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

Autor: Bauman KD; Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, USA., Shende VV; Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, USA., Chen PY; Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, USA.; Morphic Therapeutics, Waltham, MA, USA., Trivella DBB; Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, USA.; Brazilian Biosciences National Laboratory, National Center for Research in Energy and Materials, Campinas, Brazil.; Institute of Chemistry, University of Campinas, Campinas, Brazil., Gulder TAM; Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, USA.; Chair of Technical Biochemistry, Technical University of Dresden, Dresden, Germany., Vellalath S; Department of Chemistry and Biochemistry, Baylor University, Waco, TX, USA., Romo D; Department of Chemistry and Biochemistry, Baylor University, Waco, TX, USA., Moore BS; Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, USA. bsmoore@ucsd.edu.; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA. bsmoore@ucsd.edu.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2022 May; Vol. 18 (5), pp. 538-546. Date of Electronic Publication: 2022 Mar 21.
DOI: 10.1038/s41589-022-00993-w
Abstrakt: 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.
(© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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