Enzymatic assembly of the salinosporamide gamma-lactam-beta-lactone anticancer warhead

Autor(es)

Bauman, Katherine D. ; Shende, Vikram V. ; Chen, Percival Yang-Ting ; Trivella, Daniela B. B. ; Gulder, Tobias A. M. ; Vellalath, Sreekumar ; Romo, Daniel ; Moore, Bradley S.

• Tipo de documento: Artigo Científico
• Fonte: Nature Chemical Biology; v. 18, n. 5, p. 23-pg., 2022-03-21.

Resumo

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-angstrom 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. (AU)

• Processo FAPESP: 11/21358-5 - Triagem de compostos orgânicos (bio)sintéticos frente a alvos biológicos contra o câncer
• Beneficiário: Daniela Barretto Barbosa Trivella
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado