9CJN

Ligase Cp1B

9CJN の概要

• エントリーDOI: 10.2210/pdb9cjn/pdb
• 分子名称: Ligase Cp1B, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ADENOSINE, ... (5 entities in total)
• 機能のキーワード: cp1b, e-64, ligase, epoxylsuccinate
• 由来する生物種: Aspergillus flavus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 59144.45

構造登録者

Xin, Z.,Yi, T. (登録日: 2024-07-07, 公開日: 2025-05-21)

主引用文献

Liu, M.,Zang, X.,Vlahakis, N.W.,Rodriguez, J.A.,Ohashi, M.,Tang, Y.
Enzymatic combinatorial synthesis of E-64 and related cysteine protease inhibitors.
Nat.Chem.Biol., 2025

PubMed Abstract: E-64 is an irreversible cysteine protease inhibitor prominently used in chemical biology and drug discovery. Here we uncover a nonribosomal peptide synthetase-independent biosynthetic pathway for E-64, which is widely conserved in fungi. The pathway starts with epoxidation of fumaric acid to the warhead (2S,3S)-trans-epoxysuccinic acid with an Fe(II)/α-ketoglutarate-dependent oxygenase, followed by successive condensation with an L-amino acid by an adenosine triphosphate grasp enzyme and with an amine by the fungal example of amide bond synthetase. Both amide bond-forming enzymes display notable biocatalytic potential, including scalability, stereoselectivity toward the warhead and broader substrate scopes in forming the amide bonds. Biocatalytic cascade with these amide bond-forming enzymes generated a library of cysteine protease inhibitors, leading to more potent cathepsin inhibitors. Additionally, one-pot reactions enabled the preparative synthesis of clinically relevant inhibitors. Our work highlights the importance of biosynthetic investigation for enzyme discovery and the potential of amide bond-forming enzymes in synthesizing small-molecule libraries.

PubMed: 40346252
DOI: 10.1038/s41589-025-01907-2

実験手法

X-RAY DIFFRACTION (2.7 Å)