scholarly journals A global co-expression network approach for connecting genes to specialized metabolic pathways in plants

2016 ◽  
Author(s):  
Jennifer H. Wisecaver ◽  
Alexander T. Borowsky ◽  
Vered Tzin ◽  
Georg Jander ◽  
Daniel J. Kliebenstein ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Meta Analysis ◽  
Null Distribution ◽  
Gene Clusters ◽  
Cytochrome P450s ◽  
Model Organisms ◽  
Biosynthetic Gene Clusters ◽  
Terpene Synthases ◽  
Specialized Metabolites ◽  
Data Source

AbstractPlants produce a tremendous diversity of specialized metabolites (SMs) to interact with and manage their environment. A major challenge hindering efforts to tap this seemingly boundless source of pharmacopeia is the identification of SM pathways and their constituent genes. Given the well-established observation that the genes comprising a SM pathway are co-regulated in response to specific environmental conditions, we hypothesized that genes from a given SM pathway would form tight associations (modules) with each other in gene co-expression networks, facilitating their identification. To evaluate this hypothesis, we used 10 global co-expression datasets—each a meta-analysis of hundreds to thousands of expression experiments—across eight plant model organisms to identify hundreds of modules of co-expressed genes for each species. In support of our hypothesis, 15.3-52.6% of modules contained two or more known SM biosynthetic genes (e.g., cytochrome P450s, terpene synthases, and chalcone synthases), and module genes were enriched in SM functions (e.g., glucoside and flavonoid biosynthesis). Moreover, modules recovered many experimentally validated SM pathways in these plants, including all six known to form biosynthetic gene clusters (BGCs). In contrast, genes predicted based on physical proximity on a chromosome to form plant BGCs were no more co-expressed than the null distribution for neighboring genes. These results not only suggest that most predicted plant BGCs do not represent genuine SM pathways but also argue that BGCs are unlikely to be a hallmark of plant specialized metabolism. We submit that global gene co-expression is a rich, but largely untapped, data source for discovering the genetic basis and architecture of plant natural products, which can be applied even without knowledge of the genome sequence.

scholarly journals Transporter genes in biosynthetic gene clusters predict metabolite characteristics and siderophore activity

2020 ◽  
Author(s):  
Alexander Crits-Christoph ◽  
Nicholas Bhattacharya ◽  
Matthew R. Olm ◽  
Yun S. Song ◽  
Jillian F. Banfield
Keyword(s):  
Gut Microbiome ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Gene Frequencies ◽  
Specialized Metabolites ◽  
Molecular Weights ◽  
And Function ◽  
Extracellular Environment ◽  
Siderophore Activity

AbstractBiosynthetic gene clusters (BGCs) are operonic sets of microbial genes that synthesize specialized metabolites with diverse functions, including siderophores and antibiotics, which often require export to the extracellular environment. For this reason, genes for transport across cellular membranes are essential for the production of specialized metabolites, and are often genomically co-localized with BGCs. Here we conducted a comprehensive computational analysis of transporters associated with characterized BGCs. In addition to known exporters, in BGCs we found many importer-specific transmembrane domains that co-occur with substrate binding proteins possibly for uptake of siderophores or metabolic precursors. Machine learning models using transporter gene frequencies were predictive of known siderophore activity, molecular weights, and a measure of lipophilicity (log P) for corresponding BGC-synthesized metabolites. Transporter genes associated with BGCs were often equally or more predictive of metabolite features than biosynthetic genes. Given the importance of siderophores as pathogenicity factors, we used transporters specific for siderophore BGCs to identify both known and uncharacterized siderophore-like BGCs in genomes from metagenomes from the infant and adult gut microbiome. We find that 23% of microbial genomes from the infant gut have siderophore-like BGCs, but only 3% of those assembled from adult gut microbiomes do. While siderophore-like BGCs from the infant gut are predominantly associated with Enterobactericaee and Staphylococcus, siderophore-like BGCs can be identified from taxa in the adult gut microbiome that have rarely been recognized for siderophore production. Taken together, these results show that consideration of BGC-associated transporter genes can inform predictions of specialized metabolite structure and function.

scholarly journals Complex evolutionary dynamics govern the diversity and distribution of biosynthetic gene clusters and their encoded specialized metabolites

2020 ◽  
Author(s):  
Alexander B. Chase ◽  
Douglas Sweeney ◽  
Mitchell N. Muskat ◽  
Dulce Guillén-Matus ◽  
Paul R. Jensen
Keyword(s):  
Evolutionary Dynamics ◽  
Gene Clusters ◽  
Ecological Interactions ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Evolutionary Processes ◽  
Specialized Metabolites ◽  
Marine Actinomycete ◽  
Species Specific ◽  
Gain Loss

ABSTRACTWhile specialized metabolites are thought to mediate ecological interactions, the evolutionary processes driving their distributions, particularly among closely related lineages, remain poorly understood. Here, we examine the evolutionary dynamics governing the diversity and distribution of biosynthetic gene clusters (BGCs) in 118 strains across nine described species within the marine actinomycete genus Salinispora. While previous evidence indicated that horizontal gene transfer largely contributed to BGC diversity, we find that a majority of BGCs in Salinispora genomes are maintained by processes of vertical descent. In particular, we identified species-specific signatures that were associated with both BGC distributions and the production of their encoded specialized metabolites. By analyzing nine experimentally characterized BGCs that range in conservation from species to genus specific, we find that the distribution of BGCs among Salinispora species is maintained by selection, while BGC diversification is constrained by recombination among closely related strains and strengthened by gain/loss events between species. Notably, the evolutionary processes driving BGC diversification had direct consequences for compound production, elucidating the mechanisms that lead to chemical diversification. These results support the concept that specialized metabolites, and their cognate BGCs, represent functional traits associated with ecological differentiation among Salinispora species.GRAPHICAL ABSTRACT

scholarly journals Dynamics of the compartmentalized Streptomyces chromosome during metabolic differentiation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Virginia S. Lioy ◽  
Jean-Noël Lorenzi ◽  
Soumaya Najah ◽  
Thibault Poinsignon ◽  
Hervé Leh ◽  
...  
Keyword(s):  
Chromosome Structure ◽  
Gene Clusters ◽  
Structural Features ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Linear Chromosome ◽  
Chromosome Architecture ◽  
Specialized Metabolites ◽  
Streptomyces Ambofaciens ◽  
Core Genes

AbstractBacteria of the genus Streptomyces are prolific producers of specialized metabolites, including antibiotics. The linear chromosome includes a central region harboring core genes, as well as extremities enriched in specialized metabolite biosynthetic gene clusters. Here, we show that chromosome structure in Streptomyces ambofaciens correlates with genetic compartmentalization during exponential phase. Conserved, large and highly transcribed genes form boundaries that segment the central part of the chromosome into domains, whereas the terminal ends tend to be transcriptionally quiescent compartments with different structural features. The onset of metabolic differentiation is accompanied by a rearrangement of chromosome architecture, from a rather ‘open’ to a ‘closed’ conformation, in which highly expressed specialized metabolite biosynthetic genes form new boundaries. Thus, our results indicate that the linear chromosome of S. ambofaciens is partitioned into structurally distinct entities, suggesting a link between chromosome folding, gene expression and genome evolution.

scholarly journals Discovery and characterisation of an amidine-containing ribosomally-synthesised peptide that is widely distributed in nature

2020 ◽  
Author(s):  
Alicia H. Russell ◽  
Natalia M. Vior ◽  
Edward S. Hems ◽  
Rodney Lacret ◽  
Andrew W. Truman
Keyword(s):  
Natural Product ◽  
Genome Mining ◽  
Gene Clusters ◽  
Model Organisms ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Post Translational Modifications ◽  
Streptomyces Albus ◽  
Modified Peptides ◽  
Mining Tool

ABSTRACTRibosomally synthesised and post-translationally modified peptides (RiPPs) are a structurally diverse class of natural product with a range of bioactivities. Genome mining for RiPP biosynthetic gene clusters (BGCs) is often hampered by poor detection of the short precursor peptides that are ultimately modified into the final molecule. Here, we utilise a previously described genome mining tool, RiPPER, to identify novel RiPP precursor peptides near YcaO-domain proteins, enzymes that catalyse various RiPP post-translational modifications including heterocyclisation and thioamidation. Using this dataset, we identified a novel, diverse and highly conserved family of RiPP BGCs spanning over 230 species of Actinobacteria and Firmicutes. A representative BGC from Streptomyces albus J1074 was characterised, leading to the discovery of streptamidine, a novel-amidine containing RiPP. This highlights the breadth of unexplored natural products with structurally rare features, even in model organisms.

scholarly journals Out of the abyss: Genome and metagenome mining reveals unexpected environmental distribution of abyssomicins

2019 ◽  
Author(s):  
Alba Iglesias ◽  
Adriel Latorre-Pérez ◽  
James E. M. Stach ◽  
Manuel Porcar ◽  
Javier Pascual
Keyword(s):  
Genome Mining ◽  
Gene Clusters ◽  
Metagenomic Data ◽  
Model Organisms ◽  
Bacterial Genomes ◽  
Biosynthetic Gene Clusters ◽  
Environmental Distribution ◽  
Regulatory Systems ◽  
Terrestrial Habitats ◽  
Metagenome Mining

AbstractNatural products have traditionally been discovered through the screening of culturable microbial isolates from all sort of environments. The sequencing revolution allowed the identification of dozens of biosynthetic gene clusters (BGCs) within single bacterial genomes, either from cultured or uncultured strains. However, we are still far from fully exploiting the microbial reservoir, as most of the species are non-model organisms with complex regulatory systems and yet recalcitrant to be engineered. Today, genomic and metagenomic data produced by laboratories worldwide covering the most different natural and artificial environments on Earth, are an invaluable source of raw information from which natural product biosynthesis can be accessed. In the present work, we describe the environmental distribution and evolution of the abyssomicin BGC through the analysis of publicly available genomic and metagenomic data. Our results demonstrate that the selection of a pathway-specific enzyme to direct the genome mining is an excellent strategy that led to the identification of 74 new Diels-Alderase homologs and unveiled a surprising prevalence of the abyssomicin BGC within terrestrial habitats, mainly soil and plant-associated, where we have identified five complete and 12 partial new abyssomicin BGCs and 23 new potential abyssomicin BGCs. Our results strongly support the potential of genome and metagenome mining as a key preliminary tool to inform bioprospecting strategies aiming at the identification of new bioactive compounds such as -but not restricted to-abyssomicins.

scholarly journals Bagremycin Antibiotics and Ferroverdin iron-chelators are synthetized by the Same Gene Cluster

2019 ◽  
Author(s):  
Loïc Martinet ◽  
Aymeric Naômé ◽  
Benoit Deflandre ◽  
Marta Maciejewska ◽  
Déborah Tellatin ◽  
...  
Keyword(s):  
Environmental Conditions ◽  
Biosynthetic Pathway ◽  
Gene Clusters ◽  
Iron Chelators ◽  
Hydroxybenzoic Acid ◽  
Iron Availability ◽  
Biosynthetic Gene ◽  
Single Family ◽  
Biosynthetic Gene Clusters ◽  
Specialized Metabolites

AbstractBiosynthetic gene clusters (BGCs) are organized groups of genes involved in the production of specialized metabolites. Typically, one BGC is responsible for the production of one or several similar compounds with bioactivities that usually only vary in terms of strength and/or specificity. Here we show that the previously described ferroverdins and bagremycins, which are families of metabolites with different bioactivities, are produced from the same BGC, whereby the fate of the biosynthetic pathway depends on iron availability. Under conditions of iron depletion, the monomeric bagremycins are formed, which are amino-aromatic antibiotics resulting from the condensation of 3-amino-4-hydroxybenzoic acid with p-vinylphenol. Conversely, when iron is abundantly available, the biosynthetic pathway additionally produces a molecule based on p-vinylphenyl-3-nitroso-4-hydroxybenzoate, which complexes iron to form the trimeric ferroverdins that have anticholesterol activity. Thus our work challenges the concept that BGCs should produce a single family of molecules with one type of bioactivity, the occurrence of the different metabolites being triggered by the environmental conditions.

scholarly journals luxRHomolog-Linked Biosynthetic Gene Clusters inProteobacteria

mSystems ◽  
2018 ◽  
Vol 3 (3) ◽  
Author(s):  
Carolyn A. Brotherton ◽  
Marnix H. Medema ◽  
E. Peter Greenberg
Keyword(s):  
Genome Mining ◽  
Gene Clusters ◽  
Growth Conditions ◽  
Bioactive Metabolites ◽  
Growth Media ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Specialized Metabolites ◽  
A Genome ◽  
Functionally Diverse

ABSTRACTMicrobes are a major source of antibiotics, pharmaceuticals, and other bioactive compounds. The production of many specialized microbial metabolites is encoded in biosynthetic gene clusters (BGCs). A challenge associated with natural product discovery is that many BGCs are not expressed under laboratory growth conditions. Here we report a genome-mining approach to discover BGCs withluxR-type quorum sensing (QS) genes, which code for regulatory proteins that control gene expression. Our results show that BGCs linked to genes coding for LuxR-like proteins are widespread inProteobacteria. In addition, we show that associations betweenluxRhomolog genes and BGCs have evolved independently many times, with functionally diverse gene clusters. Overall, these clusters may provide a source of new natural products for which there is some understanding about how to elicit production.IMPORTANCEBacteria biosynthesize specialized metabolites with a variety of ecological functions, including defense against other microbes. Genes that code for specialized metabolite biosynthetic enzymes are frequently clustered together. These BGCs are often regulated by a transcription factor encoded within the cluster itself. These pathway-specific regulators respond to a signal or indirectly through other means of environmental sensing. Many specialized metabolites are not produced under laboratory growth conditions, and one reason for this issue is that laboratory growth media lack environmental cues necessary for BGC expression. Here, we report a bioinformatics study that reveals that BGCs are frequently linked to genes coding for LuxR family QS-responsive transcription factors in the phylumProteobacteria. The products of theseluxRhomolog-associated gene clusters may serve as a practical source of bioactive metabolites.

scholarly journals Dynamics of the compartmentalized Streptomyces chromosome during metabolic differentiation

2020 ◽  
Author(s):  
Virginia Lioy ◽  
Jean-Noël Lorenzi ◽  
Soumaya Najah ◽  
Thibault Poinsignon ◽  
Hervé Leh ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Chromosome Structure ◽  
Gene Clusters ◽  
Structural Features ◽  
Biosynthetic Gene Clusters ◽  
Linear Chromosome ◽  
Chromosome Architecture ◽  
Specialized Metabolites ◽  
And Function ◽  
Core Genes

AbstractStreptomyces are among the most prolific bacterial producers of specialized metabolites, including antibiotics. The linear chromosome is partitioned into a central region harboring core genes and two extremities enriched in specialized metabolite biosynthetic gene clusters (SMBGCs). The molecular mechanisms governing structure and function of these compartmentalized genomes remain mostly unknown. Here we show that in exponential phase, chromosome structure correlates with genetic compartmentalization: conserved, large and highly transcribed genes form boundaries that segment the central part of the chromosome into domains, whereas the terminal ends are transcriptionally, largely quiescent compartments with different structural features. Onset of metabolic differentiation is accompanied by remodeling of chromosome architecture from an ‘open’ to a rather ‘closed’ conformation, in which the SMBGCs are expressed forming new boundaries. Altogether, our results reveal that S. ambofaciens’ linear chromosome is partitioned into structurally distinct entities, indicating a link between chromosome folding, gene expression and genome evolution.

scholarly journals Phages weaponize their bacteria with biosynthetic gene clusters

2020 ◽  
Author(s):  
Anna Dragoš ◽  
Aaron J.C. Andersen ◽  
Carlos N. Lozano-Andrade ◽  
Paul J. Kempen ◽  
Ákos T. Kovács ◽  
...  
Keyword(s):  
Pathogenic Bacteria ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Specialized Metabolites ◽  
Fitness Advantage ◽  
Large Step ◽  
Bioactive Potential ◽  
Close Relatives

ABSTRACTBacteria produce many different specialized metabolites, which are encoded by biosynthetic gene clusters (BGCs). Despite high industrial relevance owing to broad bioactive potential of these metabolites, their ecological roles remain largely unexplored. We analyze all available genomes for BGCs of phage origin. The BGCs predominantly reside within temperate phages infecting certain commensal and pathogenic bacteria. Nearly all phage BGCs encode bacteriocins, which appear to serve as a strong proxy for phage specificity. Using the gut-associated bacterium Bacillus subtilis, we demonstrate how a temperate phage equips its host with a functional BGC, providing it with a competitive fitness advantage over close relatives. Therefore, certain temperate phages use BGCs to weaponize their bacteria against close relatives, leading to evolutionary benefits from lysogeny to the infected host, and hence, to the phage itself. Our study is a large step towards understanding the natural role of specialized metabolites, as well as mutualistic phage-host relationships.

scholarly journals Cycad coralloid roots contain bacterial communities including cyanobacteria and Caulobacter spp that encode niche-specific biosynthetic gene clusters

2017 ◽  
Author(s):  
Karina Gutiérrez-García ◽  
Edder D. Bustos-Díaz ◽  
José Antonio Corona-Gómez ◽  
Hilda E. Ramos-Aboites ◽  
Nelly Sélem-Mojica ◽  
...  
Keyword(s):  
Genome Mining ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Natural Habitats ◽  
Shotgun Metagenomics ◽  
Specialized Metabolites ◽  
Symbiotic Relationships ◽  
Functional Patterns ◽  
Coralloid Roots

AbstractCycads are the only early seed plants that have evolved a specialized root to host endophytic bacteria that fix nitrogen. To provide evolutionary and functional insights into this million-year old symbiosis, we investigate endophytic bacterial sub-communities isolated from coralloid roots of species from Dioon (Zamiaceae) sampled from their natural habitats. We employed a sub-community co-culture experimental strategy to reveal both predominant and rare bacteria, which were characterized using phylogenomics and detailed metabolic annotation. Diazotrophic plant endophytes, including Bradyrhizobium, Burkholderia, Mesorhizobium, Nostoc, and Rhizobium species, dominated the epiphyte-free sub-communities. Draft genomes of six cyanobacteria species were obtained after shotgun metagenomics of selected sub-communities and used for whole-genome inferences that suggest two Dioon-specific monophyletic groups and a level of specialization characteristic of co-evolved symbiotic relationships. In agreement with this, the genomes of these cyanobacteria were found to encode unique biosynthetic gene clusters, predicted to direct the synthesis of specialized metabolites, mainly involving peptides. After combining genome mining with metabolite profiling using multiphoton excitation fluorescence microscopy, we also show that Caulobacter species co-exist with cyanobacteria, and may interact with them by means of a novel indigoidine-like specialized metabolite. We provide an unprecedented view of the composition of the cycad coralloid root, including phylogenetic and functional patterns mediated by specialized metabolites that may be important for the evolution of ancient symbiotic adaptations.

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