7S2X

Structure of SalC, a gamma-lactam-beta-lactone bicyclase for salinosporamide biosynthesis

Summary for 7S2X

• Entry DOI: 10.2210/pdb7s2x/pdb
• Descriptor: SalC, POTASSIUM ION, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (4 entities in total)
• Functional Keywords: salinosporamide, marizomib, bicyclase, cyclase, lactam, lactone, ketosynthase, transferase, biosynthetic protein
• Biological source: Salinispora tropica
• Total number of polymer chains: 4
• Total formula weight: 259921.12

Authors

Chen, P.Y.-T.,Trivella, D.B.B.,Bauman, K.D.,Moore, B.S. (deposition date: 2021-09-04, release date: 2022-04-06, Last modification date: 2023-10-18)

Primary citation

Bauman, K.D.,Shende, V.V.,Chen, P.Y.,Trivella, D.B.B.,Gulder, T.A.M.,Vellalath, S.,Romo, D.,Moore, B.S.
Enzymatic assembly of the salinosporamide gamma-lactam-beta-lactone anticancer warhead.
Nat.Chem.Biol., 18:538-546, 2022

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.

PubMed: 35314816
DOI: 10.1038/s41589-022-00993-w

Experimental method

X-RAY DIFFRACTION (2.85 Å)