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Publication Abstract from PubMed

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 gamma-lactam-beta-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/beta-lactone synthase with roles in both transacylation and bond-forming reactions. Additionally, we present the 2.85-A 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.

Enzymatic assembly of the salinosporamide gamma-lactam-beta-lactone anticancer warhead.,Bauman KD, Shende VV, Chen PY, Trivella DBB, Gulder TAM, Vellalath S, Romo D, Moore BS Nat Chem Biol. 2022 Mar 21. pii: 10.1038/s41589-022-00993-w. doi:, 10.1038/s41589-022-00993-w. PMID:35314816^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.