ArticleNature chemical biology2024
Cryptic enzymatic assembly of peptides armed with β-lactone warheads.
Article in Nature chemical biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Alternative enzymatic pathways to penicillin antibiotics.Nature communications · 2026Article
- Biocatalytic Tetrapeptide Macrocyclization by Cryptic Penicillin-Binding Protein-Type Thioesterases.Biochemistry · 2026Article
- Reaction Engineering of In Vitro Natural Product Biosynthesis: Challenges and Strategies.Chembiochem : a European journal of chemical biology · 2025Review
- Enhancing the β-Oxidation-Like Pathway for the Optimal Production of the Immunosuppressant Mycophenolic Acid.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Enzymatic combinatorial synthesis of E-64 and related cysteine protease inhibitors.Nature chemical biology · 2025Article
- Advances in Peptidomimetics for Next-Generation Therapeutics: Strategies, Modifications, and Applications.Chemical reviews · 2025Review
- Biocatalytic Tetrapeptide Macrocyclization by Cryptic Penicillin-binding Protein-type Thioesterases.bioRxiv : the preprint server for biology · 2025Article
- Genome Mining of Isoindolinone-Containing Peptide Natural Products.Journal of the American Chemical Society · 2025Article
- Discovery of Noncanonical Iron and 2-Oxoglutarate Dependent Enzymes Involved in C-C and C-N Bond Formation in Biosynthetic Pathways.ACS bio & med chem Au · 2025Review
- Enzymatic Cascades for Stereoselective and Regioselective Amide Bond Assembly.Angewandte Chemie (International ed. in English) · 2025Article
Corrections and comments
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Authors and funding
12 authors.
Funding
Abstract
Nature has evolved biosynthetic pathways to molecules possessing reactive warheads that inspired the development of many therapeutic agents, including penicillin antibiotics. Peptides armed with electrophilic warheads have proven to be particularly effective covalent inhibitors, providing essential antimicrobial, antiviral and anticancer agents. Here we provide a full characterization of the pathways that nature deploys to assemble peptides with β-lactone warheads, which are potent proteasome inhibitors with promising anticancer activity. Warhead assembly involves a three-step cryptic methylation sequence, which is likely required to reduce unfavorable electrostatic interactions during the sterically demanding β-lactonization. Amide-bond synthetase and adenosine triphosphate (ATP)-grasp enzymes couple amino acids to the β-lactone warhead, generating the bioactive peptide products. After reconstituting the entire pathway to β-lactone peptides in vitro, we go on to deliver a diverse range of analogs through enzymatic cascade reactions. Our approach is more efficient and cleaner than the synthetic methods currently used to produce clinically important warhead-containing peptides.
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Registered trials
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