Stendomycin and Pantomycin Are Identical Natural Products: Preparation of a Functionalized Bioactive Analogue

Villadsen, Nikolaj L.; Hansen, Bente K.; Svenningsen, Esben B.; Jørgensen, Katrine; Tørring, Thomas; Poulsen, Thomas B.

doi:10.1021/acs.joc.8b00553

Cited by 4 publications

(4 citation statements)

References 16 publications

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“…This BGC (region 32.1, candidate BGC 35 kb; Supplementary Table S6 ) contains a N-terminal acyl ligase domain, which is associated with lipopeptide biosynthesis ( Kersten et al, 2011 ), in addition to NRPS modules. It further shares sequence similarity with Streptomyces RTd22 ( Chagas et al, 2016 ) and ATCC53653 BGCs, the latter reported previously as a producer of stendomycin lipopeptides— Supplementary Figures S11 , S12 ; Supplementary Table S5 ( Kersten et al, 2011 ; Villadsen et al, 2018 ). A complex regulatory system is found within this BGC, which harbours TetR, LysR, sensor histidine kinase, SARP, and LuxR regulators.…”

Section: Resultssupporting

confidence: 61%

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: Resultssupporting

confidence: 61%

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

et al. 2022

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“…In fact, enzyme-catalyzed conjugate additions of thiols to ΔAla and ΔAbu are involved in the biosynthesis of lantibiotics . However, a close look at the literature reveals that uncatalyzed conjugate additions of thiols to ΔAAs larger than ΔAla typically require large excesses of thiol to proceed . Alternatively, placement of the ΔAA at the C -terminus of a peptide instead of embedded within the backbone can increase its electrophilicity .…”

Section: Resultsmentioning

confidence: 99%

Impact of Dehydroamino Acids on the Structure and Stability of Incipient 3₁₀-Helical Peptides

et al. 2019

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A comparative study of the impact of small, medium-sized, and bulky α,β-dehydroamino acids (ΔAAs) on the structure and stability of Balaram’s incipient 310-helical peptide (1) is reported. Replacement of the N-terminal Aib residue of 1 with a ΔAA afforded peptides 2a–c that maintained the 310-helical shape of 1. In contrast, installation of a ΔAA in place of Aib-3 yielded peptides 3a–c that preferred a β-sheet-like conformation. The impact of the ΔAA on peptide structure was independent of size, with small (ΔAla), medium-sized (Z-ΔAbu), and bulky (ΔVal) ΔAAs exerting similar effects. The proteolytic stabilities of 1 and its analogs were determined by incubation with Pronase. Z-ΔAbu and ΔVal increased the resistance of peptides to proteolysis when incorporated at the 3-position and had negligible impact on stability when placed at the 1-position, whereas ΔAla-containing peptides degraded rapidly regardless of position. Exposure of peptides 2a–c and 3a–c to the reactive thiol cysteamine revealed that ΔAla-containing peptides underwent conjugate addition at room temperature, while Z-ΔAbu- and ΔVal-containing peptides were inert even at elevated temperatures. These results suggest that both bulky and more accessible medium-sized ΔAAs should be valuable tools for bestowing rigidity and proteolytic stability on bioactive peptides.

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“…121 Recent structural elucidation has revealed that pantomycin is in fact identical to stendomycin. 122 2.1.11 Enduracidins. Enduracidin A and B are produced by S. fungicidicus no.…”

Section: Reviewmentioning

confidence: 99%

“…121 Recent structural elucidation has revealed that pantomycin is in fact identical to stendomycin. 122…”

Section: Identification and Biosynthesis Of Lipopeptides From Strepto...mentioning

confidence: 99%

Structural diversity, biosynthesis, and biological functions of lipopeptides fromStreptomyces

et al. 2023

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Stendomycin and Pantomycin Are Identical Natural Products: Preparation of a Functionalized Bioactive Analogue

Cited by 4 publications

References 16 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

Impact of Dehydroamino Acids on the Structure and Stability of Incipient 3₁₀-Helical Peptides

Structural diversity, biosynthesis, and biological functions of lipopeptides fromStreptomyces

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Stendomycin and Pantomycin Are Identical Natural Products: Preparation of a Functionalized Bioactive Analogue

Cited by 4 publications

References 16 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

Impact of Dehydroamino Acids on the Structure and Stability of Incipient 310-Helical Peptides

Structural diversity, biosynthesis, and biological functions of lipopeptides fromStreptomyces

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Product

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Impact of Dehydroamino Acids on the Structure and Stability of Incipient 3₁₀-Helical Peptides