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Structural organization of syringomycin, amonabactins, icosalide, albicidin, and locillomycin synthetases with an "out of the rules" mode of biosynthesis. A, adenylation domain; C ( L CL, D CL, or Cstart), condensation domain; C/E, dual condensation and epimerization domain; T, thiolation domain; E, epimerization domain; MT, methyl transferase domain; AL, acyl-CoA ligase domain; ACP, acyl carrier protein; KS, ketosynthase domain; DH, dehydrogenase domain; KR, ketoreductase domain; ANL, α-ANH-like domain. The nonfunctionnal second A domain of albicidin synthetase is depicted with a green broken rounded square. The white squared domains are related to PKSs.
Source publication
Nonribosomal peptides are microbial secondary metabolites exhibiting a tremendous structural diversity and a broad range of biological activities useful in the medical and agro-ecological fields. They are built up by huge multimodular enzymes called nonribosomal peptide synthetases. These synthetases are organized in modules constituted of adenylat...
Contexts in source publication
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... peculiar feature has been used to identify putative CLP gene clusters by in silico analysis [97]. Interestingly, whereas peptin, factin, and mycin families may be co-produced by P. syringae strains, only the peptin and factin NRPSs display a tandem of Te, whereas mycin synthetases possess a single Te domain [28] (Figures 2 and 3). The role of each of Te domain in a tandem architecture is not clearly established. ...
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... the ninth amino acid is provided by the separate NRPS stand-alone module encoded by syrB1 located upstream of syrE. In fact, the last module is split on SyrB1 [A-T] and on the end of SyrE [C-T-Te] (Figure 3). During the synthesis, the eight first amino acids are condensated according to the SyrE template in a collinear mode. ...
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... slightly different situation concerns the biosynthetic assembly line of the hybrid PK/NRP potent DNA gyrase inhibitor and phytotoxin albicidin, for which the A domain is present but not functional. The biosynthetic machinery of albicidin involves noncanonical complementation in trans of an inactive A domain within the main assembly line by a stand-alone unusual [A-T] di-domain module (Figure 3). Indeed, the A domain expected by the collinearity rule to incorporate a cyano-L-Ala in the final peptide is not functional due to low sequence conservation in the core motifs required for the correct activation and adenylation of a monomer. ...
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... constitute a family of four variants of catechol peptidic siderophores thanks to a unique mode of biosynthesis with alternative, iterative and optional use of domains [26]. The relationship between the domain organization of the NRPS (Figure 3) and the structures of amonabactins was demonstrated by the construction of mutants [26]. The mode of biosynthesis was qualified as an alternative because of the flexibility of the A domain of AmoG able to recruit indifferently Phe or Trp residues. ...
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... peculiar feature has been used to identify putative CLP gene clusters by in silico analysis [97]. Interestingly, whereas peptin, factin, and mycin families may be co-produced by P. syringae strains, only the peptin and factin NRPSs display a tandem of Te, whereas mycin synthetases possess a single Te domain [28] (Figures 2 and 3). The role of each of Te domain in a tandem architecture is not clearly established. ...
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... the ninth amino acid is provided by the separate NRPS stand-alone module encoded by syrB1 located upstream of syrE. In fact, the last module is split on SyrB1 [A-T] and on the end of SyrE [C-T-Te] (Figure 3). During the synthesis, the eight first amino acids are condensated according to the SyrE template in a collinear mode. ...
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... slightly different situation concerns the biosynthetic assembly line of the hybrid PK/NRP potent DNA gyrase inhibitor and phytotoxin albicidin, for which the A domain is present but not functional. The biosynthetic machinery of albicidin involves noncanonical complementation in trans of an inactive A domain within the main assembly line by a stand-alone unusual [A-T] di-domain module (Figure 3). Indeed, the A domain expected by the collinearity rule to incorporate a cyano-L-Ala in the final peptide is not functional due to low sequence conservation in the core motifs required for the correct activation and adenylation of a monomer. ...
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... constitute a family of four variants of catechol peptidic siderophores thanks to a unique mode of biosynthesis with alternative, iterative and optional use of domains [26]. The relationship between the domain organization of the NRPS (Figure 3) and the structures of amonabactins was demonstrated by the construction of mutants [26]. The mode of biosynthesis was qualified as an alternative because of the flexibility of the A domain of AmoG able to recruit indifferently Phe or Trp residues. ...
Citations
... Using the genome-wide ANI values of all orthologous genes shared between every pair of genomes [31], we delineated 55 species based on the 95 % ANI threshold (Figs 1a and S2, Table S2). Only seven species, designated as species 18,21,40,44,52,53, and 55, were represented by more than five genomes. A total of 32 Streptomyces species were represented by a single genome. ...
... Further modifications in hybrid BGCs are derived from alterations in the linear order of each BGC domain in the chromosome, which can alter the order of synthesis of compounds and their structural derivatives [51,52]. For example, we found NRPS-T1PKS and T1PKS-NRPS in 48 and 29 genomes, respectively. ...
... The alternating orange and yellow strip represent the species boundaries calculated using the genome-wide average nucleotide identity (ANI). For visual clarity, only the species represented by more than five genomes are labelled (sp.18,21,40,44,52,53,55). Coloured dots next to the tree indicate the bat species (labelled 1) and site (labelled 2) from which the isolate was obtained. ...
Streptomyces are prolific producers of secondary metabolites from which many clinically useful compounds have been derived. They inhabit diverse habitats but have rarely been reported in vertebrates. Here, we aim to determine to what extent the ecological source (bat host species and cave sites) influence the genomic and biosynthetic diversity of Streptomyces bacteria. We analysed draft genomes of 132 Streptomyces isolates sampled from 11 species of insectivorous bats from six cave sites in Arizona and New Mexico, USA. We delineated 55 species based on the genome-wide average nucleotide identity and core genome phylogenetic tree. Streptomyces isolates that colonize the same bat species or inhabit the same site exhibit greater overall genomic similarity than they do with Streptomyces from other bat species or sites. However, when considering biosynthetic gene clusters (BGCs) alone, BGC distribution is not structured by the ecological or geographical source of the Streptomyces that carry them. Each genome carried between 19–65 BGCs (median=42.5) and varied even among members of the same Streptomyces species. Nine major classes of BGCs were detected in ten of the 11 bat species and in all sites: terpene, non-ribosomal peptide synthetase, polyketide synthase, siderophore, RiPP-like, butyrolactone, lanthipeptide, ectoine, melanin. Finally, Streptomyces genomes carry multiple hybrid BGCs consisting of signature domains from two to seven distinct BGC classes. Taken together, our results bring critical insights to understanding Streptomyces -bat ecology and BGC diversity that may contribute to bat health and in augmenting current efforts in natural product discovery, especially from underexplored or overlooked environments.
... Nonribosomal peptides (NRPs) are a novel agent that lower side effects and exhibit high therapeutic efficacy. NRPs found in bacteria, cyanobacteria, and fungi are secondary bioactive metabolites required for positive or negative regulation at the transcriptional or post-translational level [33]. These peptides form another class of cancer treatments [34] (Fig. 4). ...
... Among them was pantothenic acid, a precursor of acetyl-CoA, an essential compound in coenzyme A (CoA) synthesis. Acetyl-CoA plays a critical role in lipid synthesis and in the synthesis of NRPS compounds via acyl-CoA ligase and acyl-CoA synthetases [39]. Finally, we confirmed that exudates of both WT and Δtmk3 mutant contained purines, including GMP, AMP, and adenine (Fig 8D), supporting our BarSeq data showing that the fitness defects of purine mutants in rhizosphere bacteria were recovered when exposed to exudates from T. atroviride. ...
Trichoderma spp. are ubiquitous rhizosphere fungi capable of producing several classes of secondary metabolites that can modify the dynamics of the plant-associated microbiome. However, the bacterial-fungal mechanisms that mediate these interactions have not been fully characterized. Here, a random barcode transposon-site sequencing (RB-TnSeq) approach was employed to identify bacterial genes important for fitness in the presence of Trichoderma atroviride exudates. We selected three rhizosphere bacteria with RB-TnSeq mutant libraries that can promote plant growth: the nitrogen fixers Klebsiella michiganensis M5aI and Herbaspirillum seropedicae SmR1, and Pseudomonas simiae WCS417. As a non-rhizosphere species, Pseudomonas putida KT2440 was also included. From the RB-TnSeq data, nitrogen-fixing bacteria competed mainly for iron and required the siderophore transport system TonB/Exb for optimal fitness in the presence of T. atroviride exudates. In contrast, P. simiae and P. putida were highly dependent on mechanisms associated with membrane lipid modification that are required for resistance to cationic antimicrobial peptides (CAMPs). A mutant in the Hog1-MAP kinase (Δtmk3) gene of T. atroviride showed altered expression patterns of many nonribosomal peptide synthetase (NRPS) biosynthetic gene clusters with potential antibiotic activity. In contrast with exudates from wild-type T. atroviride, bacterial mutants containing lesions in genes associated with resistance to antibiotics did not show fitness defects when RB-TnSeq libraries were exposed to exudates from the Δtmk3 mutant. Unexpectedly, exudates from wild-type T. atroviride and the Δtmk3 mutant rescued purine auxotrophic mutants of H. seropedicae, K. michiganensis and P. simiae. Metabolomic analysis on exudates from wild-type T. atroviride and the Δtmk3 mutant showed that both strains excrete purines and complex metabolites; functional Tmk3 is required to produce some of these metabolites. This study highlights the complex interplay between Trichoderma-metabolites and soil bacteria, revealing both beneficial and antagonistic effects, and underscoring the intricate and multifaceted nature of this relationship.
... To create two among the four main types of secondary metabolites, fungi use megasynthases, large modular enzymes such as NRPS, nonribosomal peptide synthetase [170], or PKS (polyketide synthase) [171] (Figure 1a,b and Figure 3a). In these modular enzymes, catalytic domains with a number of functions, required for the polymerization of (i) amino acids, including non-proteinogenic acids (in the case of NRPS), or (ii) acyl groups, from acetyl-CoA to malonyl-CoA (in the case of PKS), are assembled into one huge polypeptide chain [172,173]. ...
... To create two among the four main types of secondary metabolites, fungi use megasynthases, large modular enzymes such as NRPS, nonribosomal peptide synthetase [170], or PKS (polyketide synthase) [171] (Figures 1a,b and 3a). In these modular enzymes, catalytic domains with a number of functions, required for the polymerization of (i) amino acids, including non-proteinogenic acids (in the case of NRPS), or (ii) acyl groups, from acetyl-CoA to malonyl-CoA (in the case of PKS), are assembled into one huge polypeptide chain [172,173]. ...
Filamentous fungi are one of the most important producers of secondary metabolites. Some of them can havse a toxic effect on the human body, leading to diseases. On the other hand, they are widely used as pharmaceutically significant drugs, such as antibiotics, statins, and immunosuppressants. A single fungus species in response to various signals can produce 100 or more secondary metabolites. Such signaling is possible due to the coordinated regulation of several dozen biosynthetic gene clusters (BGCs), which are mosaically localized in different regions of fungal chromosomes. Their regulation includes several levels, from pathway-specific regulators, whose genes are localized inside BGCs, to global regulators of the cell (taking into account changes in pH, carbon consumption, etc.) and global regulators of secondary metabolism (affecting epigenetic changes driven by velvet family proteins, LaeA, etc.). In addition, various low-molecular-weight substances can have a mediating effect on such regulatory processes. This review is devoted to a critical analysis of the available data on the “turning on” and “off” of the biosynthesis of secondary metabolites in response to signals in filamentous fungi. To describe the ongoing processes, the model of “piano regulation” is proposed, whereby pressing a certain key (signal) leads to the extraction of a certain sound from the “musical instrument of the fungus cell”, which is expressed in the production of a specific secondary metabolite.
... Additional secondary domains are found integrated into the assembly line and are involved in substrate modification (epimerization, methylation, cyclization). Finally, hydrolysis of the final peptide from the last T domain of the assembly line is catalyzed by a thioesterase (TE-domain) [55]. The synthesis also requires non-integrated enzymes that catalyze the synthesis of aryl substrates or non-proteinogenic amino acids and sometimes rely on the activity of a polyketide synthase (PKS) domain [56,57]. ...
Siderophores are small metal chelators synthesized by numerous organisms to access iron. These secondary metabolites are ubiquitously present on Earth, and because their production represents the main strategy to assimilate iron, they play an important role in both positive and negative interactions between organisms. In addition, siderophores are used in biotechnology for diverse applications in medicine, agriculture and the environment. The generation of non-natural siderophore analogs provides a new opportunity to create new-to-nature chelating biomolecules that can offer new properties to expand applications. This review summarizes the main strategies of combinatorial biosynthesis that have been used to generate siderophore analogs. We first provide a brief overview of siderophore biosynthesis, followed by a description of the strategies, namely, precursor-directed biosynthesis, the design of synthetic or heterologous pathways and enzyme engineering, used in siderophore biosynthetic pathways to create diversity. In addition, this review highlights the engineering strategies that have been used to improve the production of siderophores by cells to facilitate their downstream utilization.
... Search for KK-1 biosynthetic non-ribosomal peptide synthetase gene In many peptide secondary metabolites, the peptide backbone is known to be synthesized by non-ribosomal peptide synthetase (NRPS). NRPSs are large enzyme complexes that have modular structures, each containing multiple functional domains with specific activities and being capable of catalyzing the synthesis of peptide chains without depending on ribosomal machinery (Hur et al., 2012;Duban et al., 2022). Each module basically contains an adenylation domain (A domain), peptidyl carrier protein domain (PCP domain), and condensation domain (C domain), which are essential for the synthesis of the peptide backbone, and a thioesterase domain (TE domain) that is generally located at the C-terminus in the final module of NRPS and is responsible for the cyclization of the peptide chain (Hur et al., 2012;Duban et al., 2022). ...
... NRPSs are large enzyme complexes that have modular structures, each containing multiple functional domains with specific activities and being capable of catalyzing the synthesis of peptide chains without depending on ribosomal machinery (Hur et al., 2012;Duban et al., 2022). Each module basically contains an adenylation domain (A domain), peptidyl carrier protein domain (PCP domain), and condensation domain (C domain), which are essential for the synthesis of the peptide backbone, and a thioesterase domain (TE domain) that is generally located at the C-terminus in the final module of NRPS and is responsible for the cyclization of the peptide chain (Hur et al., 2012;Duban et al., 2022). The other domains have the function of modifying the peptide backbone that is synthesized by these essential domains (Hur et al., 2012;Duban et al., 2022). ...
... Each module basically contains an adenylation domain (A domain), peptidyl carrier protein domain (PCP domain), and condensation domain (C domain), which are essential for the synthesis of the peptide backbone, and a thioesterase domain (TE domain) that is generally located at the C-terminus in the final module of NRPS and is responsible for the cyclization of the peptide chain (Hur et al., 2012;Duban et al., 2022). The other domains have the function of modifying the peptide backbone that is synthesized by these essential domains (Hur et al., 2012;Duban et al., 2022). Since the order and number of the module structures and the characteristics of their constituent domains are consistent with those of amino acid residues of the corresponding peptide, it is possible to presume that NRPS is involved in the biosynthesis of peptide secondary metabolites based on this information. ...
KK-1, a cyclic depsipeptide with 10 residues produced by a filamentous fungus Curvularia clavata BAUA-2787, is a promising pesticide active compound with high activity against many plant pathogens, especially Botrytis cinerea . As a first step toward the future mass production of KK-1 through synthetic biological approaches, we aimed to identify the genes responsible for the KK-1 biosynthesis. To achieve this, we conducted whole genome sequencing and transcriptome analysis of C. clavata BAUA-2787 to predict the KK-1 biosynthetic gene cluster. We then generated the overexpression and deletion mutants for each cluster gene using our originally developed transformation system for this fungus, and analyzed the KK-1 production and the cluster gene expression levels to confirm their involvement in KK-1 biosynthesis. As a result of these, a region of approximately 71 kb was found, containing 10 open reading frames, which were co-induced during KK-1 production, as a biosynthetic gene cluster. These include kk1B , which encodes nonribosomal peptide synthetase with a domain structure that is consistent with the structural features of KK-1, and kk1F , which encodes a transcription factor. The overexpression of kk1F increased the expression of the entire cluster genes and, consequently, improved KK-1 production, whereas its deletion decreased the expression of the entire cluster genes and almost eliminated KK-1 production, demonstrating that the protein encoded by kk1F regulates the expressions of the other nine cluster genes cooperatively as the pathway-specific transcription factor. Furthermore, the deletion of each cluster gene caused a reduction in KK-1 productivity, indicating that each gene is involved in KK-1 production. The genes kk1A , kk1D , kk1H , and kk1I , which showed a significant decrease in KK-1 productivity due to deletion, were presumed to be directly involved in KK-1 structure formation, including the biosynthesis of the constituent residues. kk1C , kk1E , kk1G , and kk1J , which maintained a certain level of KK-1 productivity despite deletion, were possibly involved in promoting or assisting KK-1 production, such as extracellular transportation and the removal of aberrant units incorporated into the peptide chain.
... As such, each module governs, according to the collinearity rule, the incorporation of a monomer within the growing peptide. The release of the peptide from the assembly chain is finally performed by a terminal core thioesterase domain (Duban et al 2022). ...
... Expression analysis was additionally performed for secondary metabolism-related genes, and significant differences were found for 11.00% of the genes. Notably, the expression levels of core enzymes in multiple secondary metabolite gene clusters were significantly upregulated, mainly including non-ribosomal peptide synthetase, polyketide, and cytochrome P450 monooxygenase, which were thought to play an important role in the synthesis and modification of secondary metabolite [33][34][35][36]. Overexpression of the gene laeA in A. niger also resulted in differential expression of numerous secondary metabolite genes [37], suggesting that llm1 may resemble laeA as a global regulator gene that controls the expression of secondary metabolite gene clusters. ...
Putative methyltransferases are thought to be involved in the regulation of secondary metabolites in filamentous fungi. Here, we report the effects of overexpression of a predicted LaeA-like methyltransferase gene llm1 on the synthesis of secondary metabolites in Aspergillus cristatus. Our results revealed that overexpression of the gene llm1 in A. cristatus significantly hindered the production of conidia and enhanced sexual development, and reduced oxidative tolerance to hydrogen peroxide. Compared with the wild-type, the metabolic profile of the overexpression transformant was distinct, and the contents of multiple secondary metabolites were markedly increased, mainly including terpenoids and flavonoids, such as (S)-olEuropeic acid, gibberellin A62, gibberellin A95, ovalitenone, PD 98059, and 1-isomangostin. A total of 600 significantly differentially expressed genes (DEGs) were identified utilizing transcriptome sequencing, and the DEGs were predominantly enriched in transmembrane transport and secondary metabolism-related biological processes. In summary, the strategy of overexpressing global secondary metabolite regulators successfully activated the expression of secondary metabolite gene clusters, and the numerous secondary metabolites were greatly strengthened in A. cristatus. This study provides new insights into the in-depth exploitation and utilization of novel secondary metabolites of A. cristatus.
... Bacteria and fungi produce many of these compounds as a courtesy of nonribosomal biosynthetic enzymatic pathways, which involve multimodular megaenzymes named nonribosomal peptide synthetases (NRPSs). This Special Issue includes a review highlighting recent progress in understanding the complexity of the mechanisms of nonribosomal synthesis [1], and five research articles describing the successful discovery of new nonribosomal peptides [2][3][4][5], their structural characterization [3,5], and their relationship with the taxonomic position of the producing strains [6]. ...
... The mechanism leading to the assembly of the monomers to build up the peptide generally follows canonical rules using the core enzymatic domains referred to as A (adenylation) domain, T (thiolation) domain, C (condensation) domain, and a TE (thioesterase) domain ending the assembly line. However, the constantly expanding literature presents many examples of NRPSs exhibiting very rare domains and/or noncanonical organizations of domains and modules, thus revealing amazing strategies developed by microorganisms to synthesize nonribosomal peptides [1]. ...
... In their review, Duban et al. [1] discuss examples of secondary metabolites biosynthesized through pathways diverging from the canonical colinear mode, and hence involving NRPSs displaying either very rare domains and/or a noncanonical organization of modules and domains. This long (although probably inexhaustive) list of examples tells us that it is necessary to enlarge our vision of the nonribosomal peptide synthesis. ...
Microbial secondary metabolites are natural products that display various therapeutical or agrochemical relevant activities (e [...]
Plants face numerous challenges in their ongoing battle against pests and diseases. Traditional protection methods often involve synthetic pesticides, which have a detrimental impact on the environment and human health. However, the quest for eco-friendly and sustainable solutions has brought surfactin into the spotlight as a promising defender of plants. Surfactin, a biometabolite produced by Bacillus spp., has gained attention due to its multifaceted properties contributing to plant defense. This review highlights the eco-friendly nature of surfactin and explores its notable functions as an antimicrobial agent, the ability to modulate plant defense mechanisms, enhance colonization and biofilm formation of antagonists, and ultimately promote plant growth. Furthermore, the environmentally friendly characteristics of surfactin, such as its biodegradability and low toxicity, make it an ideal candidate for sustainable plant protection strategies. The potential applications and challenges in utilizing surfactin as an eco-friendly defender of plants are discussed, providing insights for future research and the development of innovative and sustainable agricultural practices.
