scholarly journals Expanding gene families helps generate the metabolic robustness required for antibiotic biosynthesis

2017 ◽  
Author(s):  
Jana K Schniete ◽  
Pablo Cruz-Morales ◽  
Nelly Selem ◽  
Lorena T. Fernández-Martínez ◽  
Iain S Hunter ◽  
...  
Keyword(s):  
Gene Families ◽  
Gene Clusters ◽  
Central Carbon Metabolism ◽  
Metabolic Adaptation ◽  
Antibiotic Biosynthesis ◽  
Biosynthetic Gene Clusters ◽  
Metabolic Plasticity ◽  
Central Carbon ◽  
Metabolic Robustness ◽  
Cell Functionality

Introductory paragraphExpanding the genetic repertoire of an organism by gene duplication or horizontal gene transfer (HGT) can aid adaptation. Streptomyces species are prolific producers of bioactive specialised metabolites with adaptive functions in nature and some have found utility in human medicine such as antibiotics. Whilst the biosynthesis of these specialised metabolites is directed by dedicated biosynthetic gene clusters (BGCs), little attention has been focussed on how these organisms have evolved robustness into their genomes to facilitate the metabolic plasticity required to provide chemical precursors for biosynthesis. Here we show that specific expansions of gene families in central carbon metabolism have evolved and become fixed in Streptomyces bacteria to enable plasticity and robustness that maintain cell functionality whilst costly specialised metabolites are produced. These expanded gene families, in addition to being a metabolic adaptation, make excellent targets for metabolic engineering of industrial specialised metabolite producing bacteria.

scholarly journals Flor yeasts rewire the central carbon metabolism during wine alcoholic fermentation

2021 ◽  
Author(s):  
Emilien Peltier ◽  
Charlotte Vion ◽  
Omar Abou Saada ◽  
Anne Friedrich ◽  
Joseph Schacherer ◽  
...  
Keyword(s):  
Carbon Metabolism ◽  
Parental Strain ◽  
Tricarboxylic Acid Cycle ◽  
Phenotypic Variability ◽  
Central Carbon Metabolism ◽  
Metabolic Adaptation ◽  
Flor Yeast ◽  
Central Carbon ◽  
Flor Yeasts ◽  
Allelic Variations

AbstractThe identification of natural allelic variations controlling quantitative traits could contribute to decipher metabolic adaptation mechanisms within different populations of the same species. Such variations could result from man-mediated selection pressures and participate to the domestication. In this study, the genetic causes of the phenotypic variability of the central carbon metabolism Saccharomyces cerevisiae were investigated in the context of the enological fermentation. Carbon dioxide and glycerol production as well as malic acid consumption modulate the fermentation yield revealing a high level of genetic complexity. Their genetic determinism was found out by a multi environment QTL mapping approach allowing the identification of 14 quantitative trait loci from which 8 of them were validated down to the gene level by genetic engineering. Most of the validated genes had allelic variations involving flor yeast specific alleles. Those alleles were brought in the offspring by one parental strain that is closely related to the flor yeast genetic group while the second parental strain is part of the wine group. The causative genes identified are functionally linked to quantitative proteomic variations that would explain divergent metabolic features of wine and flor yeasts involving the tricarboxylic acid cycle (TCA), the glyoxylate shunt and the homeostasis of proton and redox cofactors. Overall, this work led to the identification of genetic factors that are hallmarks of adaptive divergence between flor yeast and wine yeast in the wine biotope. These alleles can also be used in the context of yeast selection to improve oenological traits linked to fermentation yield.

scholarly journals GRINS: Genetic elements that recode assembly-line polyketide synthases and accelerate their diversification

2021 ◽  
Vol 118 (26) ◽  
pp. e2100751118 ◽  
Author(s):  
Aleksandra Nivina ◽  
Sur Herrera Paredes ◽  
Hunter B. Fraser ◽  
Chaitan Khosla
Keyword(s):  
Molecular Mechanisms ◽  
Assembly Line ◽  
Gene Families ◽  
Gene Clusters ◽  
Nucleotide Composition ◽  
Polyketide Synthases ◽  
Bacterial Genomes ◽  
Biosynthetic Gene Clusters ◽  
Bacterial Phyla ◽  
Genetic Elements

Assembly-line polyketide synthases (PKSs) are large and complex enzymatic machineries with a multimodular architecture, typically encoded in bacterial genomes by biosynthetic gene clusters. Their modularity has led to an astounding diversity of biosynthesized molecules, many with medical relevance. Thus, understanding the mechanisms that drive PKS evolution is fundamental for both functional prediction of natural PKSs as well as for the engineering of novel PKSs. Here, we describe a repetitive genetic element in assembly-line PKS genes which appears to play a role in accelerating the diversification of closely related biosynthetic clusters. We named this element GRINS: genetic repeats of intense nucleotide skews. GRINS appear to recode PKS protein regions with a biased nucleotide composition and to promote gene conversion. GRINS are present in a large number of assembly-line PKS gene clusters and are particularly widespread in the actinobacterial genus Streptomyces. While the molecular mechanisms associated with GRINS appearance, dissemination, and maintenance are unknown, the presence of GRINS in a broad range of bacterial phyla and gene families indicates that these genetic elements could play a fundamental role in protein evolution.

scholarly journals Differential transcription of expanded gene families in central carbon metabolism of Streptomyces coelicolor A3(2)

2019 ◽  
Author(s):  
Jana K Schniete ◽  
Richard Reumerman ◽  
Leena Kerr ◽  
Nicholas P Tucker ◽  
Iain S Hunter ◽  
...  
Keyword(s):  
Carbon Source ◽  
Streptomyces Coelicolor ◽  
Carbon Sources ◽  
Gene Families ◽  
Gene Clusters ◽  
Central Carbon Metabolism ◽  
Rna Seq ◽  
Enzymatic Function ◽  
Expression Of Genes ◽  
Genes Encoding

AbstractBackgroundStreptomycete bacteria are prolific producers of specialised metabolites, many of which have clinically relevant bioactivity. A striking feature of their genomes is the expansion of gene families that encode the same enzymatic function. Genes that undergo expansion events, either by horizontal gene transfer or duplication, can have a range of fates: genes can be lost, or they can undergo neo-functionalisation or sub-functionalisation. To test whether expanded gene families in Streptomyces exhibit differential expression, an RNA-Seq approach was used to examine cultures of wild-type Streptomyces coelicolor grown with either glucose or tween as the sole carbon source.ResultsRNA-Seq analysis showed that two-thirds of genes within expanded gene families show transcriptional differences when strains were grown on tween compared to glucose. In addition, expression of specialised metabolite gene clusters (actinorhodin, isorenieratane, coelichelin and a cryptic NRPS) was also influenced by carbon source.ConclusionsExpression of genes encoding the same enzymatic function had transcriptional differences when grown on different carbon sources. This transcriptional divergence enables partitioning to function under different physiological conditions. These approaches can inform metabolic engineering of industrial Streptomyces strains and may help develop cultivation conditions to activate the so-called silent biosynthetic gene clusters.

scholarly journals A Hierarchical Network of Four Regulatory Genes Controlling Production of the Polyene Antibiotic Candicidin in Streptomyces sp. Strain FR-008

2020 ◽  
Vol 86 (9) ◽  
Author(s):  
Yanping Zhu ◽  
Wenhao Xu ◽  
Jing Zhang ◽  
Peipei Zhang ◽  
Zhilong Zhao ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Regulatory Network ◽  
Gene Clusters ◽  
Biosynthetic Gene Cluster ◽  
Regulatory Genes ◽  
Transcriptional Analysis ◽  
Antibiotic Biosynthesis ◽  
Biosynthetic Gene ◽  
Polyene Antibiotic ◽  
Biosynthetic Gene Clusters

ABSTRACT The four regulatory genes fscR1 to fscR4 in Streptomyces sp. strain FR-008 form a genetic arrangement that is widely distributed in macrolide-producing bacteria. Our previous work has demonstrated that fscR1 and fscR4 are critical for production of the polyene antibiotic candicidin. In this study, we further characterized the roles of the other two regulatory genes, fscR2 and fscR3, focusing on the relationship between these four regulatory genes. Disruption of a single or multiple regulatory genes did not affect bacterial growth, but transcription of genes in the candicidin biosynthetic gene cluster decreased, and candicidin production was abolished, indicating a critical role for each of the four regulatory genes, including fscR2 and fscR3, in candicidin biosynthesis. We found that fscR1 to fscR4, although differentially expressed throughout the growth phase, displayed similar temporal expression patterns, with an abrupt increase in the early exponential phase, coincident with initial detection of antibiotic production in the same phase. Our data suggest that the four regulatory genes fscR1 to fscR4 have various degrees of control over structural genes in the biosynthetic cluster under the conditions examined. Extensive transcriptional analysis indicated that complex regulation exists between these four regulatory genes, forming a regulatory network, with fscR1 and fscR4 functioning at a lower level. Comprehensive cross-complementation analysis indicates that functional complementation is restricted among the four regulators and unidirectional, with fscR1 complementing the loss of fscR3 or -4 and fscR4 complementing loss of fscR2. Our study provides more insights into the roles of, and the regulatory network formed by, these four regulatory genes controlling production of an important pharmaceutical compound. IMPORTANCE The regulation of antibiotic biosynthesis by Streptomyces species is complex, especially for biosynthetic gene clusters with multiple regulatory genes. The biosynthetic gene cluster for the polyene antibiotic candicidin contains four consecutive regulatory genes, which encode regulatory proteins from different families and which form a subcluster within the larger biosynthetic gene cluster in Streptomyces sp. FR-008. Syntenic arrangements of these regulatory genes are widely distributed in polyene gene clusters, such as the amphotericin and nystatin gene clusters, suggesting a conserved regulatory mechanism controlling production of these clinically important medicines. However, the relationships between these multiple regulatory genes are unknown. In this study, we determined that each of these four regulatory genes is critical for candicidin production. Additionally, using transcriptional analyses, bioassays, high-performance liquid chromatography (HPLC) analysis, and genetic cross-complementation, we showed that FscR1 to FscR4 comprise a hierarchical regulatory network that controls candicidin production and is likely representative of how expression of other polyene biosynthetic gene clusters is controlled.

scholarly journals Kill and cure: genomic phylogeny and bioactivity of a diverse collection of Burkholderia gladioli bacteria capable of pathogenic and beneficial lifestyles

2020 ◽  
Author(s):  
Cerith Jones ◽  
Gordon Webster ◽  
Alex J. Mullins ◽  
Matthew Jenner ◽  
Matthew J. Bull ◽  
...  
Keyword(s):  
Food Poisoning ◽  
Gene Clusters ◽  
Soft Rot ◽  
Toxin Production ◽  
Antibiotic Biosynthesis ◽  
Biosynthetic Gene Clusters ◽  
Burkholderia Gladioli ◽  
Bongkrekic Acid ◽  
Beneficial Traits ◽  
Rot Disease

ABSTRACTBurkholderia gladioli is one of few bacteria with a broad ecology spanning disease in humans, animals, and plants, and encompassing beneficial interactions with multiple eukaryotic hosts. It is a plant pathogen, a bongkrekic acid toxin producing food-poisoning agent, and a lung pathogen in people with cystic fibrosis (CF). Contrasting beneficial traits include antifungal production exploited by insects to protect their eggs, plant protective abilities and antibiotic biosynthesis. We explored the ecological diversity and specialized metabolite biosynthesis of 206 B. gladioli strains, phylogenomically defining 5 evolutionary clades. Historical disease pathovars (pv) B. gladioli pv. allicola and B. gladioli pv. cocovenenans were phylogenetically distinct, while B. gladioli pv. gladioli and B. gladioli pv. agaricicola were indistinguishable. Soft-rot disease and CF infection pathogenicity traits were conserved across all pathovars. Biosynthetic gene clusters for toxoflavin, caryoynencin and enacyloxin were dispersed across B. gladioli, but bongkrekic acid and gladiolin production were clade specific. Strikingly, 13% of CF-infection strains characterised (n=194) were bongkrekic acid toxin positive, uniquely linking this food-poisoning risk factor to chronic lung disease. Toxin production was suppressed by exposing strains to the antibiotic trimethoprim, providing a potential therapeutic strategy to minimise poisoning risk in CF.

scholarly journals Differential transcription of expanded gene families in central carbon metabolism of Streptomyces coelicolor A3(2)

2020 ◽  
Vol 2 (6) ◽  
Author(s):  
Jana K. Schniete ◽  
Richard Reumerman ◽  
Leena Kerr ◽  
Nicholas P. Tucker ◽  
Iain S. Hunter ◽  
...  
Keyword(s):  
Carbon Source ◽  
Streptomyces Coelicolor ◽  
Carbon Sources ◽  
Gene Families ◽  
Gene Clusters ◽  
Central Carbon Metabolism ◽  
Rna Seq ◽  
Content Type ◽  
Link Type ◽  
Enzymatic Function

Background. Streptomycete bacteria are prolific producers of specialized metabolites, many of which have clinically relevant bioactivity. A striking feature of their genomes is the expansion of gene families that encode the same enzymatic function. Genes that undergo expansion events, either by horizontal gene transfer or duplication, can have a range of fates: genes can be lost, or they can undergo neo-functionalization or sub-functionalization. To test whether expanded gene families in Streptomyces exhibit differential expression, an RNA-Seq approach was used to examine cultures of wild-type Streptomyces coelicolor grown with either glucose or tween as the sole carbon source. Results. RNA-Seq analysis showed that two-thirds of genes within expanded gene families show transcriptional differences when strains were grown on tween compared to glucose. In addition, expression of specialized metabolite gene clusters (actinorhodin, isorenieratane, coelichelin and a cryptic NRPS) was also influenced by carbon source. Conclusions. Expression of genes encoding the same enzymatic function had transcriptional differences when grown on different carbon sources. This transcriptional divergence enables partitioning to function under different physiological conditions. These approaches can inform metabolic engineering of industrial Streptomyces strains and may help develop cultivation conditions to activate the so-called silent biosynthetic gene clusters.

scholarly journals Genome Mining of Secondary Metabolites From a Marine-derived Aspergillus Terreus B12

2021 ◽  
Author(s):  
xinyang du ◽  
Huanhuan Li ◽  
Jiangfeng Qi ◽  
Chaoyi Chen ◽  
Yuanyuan Lu ◽  
...  
Keyword(s):  
Pathogenic Bacteria ◽  
Aspergillus Terreus ◽  
Genome Mining ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Metabolic Plasticity ◽  
Adaptive Resilience ◽  
Strain Genome ◽  
Biochemical Diversity

Abstract As an important saprophytic filamentous fungus, Aspergillus terreus is ubiquitously distributed, including soil rhizospheres and marine environments. Due to the prominent capabilities of bioconversion and biosynthesis, A. terreus has become attractive in biotechnical and pharmaceutical industry. In this work, an A. terreus strain, B12, was isolated from sponge in South China Sea, which demonstrated broad bacteriostatic effects against a variety of pathogenic bacteria. The whole genome was sequenced, showing a genetic richness of BGCs, which might underpin the metabolic plasticity and adaptive resilience for the strain. Genome mining identified 67 biosynthetic gene clusters (BGCs), among which, 6 gene clusters could allocate to known BGCs (100% identity), corresponding to diverse metabolites like clavaric acid, dihydroisoflavipucine /isoflavipucine, dimethylcoprogen, alternariol, aspterric acid and pyranonigrin E. However, instead of the putative compounds, several other products were obtained from the B12 fermentation, including terrein, butyrolactone I, terretonin A&E, acoapetaline B and epi-aszonalenins A. Of note, acoapetaline B and epi-aszonalenins A, discovered natural products recently with little information, unexpectedly were reported in this A. terreus strain. The genomic and heterogeneity observed in strain B12, should be at least partially attributed to the genetic variability and biochemical diversity of A. terreus , which could be an interesting issue open to future efforts.

scholarly journals Flor Yeasts Rewire the Central Carbon Metabolism During Wine Alcoholic Fermentation

2021 ◽  
Vol 2 ◽  
Author(s):  
Emilien Peltier ◽  
Charlotte Vion ◽  
Omar Abou Saada ◽  
Anne Friedrich ◽  
Joseph Schacherer ◽  
...  
Keyword(s):  
Carbon Metabolism ◽  
Tricarboxylic Acid Cycle ◽  
Phenotypic Variability ◽  
Central Carbon Metabolism ◽  
Genetic Group ◽  
Metabolic Adaptation ◽  
Flor Yeast ◽  
Central Carbon ◽  
Flor Yeasts ◽  
Allelic Variations

The identification of natural allelic variations controlling quantitative traits could contribute to decipher metabolic adaptation mechanisms within different populations of the same species. Such variations could result from human-mediated selection pressures and participate to the domestication. In this study, the genetic causes of the phenotypic variability of the central carbon metabolism of Saccharomyces cerevisiae were investigated in the context of the enological fermentation. The genetic determinism of this trait was found out by a quantitative trait loci (QTL) mapping approach using the offspring of two strains belonging to the wine genetic group of the species. A total of 14 QTL were identified from which 8 were validated down to the gene level by genetic engineering. The allelic frequencies of the validated genes within 403 enological strains showed that most of the validated QTL had allelic variations involving flor yeast specific alleles. Those alleles were brought in the offspring by one parental strain that contains introgressions from the flor yeast genetic group. The causative genes identified are functionally linked to quantitative proteomic variations that would explain divergent metabolic features of wine and flor yeasts involving the tricarboxylic acid cycle (TCA), the glyoxylate shunt and the homeostasis of proton and redox cofactors. Overall, this work led to the identification of genetic factors that are hallmarks of adaptive divergence between flor yeast and wine yeast in the wine biotope. These results also reveal that introgressions originated from intraspecific hybridization events promoted phenotypic variability of carbon metabolism observed in wine strains.

scholarly journals MtrA is an essential regulator that coordinates antibiotic production and sporulation in Streptomyces species

2016 ◽  
Author(s):  
Nicolle F. Som ◽  
Daniel Heine ◽  
John T. Munnoch ◽  
Neil A. Holmes ◽  
Felicity Knowles ◽  
...  
Keyword(s):  
Secondary Metabolism ◽  
Response Regulator ◽  
Antibiotic Production ◽  
Gene Clusters ◽  
Antibiotic Biosynthesis ◽  
Biosynthetic Gene ◽  
Global Regulator ◽  
Major Focus ◽  
Biosynthetic Gene Clusters ◽  
Streptomyces Species

AbstractStreptomyces bacteria make numerous secondary metabolites, including half of all known antibiotics. Understanding the global regulation of secondary metabolism is important because most Streptomyces natural products are not made under laboratory conditions and unlocking ‘cryptic’ biosynthetic gene clusters (BGCs) is a major focus for natural product discovery. Production is coordinated with sporulation but the regulators that coordinate development with antibiotic biosynthesis are largely unknown. Here we characterise a highly conserved actinobacterial response regulator called MtrA in antibiotic-producing Streptomyces species. We show that MtrA is an essential global regulator of secondary metabolism that directly activates antibiotic production in in S. coelicolor and S. venezuelae. MtrA also controls key developmental genes required for DNA replication and cell division and we propose that MtrA is the missing link that coordinates secondary metabolism with development in Streptomyces species.

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