Interplay between carbon, nitrogen and phosphate utilization in the control of secondary metabolite production in Streptomyces

Romero-Rodríguez, Alba; Maldonado-Carmona, Nidia; Ruíz-Villafán, Beatriz; Koirala, Niranjan; Rocha, Diana; Sánchez, Sergio

doi:10.1007/s10482-018-1073-1

Cited by 44 publications

(30 citation statements)

References 115 publications

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“…However, A-factor seems to be essential in the induction of antibiotics and extracellular protease production, regardless of medium composition. Rich medium supports the production of more antibiotics that is in good agreement with the fact that secondary metabolites require nitrogen compound precursors [Romero-Rodríguez et al, 2018]. On the contrary, elevated extracellular protease production was observed during nutrient limitation.…”

Section: Discussionsupporting

confidence: 74%

Mutation in afsR Leads to A-Factor Deficiency in Streptomyces griseus B2682

et al. 2018

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Background/Aims: A-factor, a γ-butyrolactone autoregulator, in Streptomyces griseus is involved in the regulation of differentiation and antibiotic production. Here we studied the S. griseus B2682-AFN (A-factor negative) bald mutant that harbors a nonsense mutation in the afsR gene encoding a pleiotropic regulator. Our aim was to prove that this mutation is the cause of the A-factor deficiency in AFN. We also studied whether AfsR regulates A-factor production by AfsA, which is supposed to be the only specific key enzyme in A-factor biosynthesis. Methods: Wild afsR was cloned to the pHJL401 shuttle vector and was transformed to the S. griseus AFN and B2682 strains. During phenotypic characterization, sporulation, antibiotic, protease, A-factor, and AfsA protein production were studied. Results: Transformation of AFN by a wild afsR restored its phenotype including sporulation, antibiotic, extracellular protease, and A-factor production. Introduction of afsR to the B2682 wild-type strain resulted in antibiotic and extracellular protease overproduction that was accompanied with an elevated A-factor level. AfsA was detected both in AFN and B2682. Conclusions: AfsR has an effect on the regulation of A-factor production in S. griseus. The presence of AfsA is not sufficient for normal A-factor production. AfsR regulates A-factor biosynthesis independently of AfsA.

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Section: Discussionsupporting

confidence: 74%

Mutation in afsR Leads to A-Factor Deficiency in Streptomyces griseus B2682

et al. 2018

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“…Our study revealed the nature of the metabolic features underlying the drastically different abilities of SL and SC to produce antibiotics. We believe that these differences are likely to be due, at least in part, to the weaker expression of PhoR/PhoP in SC compared to SL leading to the relief of the indirect negative impact that PhoR/ PhoP exerts on antibiotic production 75,98 . However, since the causes of the low expression of PhoR/PhoP in SC remain to be clarified further investigation would be needed to confirm this hypothesis.…”

Section: Resultsmentioning

confidence: 99%

Expression of genes of the Pho regulon is altered in Streptomyces coelicolor

Millán-Oropeza

Henry

Lejeune

et al. 2020

Sci Rep

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Most currently used antibiotics originate from Streptomycetes and phosphate limitation is an important trigger of their biosynthesis. Understanding the molecular processes underpinning such regulation is of crucial importance to exploit the great metabolic diversity of these bacteria and get a better understanding of the role of these molecules in the physiology of the producing bacteria. To contribute to this field, a comparative proteomic analysis of two closely related model strains, Streptomyces lividans and Streptomyces coelicolor was carried out. These strains possess identical biosynthetic pathways directing the synthesis of three well-characterized antibiotics (CDA, RED and ACT) but only S. coelicolor expresses them at a high level. Previous studies established that the antibiotic producer, S. coelicolor, is characterized by an oxidative metabolism and a reduced triacylglycerol content compared to the none producer, S. lividans, characterized by a glycolytic metabolism. Our proteomic data support these findings and reveal that these drastically different metabolic features could, at least in part, due to the weaker abundance of proteins of the two component system PhoR/PhoP in S. coelicolor compared to S. lividans. In condition of phosphate limitation, PhoR/PhoP is known to control positively and negatively, respectively, phosphate and nitrogen assimilation and our study revealed that it might also control the expression of some genes of central carbon metabolism. The tuning down of the regulatory role of PhoR/PhoP in S. coelicolor is thus expected to be correlated with low and high phosphate and nitrogen availability, respectively and with changes in central carbon metabolic features. These changes are likely to be responsible for the observed differences between S. coelicolor and S. lividans concerning energetic metabolism, triacylglycerol biosynthesis and antibiotic production. Furthermore, a novel view of the contribution of the bio-active molecules produced in this context, to the regulation of the energetic metabolism of the producing bacteria, is proposed and discussed.

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“…It is commonly recognized that antibiotic production is stringently regulated by pyramidal transcriptional regulatory cascades in Streptomyces. Recent years, there were several reviews on the regulatory networks of Streptomyces (Romero- Rodriguez et al, 2018;van der Heul et al, 2018;Palazzotto et al, 2019). So here we won't go into detail of the regulatory networks involved in antibiotic production.…”

Section: The Regulatory Cascades Of Antibiotic Production In Streptommentioning

confidence: 99%

“…It has been reported that GlnR and PhoR-PhoP was involved in the type of regulation depending on the carbon, nitrogen, and phosphate supply. For the similarity of binding sites, PhoP and GlnR showed competitive binding to target genes in some cases (Romero- Rodriguez et al, 2018). In Saccharopolyspora erythraea, the GlnR regulon is not only involved in nitrogen metabolism, but it also appears to control ABC-type transporters for uptake of carbon sources (Liao et al, 2015).…”

Section: The Regulatory Cascades Of Antibiotic Production In Streptommentioning

confidence: 99%

The Application of Regulatory Cascades in Streptomyces: Yield Enhancement and Metabolite Mining

Xia

et al. 2020

Front. Microbiol.

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Streptomyces is taken as an important resource for producing the most abundant antibiotics and other bio-active natural products, which have been widely used in pharmaceutical and agricultural areas. Usually they are biosynthesized through secondary metabolic pathways encoded by cluster situated genes. And these gene clusters are stringently regulated by interweaved transcriptional regulatory cascades. In the past decades, great advances have been made to elucidate the regulatory mechanisms involved in antibiotic production in Streptomyces. In this review, we summarized the recent advances on the regulatory cascades of antibiotic production in Streptomyces from the following four levels: the signals triggering the biosynthesis, the global regulators, the pathway-specific regulators and the feedback regulation. The production of antibiotic can be largely enhanced by rewiring the regulatory networks, such as overexpression of positive regulators, inactivation of repressors, fine-tuning of the feedback and ribosomal engineering in Streptomyces. The enormous amount of genomic sequencing data implies that the Streptomyces has potential to produce much more antibiotics for the great diversities and wide distributions of biosynthetic gene clusters in Streptomyces genomes. Most of these gene clusters are defined cryptic for unknown or undetectable natural products. In the synthetic biology era, activation of the cryptic gene clusters has been successfully achieved by manipulation of the regulatory genes. Chemical elicitors, rewiring regulatory gene and ribosomal engineering have been employed to crack the potential of cryptic gene clusters. These have been proposed as the most promising strategy to discover new antibiotics. For the complex of regulatory network in Streptomyces, we proposed that the discovery of new antibiotics and the optimization of industrial strains would be greatly promoted by further understanding the regulatory mechanism of antibiotic production.

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Interplay between carbon, nitrogen and phosphate utilization in the control of secondary metabolite production in Streptomyces

Cited by 44 publications

References 115 publications

Mutation in <b><i>afsR</i></b> Leads to A-Factor Deficiency in <b><i>Streptomyces griseus</i></b> B2682

Mutation in <b><i>afsR</i></b> Leads to A-Factor Deficiency in <b><i>Streptomyces griseus</i></b> B2682

Expression of genes of the Pho regulon is altered in Streptomyces coelicolor

The Application of Regulatory Cascades in Streptomyces: Yield Enhancement and Metabolite Mining

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