ArticleNature chemical biology2022
Enzymatic assembly of the salinosporamide γ-lactam-β-lactone anticancer warhead.
Article in Nature chemical biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 36 citations in OpenAlex.
- The Use of Bacteria and Their Toxins as Antitumor Agents: Present and Future.Microorganisms · 2026Review
- From Deep-Sea Natural Product to Optimized Therapeutics: Computational Design of Marizomib Analogs.International journal of molecular sciences · 2025Article
- Development of Macrocyclic Peptide-Based Proteasome Inhibitors with Enhanced Blood-Brain Barrier Penetration for Treating Brain Neoplasms.Journal of medicinal chemistry · 2025Article
- Ketosynthase Domain Catalyzes β-Lactonization in the Biosynthesis of the HMG-CoA Synthase Inhibitor Hymeglusin.Journal of the American Chemical Society · 2025Article
- Biosynthesis of lactacystin as a proteasome inhibitor.Communications chemistry · 2025Article
- Pattern-Based Genome Mining Guides Discovery of the Antibiotic Indanopyrrole A from a Marine Streptomycete.Journal of natural products · 2024Article
- Pattern-based genome mining guides discovery of the antibiotic indanopyrrole A from a marine streptomycetef.bioRxiv : the preprint server for biology · 2024Article
- Alligamycin A, an antifungal β-lactone spiroketal macrolide from Streptomyces iranensis.Nature communications · 2024Article
- Natural compounds-based nanomedicines for cancer treatment: Future directions and challenges.Drug delivery and translational research · 2024Review
- Cryptic enzymatic assembly of peptides armed with β-lactone warheads.Nature chemical biology · 2024Article
- The shikimate pathway: gateway to metabolic diversity.Natural product reports · 2024Review
- Modifications of Protein-Bound Substrates by Trans-Acting Enzymes in Natural Products Biosynthesis.Chembiochem : a European journal of chemical biology · 2024Review
- Antibacterial Polyketides Isolated from the Marine-Derived FungusJournal of fungi (Basel, Switzerland) · 2023Article
- β-Lactams from the Ocean.Marine drugs · 2023Review
- Biosynthetic gene profiling and genomic potential of the novel photosynthetic marine bacteriumFrontiers in microbiology · 2023Article
- Noncanonical Functions of Enzyme Cofactors as Building Blocks in Natural Product Biosynthesis.JACS Au · 2022Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 3 countries.
Funding
Abstract
The marine microbial natural product salinosporamide A (marizomib) is a potent proteasome inhibitor currently in clinical trials for the treatment of brain cancer. Salinosporamide A is characterized by a complex and densely functionalized γ-lactam-β-lactone bicyclic warhead, the assembly of which has long remained a biosynthetic mystery. Here, we report an enzymatic route to the salinosporamide core catalyzed by a standalone ketosynthase (KS), SalC. Chemoenzymatic synthesis of carrier protein-tethered substrates, as well as intact proteomics, allowed us to probe the reactivity of SalC and understand its role as an intramolecular aldolase/β-lactone synthase with roles in both transacylation and bond-forming reactions. Additionally, we present the 2.85-Å SalC crystal structure that, combined with site-directed mutagenesis, allowed us to propose a bicyclization reaction mechanism. This work challenges our current understanding of the role of KS enzymes and establishes a basis for future efforts toward streamlined production of a clinically relevant chemotherapeutic.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.