Sorbremnoids A and B: NLRP3 Inflammasome Inhibitors Discovered from Spatially Restricted Crosstalk of Biosynthetic Pathways

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(26), P. 18172 - 18183

Published: June 18, 2024

Crosstalk-oriented chemical evolution of natural products (NPs) is an efficacious strategy for generating novel skeletons through coupling reactions between NP fragments. In this study, two NOD-like receptor protein 3 (NLRP3) inflammasome inhibitors, sorbremnoids A and B (1 2), with unprecedented architectures were identified from a fungus Penicillium citrinum. Compounds 1 2 exemplify rare instances hybrid NPs formed via major facilitator superfamily (MFS)-like enzyme by reactive intermediates separate biosynthetic gene clusters (BGCs), pcisor pci56. Both are NLRP3 inhibitors. Sorbremnoid demonstrated strong inhibition IL-1β directly binding to the protein, inhibiting assembly activation in vitro, potential application diabetic refractory wound healing suppression excessive inflammatory responses. This research will inspire development anti-NLRP3 agents as lead treatments enhance knowledge pertaining derived crosstalk.

Language: Английский

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Fungal BGCs for Production of Secondary Metabolites: Main Types, Central Roles in Strain Improvement, and Regulation According to the Piano Principle

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(13), P. 11184 - 11184

Published: July 6, 2023

Filamentous fungi are one of the most important producers secondary metabolites. Some them can have a toxic effect on human body, leading to diseases. On other hand, they widely used as pharmaceutically significant drugs, such antibiotics, statins, and immunosuppressants. A single fungus species in response various signals produce 100 or more Such signaling is possible due coordinated regulation several dozen biosynthetic gene clusters (BGCs), which mosaically localized different regions fungal chromosomes. Their includes levels, from pathway-specific regulators, whose genes inside BGCs, global regulators cell (taking into account changes pH, carbon consumption, etc.) metabolism (affecting epigenetic driven by velvet family proteins, LaeA, etc.). In addition, low-molecular-weight substances mediating regulatory processes. This review devoted critical analysis available data "turning on" "off" biosynthesis metabolites filamentous fungi. To describe ongoing processes, model "piano regulation" proposed, whereby pressing certain key (signal) leads extraction sound "musical instrument cell", expressed production specific metabolite.

Language: Английский

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Plant growth–promoting fungi in plants: Insights from stress tolerance mechanism

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 469 - 511

Published: Jan. 1, 2024

Language: Английский

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How to Completely Squeeze a Fungus—Advanced Genome Mining Tools for Novel Bioactive Substances

Pharmaceutics, Journal Year: 2022, Volume and Issue: 14(9), P. 1837 - 1837

Published: Aug. 31, 2022

Fungal species have the capability of producing an overwhelming diversity bioactive substances that can beneficial but also detrimental effects on human health. These so-called secondary metabolites naturally serve as antimicrobial “weapon systems”, signaling molecules or developmental effectors for fungi and hence are produced only under very specific environmental conditions stages in their life cycle. However, these complex difficult even impossible to mimic laboratory settings, a small fraction true chemical is known so far. This implies large space potentially new pharmaceuticals remains unexplored. We here present overview current developments advanced methods be used explore this space. focus genetic genomic methods, how detect genes harbor blueprints production compounds (i.e., biosynthetic gene clusters, BGCs), ways activate silent chromosomal regions. provide in-depth view chromatin-level regulation BGCs potential use CRISPR/Cas technology activation tool.

Language: Английский

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Fungal phthalimidines-chemodiversity, bioactivity and biosynthesis of a unique class of natural products

Phytochemistry Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: April 5, 2024

Abstract A wide range of natural products important for the engineering and drug design pharmaceuticals comprise largely nitrogen-based heterocycles. Fungal have proven to be a rich source industrially-important molecules, many which are promising leads. Although, containing phthalimidine core tends not given distant classification, but compounds these structures exhibit antimicrobial, anthelmintic, antimalarial insecticidal activities, among potential target discovering new candidates. Intriguingly, primarily isolated from fungal sources very lesser extent plants or bacteria. This review surveys fungal-derived metabolites published until end 2022, both terrestrial aquatic marine with emphasis on their unique chemistry, bioactivities, biogenesis taxonomic classification. Their chemistry diverse bioactivities (including antiviral, antiproliferative, antioxidant antimicrobial) provide chemical library high medicinal potential, representing treasure trove synthetic chemists. Graphical

Language: Английский

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Biosynthesis of oxindole alkaloids: Recent advances and challenges

Current Opinion in Plant Biology, Journal Year: 2024, Volume and Issue: 82, P. 102648 - 102648

Published: Oct. 3, 2024

Language: Английский

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Discovery of a Chimeric Polyketide Family as Cancer Immunogenic Chemotherapeutic Leads

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 28, 2024

Discovery of cancer immunogenic chemotherapeutics represents an emerging, highly promising direction for treatment that uses a chemical drug to achieve the efficacy both chemotherapy and immunotherapy. Herein, we report high-throughput screening platform subsequent discovery new class chemotherapeutic leads. Our integrates informatics-based activity metabolomics rapid identification microbial natural products with novel structures potent activities. Additionally, demonstrate use microcrystal electron diffraction (MicroED) direct structure elucidation lead compounds from partially purified mixtures. Using this strategy screen geographically phylogenetically diverse metabolites against pseudomyxoma peritonei, rare severe cancer, discovered leads, aspercyclicins. The aspercyclicins feature unprecedented tightly packed polycyclic polyketide scaffold comprises continuous fused, bridged, spiro rings. biogenesis involves two distinct biosynthetic pathways, leading formation chimeric cannot be predicted by bottom-up approaches mining product genes. With comparable potency some clinically used anticancer drugs, are active multiple cell types inducing death (ICD), including release damage-associated molecular patterns phagocytosis cells. broad-spectrum ICD-inducing aspercyclicins, combined their low toxicity normal cells, potential and, particularly, first peritonei treatment.

Language: Английский

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Profiles of Metabolic Genes in Uncaria rhynchophylla and Characterization of the Critical Enzyme Involved in the Biosynthesis of Bioactive Compounds-(iso)Rhynchophylline

Biomolecules, Journal Year: 2022, Volume and Issue: 12(12), P. 1790 - 1790

Published: Nov. 30, 2022

Rhynchophylline (RIN) and isorhynchophylline (IRN), two of the representative types indole alkaloids, showed unique spiroindole structures produced in Uncaria rhynchophylla. As bioactive constituent U. rhynchophylla, IRN has recently drawn extensive attention toward antihypertensive neuroprotective activities. Despite their medicinal importance chemical structure, biosynthetic pathways plant alkaloids are still largely unknown. In this study, we used extensively traditional Chinese medicine (TCM), a widely cultivated genus, to investigate genes characterize functional enzymes alkaloids. We aim use transcriptome platform analyse tissue-specific gene expression alkaloids-producing tissues, including root, bud, stem bark leaf. The critical involved biosynthesis precursors scaffold formation were discovered characterized. datasets from work provide an essential resource for further investigating metabolic rhynchophylla facilitate novel enzyme characterization good biopharming approach

Language: Английский

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Functional Crosstalk between Discrete Indole Terpenoid Gene Clusters in Tolypocladium album

Organic Letters, Journal Year: 2023, Volume and Issue: 25(41), P. 7470 - 7475

Published: Oct. 5, 2023

Indole terpenoids make up a large group of secondary metabolites that display an enticing array bioactivities. While indole diterpene (IDT) and rarely sesquiterpene (IST) pathways have been found individually in filamentous fungi, here we show both cluster types are encoded within the genome Tolypocladium album. Through heterologous reconstruction, demonstrate SES encodes for IST biosynthesis can tailor IDT substrates produced by TER cluster.

Language: Английский

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Alkaloids of forest fungi: diversity and therapeutic applications

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 343 - 367

Published: Sept. 13, 2024

Language: Английский

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