Download MendeleyEnzymatic assembly of the salinosporamide gamma-lactam-beta-lactone anticancer warhead.
Bauman, K.D., Shende, V.V., Chen, P.Y., Trivella, D.B.B., Gulder, T.A.M., Vellalath, S., Romo, D., Moore, B.S.(2022) Nat Chem Biol 18: 538-546
- PubMed: 35314816
- DOI: https://doi.org/10.1038/s41589-022-00993-w
- Primary Citation of Related Structures:
7S2X - PubMed 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.
Organizational Affiliation:
Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, USA.
