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Microviridin 1777: A Toxic Chymotrypsin Inhibitor Discovered by a Metabologenomic Approach


Sieber, Simon; Grendelmeier, Simone M; Harris, Lonnie A; Mitchell, Douglas A; Gademann, Karl (2020). Microviridin 1777: A Toxic Chymotrypsin Inhibitor Discovered by a Metabologenomic Approach. Journal of natural products, 83(2):438-446.

Abstract

The toxicity of the cyanobacterium Microcystis aeruginosa EAWAG 127a was evaluated against the sensitive grazer Thamnocephalus platyurus, and the extract possessed strong activity. To investigate the compounds responsible for cytotoxicity, a series of peptides from this cyanobacterium were studied using a combined genomic and molecular networking approach. The results led to the isolation, structure elucidation, and biological evaluation of microviridin 1777, which represents the most potent chymotrypsin inhibitor characterized from this family of peptides to date. Furthermore, the biosynthetic gene clusters of microviridin, anabaenopeptin, aeruginosin, and piricyclamide were located in the producing organism, and six additional natural products were identified by tandem mass spectrometry analyses. These results highlight the potential of modern techniques for the identification of natural products, demonstrate the ecological role of protease inhibitors produced by cyanobacteria, and raise ramifications concerning the presence of novel, yet uncharacterized, toxin families in cyanobacteria beyond microcystin.

Abstract

The toxicity of the cyanobacterium Microcystis aeruginosa EAWAG 127a was evaluated against the sensitive grazer Thamnocephalus platyurus, and the extract possessed strong activity. To investigate the compounds responsible for cytotoxicity, a series of peptides from this cyanobacterium were studied using a combined genomic and molecular networking approach. The results led to the isolation, structure elucidation, and biological evaluation of microviridin 1777, which represents the most potent chymotrypsin inhibitor characterized from this family of peptides to date. Furthermore, the biosynthetic gene clusters of microviridin, anabaenopeptin, aeruginosin, and piricyclamide were located in the producing organism, and six additional natural products were identified by tandem mass spectrometry analyses. These results highlight the potential of modern techniques for the identification of natural products, demonstrate the ecological role of protease inhibitors produced by cyanobacteria, and raise ramifications concerning the presence of novel, yet uncharacterized, toxin families in cyanobacteria beyond microcystin.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Scopus Subject Areas:Physical Sciences > Analytical Chemistry
Life Sciences > Molecular Medicine
Life Sciences > Pharmacology
Life Sciences > Pharmaceutical Science
Life Sciences > Drug Discovery
Health Sciences > Complementary and Alternative Medicine
Physical Sciences > Organic Chemistry
Uncontrolled Keywords:Organic Chemistry, Analytical Chemistry, Molecular Medicine, Pharmacology, Drug Discovery, Pharmaceutical Science
Language:English
Date:28 February 2020
Deposited On:20 Jan 2021 13:13
Last Modified:25 May 2024 01:43
Publisher:American Chemical Society (ACS)
ISSN:0163-3864
OA Status:Green
Publisher DOI:https://doi.org/10.1021/acs.jnatprod.9b00986
Project Information:
  • : FunderSNSF
  • : Grant IDCRSII5_186410
  • : Project TitleA New Class of Signal Molecules in Bacteria: Data-Driven Discovery, Mechanism, and Biological Function (Signalinâ��Bac)
  • : FunderSNSF
  • : Grant ID200021_182043
  • : Project TitleMechanism-Based Design, Synthesis, Biological Evaluation, and Delivery of Next-Generation Antibiotics
  • Content: Accepted Version