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Adrenaline-mediated activation of antibiotic production in Streptomyces highlights catechol as elicitor of specialized metabolism

ABSTRACT: Actinobacteria are a rich source of bioactive molecules, and genome sequencing has shown that the vast majority of their biosynthetic potential has yet to be explored. However, many of their biosynthetic gene clusters (BGCs) are poorly expressed in the laboratory, which prevents discovery of their cognate natural products. To exploit their full biosynthetic potential, better understanding of the signals that promote the expression of BGCs is needed. Here, we show that the human stress hormone epinephrine (adrenaline) elicits antibiotic production by Actinobacteria. Catechol was established as the likely eliciting moiety, since similar responses were seen for catechol and for the catechol-containing molecules dopamine and catechin but not for related molecules. Exploration of the catechol-responsive strain Streptomyces sp. MBT84 using mass spectral networking revealed elicitation of a BGC that produces the angucycline glycosides aquayamycin, urdamycinone B and galtamycin C. Heterologous expression of the catechol-cleaving enzymes catechol 1,2-dioxygenase or catechol 2,3 dioxygenase counteracted the eliciting effect of catechol. Thus, for the first time we show the activation of natural product biosynthesis by a human hormone, leading to the identification of the ubiquitous catechol moiety as elicitor of BGCs for siderophores and antibiotics.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Streptomyces Sp. Mbt84

SUBMITTER: Chao DU

LAB HEAD: Prof.Dr. G.P. van Wezel

PROVIDER: PXD030484 | Pride | 2022-01-10

REPOSITORIES: Pride

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Adrenaline-mediated activation of antibiotic production in Streptomyces highlights catechol as elicitor of specialized metabolism

Project description:Actinobacteria are a rich source of bioactive molecules, and genome sequencing has shown that the vast majority of their biosynthetic potential has yet to be explored. However, many of their biosynthetic gene clusters (BGCs) are poorly expressed in the laboratory, which prevents discovery of their cognate natural products. To exploit their full biosynthetic potential, better understanding of the signals that promote the expression of BGCs is needed. Here, we show that the human stress hormone epinephrine (adrenaline) elicits antibiotic production by Actinobacteria. Catechol was established as the likely eliciting moiety, since similar responses were seen for catechol and for the catechol-containing molecules dopamine and catechin but not for related molecules. Exploration of the catechol-responsive strain Streptomyces sp. MBT84 using mass spectral networking revealed elicitation of a BGC that produces the angucycline glycosides aquayamycin, urdamycinone B and galtamycin C. Heterologous expression of the catechol-cleaving enzymes catechol 1,2-dioxygenase or catechol 2,3 dioxygenase counteracted the eliciting effect of catechol. Thus, for the first time we show the activation of natural product biosynthesis by a human hormone, leading to the identification of the ubiquitous catechol moiety as elicitor of BGCs for siderophores and antibiotics.

2022-02-04 | PXD030319 | Pride

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Project description:The goal of this study is to obtain a genomic view of the Fur regulatory network under both iron replete and iron deficient conditions in Bacillus subtilis using ChIP-seq. Besides the known Fur target sites, 70 putative DNA binding sites were identified, and the vast majority had higher occupancy under iron sufficient conditions. In addition,we discovered a role for catechol degradation in bacillibactin metabolism, and provided evidence that catechol 2,3-dioxygenase can detoxify endogenously produced catechol substrates in addition to its more widely studied role in biodegradation of environmental aromatic compounds and pollutants.

2018-08-29 | GSE119163 | GEO

Operation of a TCA cycle subnetwork in the mammalian nucleus

Project description:Nucleic acid and histone modifications critically depend on central metabolism for substrates and co-factors. Although a few enzymes related to the formation of these metabolites have been reported in the nucleus, the corresponding metabolic pathways are considered to function elsewhere in the cell. Here we show that a substantial part of the mitochondrial tricarboxylic acid (TCA) cycle, the biosynthetic hub of epigenetic modification factors, is operational also in the nucleus. Using 13C-tracer analysis, we identified activity of glutamine-to-fumarate, citrate-to-succinate, and glutamine-to-aspartate routes in the nuclei of HeLa cells. Proximity labeling mass-spectrometry revealed a spatial vicinity of the involved enzymes with core nuclear proteins, supporting their nuclear location. We further show nuclear localization of aconitase 2 and 2-oxoglutarate dehydrogenase in mouse embryonic stem cells. Together, our results demonstrate operation of an extended metabolic pathway in the nucleus warranting a revision of the canonical view on metabolic compartmentalization and gene expression regulation.

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Project description:The predatory choanoflagellate Salpingoeca rosetta has emerged as important model systems to study the evolution of multicellularity and chemical origin of bacterial-eukaryote communication mechanisms. In this study we elaborated on the function and possible proteogenic binding partners of the bacterial sulfonolipid IOR-1A, which serves as bacterial inhibitor of rosette formation in S. rosetta. To study the function of IOR-1A, a new, modular and scalable total synthesis of IOR-1A (six steps, 30% overall yield) was developed, which features a decarboxylative cross-coupling reaction of a desymmetrized tartaric acid derivative carrying a protected sulfonic acid moiety with an alkyl zink reagents of choice. Synthesis of twelve IOR derivates, including fluorescent and photoaffinity-based probes, allowed to determine the abundance of IOR-1A, evaluation of structure-activity relations, localization studies within S. rosetta and de novo chemical proteomic identification of IOR-binding proteins in bacteria and S. rosetta. The combined results will catalyse future studies aiming at deciphering the biochemical basis of cell differentiation processes within rosette formation of S. rosetta.

2022-08-29 | PXD034064 | Pride

Overexpression of sigC in the wild type

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2016-08-22 | E-GEOD-72451 | biostudies-arrayexpress

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Project description:RNA polymerase II (RNAPII) controls the expression of all protein coding genes and most noncoding loci in higher eukaryotes. The ultimate rate of transcription is regulated at the level of multiple checkpoints during the transcription cycle (initiation, pausing, termination). Calibrating the activity of RNAPII is fundamental to all cellular processes and requires an assortment of polymerase-associated factors that are recruited at sites of active transcription. The Integrator complex is one of the most elusive transcriptional regulators in metazoans, deemed to be recruited after initiation to help establish and modulate paused RNAPII. Recent structural, biochemical, and functional evidence suggest that Integrator is composed of 14 subunits that assemble and operate in a modular fashion. We employed proteomics and machine-learning structure prediction (AlphaFold2) approaches to identify a novel Integrator subunit, INTS15. We report that INTS15 assembles primarily with the INTS13/INTS14/INTS10 module and interfaces with the core of the Int-PP2A complex. Functional genomics analysis further reveals a role for INTS15 in modulating RNAPII pausing at a subset of genes in human cell lines. Our study shows that omics approaches combined with AlphaFold2-based predictions provide novel insights into the molecular architecture of large and flexible multiprotein complexes.

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Brain_22A-Scrapie_End-point_PR04-39-to-46_using_GPL7118

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2010-05-19 | E-GEOD-12321 | biostudies-arrayexpress

Brain_22A-Scrapie_End-point_PR06-11-to-14_using_GPL7121

Project description:Examining the transcriptional change in whole mouse (VM) brain miRNA expression during prion (22A) induced neurodegeneration in order to identify miRNAs that are differentially expressed. MicroRNAs (miRNAs) are small, non-coding RNA molecules which are emerging as key regulators of numerous cellular processes. Compelling evidence links miRNAs to the control of neuronal development and differentiation, however, little is known about their role in neurodegeneration. De-regulation of a unique subset of miRNAs may suggest a conserved, disease-specific pattern of differentially expressed miRNAs is associated with prionâ??induced neurodegeneration. MiRNA extracted from the whole brains of 4 VM mice treated with mouse-adapted 22A scrapie strain were analyzed on GPL7121 (array was divided into top and bottom) for differential expression. Age-matched, PBS treated control mice were used for comparison (competitive hybridization). A technical replicate for each mouse was performed as well as a technical replicate for each of the dye-swaps.

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