC.
AT-N: Postdoctoral Fellow, Medical Mycology Research Center (MMRC), Chiba University.
TM: Research Associate, MMRC, Chiba University.
KS: Senior Director, NBRC.
NF: Senior Director, NBRC.
TG: Professor, MMRC, Chiba University.
Type-I polyketide synthase
Nonribosomal peptide synthetase
Biological Resource Center, National Institute of Technology and Evaluation
Medical Mycology Research Center
Acyl carrier protein
This work was supported by research grants of the Ministry of Education, Culture, Sports, Science, & Technology in Japan [grants #21406003], by the National BioResource Project (http://www.nbrp.jp/), and by the Cooperative Research Grant of NEKKEN, 2012 to TG. We thank to Mr. Syuji Yamazaki and Dr. Atsushi Yamazoe for launching the massive genome sequencing project of the genus Nocardia and for providing us with the sequences.
The GenBank/EMBL/DDBJ accession numbers for the sequences containing the type-I PKS and NRPS gene clusters are: AB685274, AB700124-AB700133, AB700557-AB700568 (Nocardia asteroides NBRC 15531T), AB700569-AB700587 (Nocardia otitidiscaviarum IFM 11049), AB701575-AB701605 (Nocardia brasiliensis IFM 10847), and AB701607-701636 (Nocardia brasiliensis NBRC 14402T).
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