Marine Streptomyces sp. Isolated From the Brazilian Endemic Tunicate Euherdmania sp. Produces Dihydroeponemycin and Analogs With Potent Antiglioma Activity

Furtado, Luciana Costa; Bauermeister, Anelize; Felício, Rafael de; Ortega, Raquel; Pinto, Francisco das Chagas L.; Machado-Neto, João Agostinho; Trivella, Daniela Barretto Barbosa; Pessoa, Otília Deusdênia Loiola; Wilke, Diego Veras; Lopes, Norberto P.; Jimenez, Paula Christine; Costa-Lotufo, Letı́cia V.

doi:10.3389/fmars.2021.644730

Cited by 3 publications

(17 citation statements)

References 115 publications

(131 reference statements)

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“…DHE (1) and DH-TMC (3) are pointed by arrows. The MS/MS annotations for 1 and 3 were based on the described by Furtado et al (2021) and Zabala et al (2016) , respectively. The parameter used for node size was intensity value ([minimum value; 100,000]: linear interpolation, [100,000; maximum value]: constant size).…”

Section: Resultsmentioning

confidence: 99%

“…To exemplify this statement, four replicates of BRA-346 cultures in the A1 medium, the standard growth medium for BRA-346 ( Furtado et al, 2021 ), were carried out (A1 C3a-c and A1 C5), in addition to the use of three different culture media (ISP2, TSBY, and TSB; Supplementary Table S2 ), in a total of seven culture conditions evaluated in this data set. The metabolome was assessed by LC–MS/MS analyses, being further evaluated by the construction and inspection of a spectra similarity molecular network (SSMN) of the representative [M + H] + ions ( de Felício et al, 2021 ; Figure 2A ).…”

Section: Resultsmentioning

confidence: 99%

“…BRA-346, isolated from the Brazilian endemic tunicate Euherdmania sp., produces epoxyketone peptides, such as dihydroeponemycin (DHE, 1), eponemycin (EPN, 2 ), dihydro TMC-86A (DH-TMC, 3 ), and TMC-86A (TMC, 4 ; Figure 1 ). Both DHE and an epoxyketone-containing enriched fraction were evaluated by Furtado et al (2021) in glioma cell lines, displaying high cytotoxicity to HOG and T98G cells (GI 50 of 1.6 and 1.7 ng/ml for DHE, and 17.6 and 28.2 ng/ml for the BRA-346 fraction, respectively). The enriched fraction inhibited the proteasome ChTL activity with IC 50 of 45 ng/ml ( Furtado et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Both DHE and an epoxyketone-containing enriched fraction were evaluated by Furtado et al (2021) in glioma cell lines, displaying high cytotoxicity to HOG and T98G cells (GI 50 of 1.6 and 1.7 ng/ml for DHE, and 17.6 and 28.2 ng/ml for the BRA-346 fraction, respectively). The enriched fraction inhibited the proteasome ChTL activity with IC 50 of 45 ng/ml ( Furtado et al, 2021 ). Additional studies showed that the epoxyketone-containing fraction (at GI 50 levels) led to the accumulation of ubiquitinated proteins and upregulation of genes related to ER-stress response, correlating to the observed proteasome inhibition.…”

Section: Introductionmentioning

confidence: 99%

“…They are irreversible inhibitors of the three proteasome proteolytic activities. DHE ( 1 ), EPN ( 2 ), and further analogs were found in BRA-346 cultures, from which the crude extract and an enriched fraction showed potent proteasome and cancer cell growth inhibition (IC 50 < 20 ng/ml; Furtado et al, 2021 ). The diversity of eponemycin analogs found in BRA-346 cultures stimulated further investigation on their biosynthesis and regulation.…”

Section: Introductionmentioning

confidence: 99%

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Production of Epoxyketone Peptide-Based Proteasome Inhibitors by Streptomyces sp. BRA-346: Regulation and Biosynthesis

et al. 2022

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Streptomyces sp. BRA-346 is an Actinobacteria isolated from the Brazilian endemic tunicate Euherdmania sp. We have reported that this strain produces epoxyketone peptides, as dihydroeponemycin (DHE) and structurally related analogs. This cocktail of epoxyketone peptides inhibits the proteasome chymotrypsin-like activity and shows high cytotoxicity to glioma cells. However, low yields and poor reproducibility of epoxyketone peptides production by BRA-346 under laboratory cultivation have limited the isolation of epoxyketone peptides for additional studies. Here, we evaluated several cultivation methods using different culture media and chemical elicitors to increase the repertoire of peptide epoxyketone production by this bacterium. Furthermore, BRA-346 genome was sequenced, revealing its broad genetic potential, which is mostly hidden under laboratory conditions. By using specific growth conditions, we were able to evidence different classes of secondary metabolites produced by BRA-346. In addition, by combining genome mining with untargeted metabolomics, we could link the metabolites produced by BRA-346 to its genetic capacity and potential regulators. A single biosynthetic gene cluster (BGC) was related to the production of the target epoxyketone peptides by BRA-346. The candidate BGC displays conserved biosynthetic enzymes with the reported eponemycin (EPN) and TMC-86A (TMC) BGCs. The core of the putative epoxyketone peptide BGC (ORFs A-L), in which ORF A is a LuxR-like transcription factor, was cloned into a heterologous host. The recombinant organism was capable to produce TMC and EPN natural products, along with the biosynthetic intermediates DH-TMC and DHE, and additional congeners. A phylogenetic analysis of the epn/tmc BGC revealed related BGCs in public databases. Most of them carry a proteasome beta-subunit, however, lacking an assigned specialized metabolite. The retrieved BGCs also display a diversity of regulatory genes and TTA codons, indicating tight regulation of this BGC at the transcription and translational levels. These results demonstrate the plasticity of the epn/tmc BGC of BRA-346 in producing epoxyketone peptides and the feasibility of their production in a heterologous host. This work also highlights the capacity of BRA-346 to tightly regulate its secondary metabolism and shed light on how to awake silent gene clusters of Streptomyces sp. BRA-346 to allow the production of pharmacologically important biosynthetic products.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Production of Epoxyketone Peptide-Based Proteasome Inhibitors by Streptomyces sp. BRA-346: Regulation and Biosynthesis

et al. 2022

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NP³ MS Workflow: An Open-Source Software System to Empower Natural Product-Based Drug Discovery Using Untargeted Metabolomics

Bazzano,

de Felicio,

Alves

et al. 2024

Anal. Chem.

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Natural products (or specialized metabolites) are historically the main source of new drugs. However, the current drug discovery pipelines require miniaturization and speeds that are incompatible with traditional natural product research methods, especially in the early stages of the research. This article introduces the NP3 MS Workflow, a robust open-source software system for liquid chromatography–tandem mass spectrometry (LC–MS/MS) untargeted metabolomic data processing and analysis, designed to rank bioactive natural products directly from complex mixtures of compounds, such as bioactive biota samples. NP3 MS Workflow allows minimal user intervention as well as customization of each step of LC–MS/MS data processing, with diagnostic statistics to allow interpretation and optimization of LC–MS/MS data processing by the user. NP3 MS Workflow adds improved computing of the MS2 spectra in an LC–MS/MS data set and provides tools for automatic [M + H]+ ion deconvolution using fragmentation rules; chemical structural annotation against MS2 databases; and relative quantification of the precursor ions for bioactivity correlation scoring. The software will be presented with case studies and comparisons with equivalent tools currently available. NP3 MS Workflow shows a robust and useful approach to select bioactive natural products from complex mixtures, improving the set of tools available for untargeted metabolomics. It can be easily integrated into natural product-based drug-discovery pipelines and to other fields of research at the interface of chemistry and biology.

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A singular shark bitter taste receptor provides insights into the evolution of bitter taste perception

Behrens,

Lang,

Korsching

2023

Proc. Natl. Acad. Sci. U.S.A.

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Many animal and plant species synthesize toxic compounds as deterrent; thus, detection of these compounds is of vital importance to avoid their ingestion. Often, such compounds are recognized by taste 2 receptors that mediate bitter taste in humans. Until now, bitter taste receptors have only been found in bony vertebrates, where they occur as a large family already in coelacanth, a “living fossil” and the earliest-diverging extant lobe-finned fish. Here, we have revisited the evolutionary origin of taste 2 receptors (T2Rs) making use of a multitude of recently available cartilaginous fish genomes. We have identified a singular T2R in 12 cartilaginous fish species (9 sharks, 1 sawfish, and 2 skates), which represents a sister clade to all bony fish T2Rs. We have examined its ligands for two shark species, a catshark and a bamboo shark. The ligand repertoire of bamboo shark represents a subset of that of the catshark, with roughly similar thresholds. Amarogentin, one of the most bitter natural substances for humans, also elicited the highest signal amplitudes with both shark receptors. Other subsets of ligands are shared with basal bony fish T2Rs indicating an astonishing degree of functional conservation over nearly 500 mya of separate evolution. Both shark receptors respond to endogenous steroids as well as xenobiotic compounds, whereas separate receptors exist for xenobiotics both in early- and late-derived bony vertebrates (coelacanth, zebrafish, and human), consistent with the shark T2R reflecting the original ligand repertoire of the ancestral bitter taste receptor at the evolutionary origin of this family.

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Marine Streptomyces sp. Isolated From the Brazilian Endemic Tunicate Euherdmania sp. Produces Dihydroeponemycin and Analogs With Potent Antiglioma Activity

Cited by 3 publications

References 115 publications

Production of Epoxyketone Peptide-Based Proteasome Inhibitors by Streptomyces sp. BRA-346: Regulation and Biosynthesis

Production of Epoxyketone Peptide-Based Proteasome Inhibitors by Streptomyces sp. BRA-346: Regulation and Biosynthesis

NP³ MS Workflow: An Open-Source Software System to Empower Natural Product-Based Drug Discovery Using Untargeted Metabolomics

A singular shark bitter taste receptor provides insights into the evolution of bitter taste perception

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Marine Streptomyces sp. Isolated From the Brazilian Endemic Tunicate Euherdmania sp. Produces Dihydroeponemycin and Analogs With Potent Antiglioma Activity

Cited by 3 publications

References 115 publications

Production of Epoxyketone Peptide-Based Proteasome Inhibitors by Streptomyces sp. BRA-346: Regulation and Biosynthesis

Production of Epoxyketone Peptide-Based Proteasome Inhibitors by Streptomyces sp. BRA-346: Regulation and Biosynthesis

NP3 MS Workflow: An Open-Source Software System to Empower Natural Product-Based Drug Discovery Using Untargeted Metabolomics

A singular shark bitter taste receptor provides insights into the evolution of bitter taste perception

Contact Info

Product

Resources

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NP³ MS Workflow: An Open-Source Software System to Empower Natural Product-Based Drug Discovery Using Untargeted Metabolomics