7S2X

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

7S2X の概要

• エントリーDOI: 10.2210/pdb7s2x/pdb
• 分子名称: SalC, POTASSIUM ION, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (4 entities in total)
• 機能のキーワード: salinosporamide, marizomib, bicyclase, cyclase, lactam, lactone, ketosynthase, transferase, biosynthetic protein
• 由来する生物種: Salinispora tropica
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 259921.12

構造登録者

Chen, P.Y.-T.,Trivella, D.B.B.,Bauman, K.D.,Moore, B.S. (登録日: 2021-09-04, 公開日: 2022-04-06, 最終更新日: 2023-10-18)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.85 Å)