Enzymatic assembly of the salinosporamide γ-lactam-β-lactone anticancer warhead

Nat Chem Biol. 2022 May;18(5):538-546. doi: 10.1038/s41589-022-00993-w. Epub 2022 Mar 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Biological Products* / pharmacology
  • Lactams*
  • Lactones / chemistry
  • Proteasome Inhibitors
  • Pyrroles / pharmacology


  • Biological Products
  • Lactams
  • Lactones
  • Proteasome Inhibitors
  • Pyrroles