9CJN
Ligase Cp1B
Summary for 9CJN
| Entry DOI | 10.2210/pdb9cjn/pdb |
| Descriptor | Ligase Cp1B, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ADENOSINE, ... (5 entities in total) |
| Functional Keywords | cp1b, e-64, ligase, epoxylsuccinate |
| Biological source | Aspergillus flavus |
| Total number of polymer chains | 1 |
| Total formula weight | 59144.45 |
| Authors | |
| Primary citation | 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 Cited by 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: 40346252DOI: 10.1038/s41589-025-01907-2 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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