Pirin: A novel redox-sensitive modulator of primary and secondary metabolism in Streptomyces

Talà, Adelfia; Damiano, Fabrizio; Gallo, Giuseppe; Pinatel, Eva; Calcagnile, Matteo; Testini, Mariangela; Fico, Daniela; Rizzo, Daniela; Sutera, Alberto; Renzone, Giovanni; Scaloni, Andrea; Bellis, Gianluca De; Siculella, Luisa; Benedetto, Giuseppe E. De; Puglia, Anna Maria; Peano, Clelia; Alifano, Pietro

doi:10.1016/j.ymben.2018.06.008

Cited by 36 publications

(38 citation statements)

References 80 publications

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“…The structure and biosynthesis of spinosyn analogues have been clearly described [4,33], and studies on the transformation of its gene clusters and the improvement of heterologous expression have been studied [7,34,35]; however, the metabolic situation in vivo is complex, and any slight metabolic disturbance will lead to complex changes, which may produce unintended consequences [11]. Therefore, the analysis of the genome characteristics of S. pogona and related regulatory proteins may help to understand their gene expression preferences.…”

Section: Discussionmentioning

confidence: 99%

“…Currently, a substantial number of proteins have been reported to regulate the metabolites of bacteria [10][11][12], including some global regulators [13,14], which are of great significance in growth, phenotype and metabolism. TetR family regulators have been reported in numerous organisms [15,16]; they are involved in the regulating biosynthesis of antibiotics, efflux pumps, osmotic stress, etc., and typically function as repressors [17] to regulate the expression of genes, such as the ameABC operon [18] and fadR operator [19].…”

Section: Introductionmentioning

confidence: 99%

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Effect of the TetR family transcriptional regulator Sp1418 on the global metabolic network of Saccharopolyspora pogona

Yuan

et al. 2020

Microb Cell Fact

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Background: Saccharopolyspora pogona is a prominent industrial strain due to its production of butenyl-spinosyn, a high-quality insecticide against a broad spectrum of insect pests. TetR family proteins are diverse in a tremendous number of microorganisms and some are been researched to have a key role in metabolic regulation. However, specific functions of TetR family proteins in S. pogona are yet to characterize. Results: In the present study, the overexpression of the tetR-like gene sp1418 in S. pogona resulted in marked effects on vegetative growth, sporulation, butenyl-spinosyn biosynthesis, and oxidative stress. By using qRT-PCR analysis, mass spectrometry, enzyme activity detection, and sp1418 knockout verification, we showed that most of these effects could be attributed to the overexpression of Sp1418, which modulated enzymes related to the primary metabolism, oxidative stress and secondary metabolism, and thereby resulted in distinct growth characteristics and an unbalanced supply of precursor monomers for butenyl-spinosyn biosynthesis. Conclusion: This study revealed the function of Sp1418 and enhanced the understanding of the metabolic network in S. pogona, and provided insights into the improvement of secondary metabolite production.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of the TetR family transcriptional regulator Sp1418 on the global metabolic network of Saccharopolyspora pogona

Yuan

et al. 2020

Microb Cell Fact

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“…Compared to the wild-type (unintegrated) strain, the strains with integrated pHG4 or pJH1R4 did not show any difference in growth. However, further study is required to investigate the effects of TG1 or R4 plasmid recombination on both primary and secondary metabolism as, for example, the integration of ϕC31 integrase-based plasmids has been shown to have pleiotropic effects on bacterial physiology(51).…”

Section: Discussionmentioning

confidence: 99%

Integrating Vectors for Genetic Studies in the Rare ActinomyceteAmycolatopsis marina

Gao

Murugesan

Hoßbach

et al. 2018

Preprint

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Few natural product pathways from rare Actinomycetes have been studied due to the difficulty in applying molecular approaches in these genetically intractable organisms. In this study, we sought to identify integrating vectors, derived using phage int/attP loci, that would efficiently integrate site-specifically in the rare Actinomycete, Amycolatopsis marina DSM45569. Analysis of the genome of A. marina DSM45569 indicated the presence of attB-like sequences for TG1 and R4 integrases. The TG1 and R4 attBs were active in in vitro recombination assays with their cognate purified integrases and attP loci. Integrating vectors containing either the TG1 or R4 int/attP loci yielded exconjugants in conjugation assays from E. coli to A. marina DSM45569. Site-specific recombination of the plasmids into the host TG1 or R4 attB sites was confirmed by sequencing. The presence of homologous TG1 and R4 attB sites in other species of this genus indicates that vectors based on TG1 and R4 integrases could be widely applicable.ImportanceRare Actinomycetes have the same potential of natural product discovery as Streptomyces, but the potential has not been fully explored due to the lack of efficient molecular biology tools. In this study, we identified two serine integrases, TG1 and R4, which could be used in the rare Actinomycetes species, Amycolatopsis marina, as tools for genome integration. The high level of conservation between the attB sites for TG1 and R4 in a number of Amycolatopsis species suggested that plasmids with the integration systems from these phages should be widely useful in this genus.

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“…Often overlooked in specialised metabolism is the requirement for maintenance of cofactor supply [21] and redox poise [42] to enable balancing of the substrate oxidation, energy supply and as key allosteric regulators of primary metabolic enzymes. Building on this, the work of Tala et al, [43] has recently shown that a modulator of oxidative stress may act on gene expression in central carbon metabolism. Tala et al, [43] demonstrated that a conserved ironcontaining Pirin protein, PirA could affect beta-oxidation pathways, disrupting polyketide precursor supply in S. ambofaciens.…”

Section: Sensing and Respondingmentioning

confidence: 93%

“…Building on this, the work of Tala et al, [43] has recently shown that a modulator of oxidative stress may act on gene expression in central carbon metabolism. Tala et al, [43] demonstrated that a conserved ironcontaining Pirin protein, PirA could affect beta-oxidation pathways, disrupting polyketide precursor supply in S. ambofaciens. This action is brought about through the negative regulation of a long chain fatty acid dehydrogenase which catalyses the first step of the betaoxidation pathway.…”

Section: Sensing and Respondingmentioning

confidence: 93%

Expanding, integrating, sensing and responding: the role of primary metabolism in specialised metabolite production

Fernández-Martínez

Hoskisson

2019

Current Opinion in Microbiology

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Producing specialised metabolites such as antibiotics, immunosuppressives, anti-cancer agents and anti-helminthics draws on primary metabolism to provide the building blocks for biosynthesis. The growth phase-dependent nature of production means that producing organisms must deal with the metabolic conflicts of declining growth rate, reduced nutrient availability, specialised metabolite production and potentially morphological development. In recent years our understanding of gene expansion events, integration of metabolic function and gene regulation events that facilitate the sensing and responding to metabolite concentrations has grown, but new data are constantly expanding our horizons. This review highlights the role evolutionary gene/pathway expansion plays in primary metabolism and examine the adoption of enzymes for specialised metabolism. We also look at recent insights into sensing and responding to metabolites. Highlights * The building blocks for specialised metabolite production are derived from primary metabolism and their supply is a key, yet often overlooked, component of the regulation of biosynthesis. * Gene duplication and horizontal gene transfer have played a central role in the evolution and adaption of metabolism for the production of specialised metabolism. This can either be via adaptive expansion across the genome or specifically located in biosynthetic gene clusters. The adoption of primary metabolic enzymes into existing gene clusters may also facilitate the evolution of new specialised metabolites. * Advances in 'omics technologies have enabled us to use the wealth of genomic, transcriptomic and metabolomic data to model metabolism and survey metabolic capabilities, yet detailed reductionist approaches studying kinetics are often still required to fully elucidate the physiological role played an enzyme.

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Pirin: A novel redox-sensitive modulator of primary and secondary metabolism in Streptomyces

Cited by 36 publications

References 80 publications

Effect of the TetR family transcriptional regulator Sp1418 on the global metabolic network of Saccharopolyspora pogona

Effect of the TetR family transcriptional regulator Sp1418 on the global metabolic network of Saccharopolyspora pogona

Integrating Vectors for Genetic Studies in the Rare ActinomyceteAmycolatopsis marina

Expanding, integrating, sensing and responding: the role of primary metabolism in specialised metabolite production

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