9J2B

Fe/Fe-SzPolF-L-isoleucine complex

Summary for 9J2B

• Entry DOI: 10.2210/pdb9j2b/pdb
• Descriptor: SzPolF, FE (II) ION, ISOLEUCINE, ... (4 entities in total)
• Functional Keywords: nonheme diiron enzyme, oxidoreductase
• Biological source: Streptomyces sp. Z26
• Total number of polymer chains: 2
• Total formula weight: 62915.70

Authors

Zhang, Z.Y.,Chen, W.Q.,Wang, B.J.,Qu, Y.,Gong, R.,Liu, J. (deposition date: 2024-08-06, release date: 2025-10-08, Last modification date: 2025-10-15)

Primary citation

Gong, R.,Qu, Y.,Liu, J.,Zhang, X.,Zhou, L.,Tian, Z.,Zeng, X.,Jin, B.,Li, Z.,Yu, L.,Chen, R.,Zhou, Y.,Liao, L.,Yang, L.,Song, X.,Cai, Y.S.,Shen, K.,Deng, Z.,Zhang, Z.,Wang, B.,Chen, W.
A two-metalloenzyme cascade constructs the azetidine-containing pharmacophore.
Nat.Chem., 2025

PubMed Abstract: Azetidine is a prominent pharmacophore present in dozens of drug-related molecules of both natural and synthetic origins. But how nature builds this moiety has long remained enigmatic. Here we address the full deciphering of a two-metalloenzyme cascade leading to polyoximic acid, an azetidine-containing moiety of the fungicide polyoxin. We demonstrate that the PolE enzyme functions as an Fe/pterin-dependent L-isoleucine desaturase. Moreover we illustrate that PolF is a new member of the emerging haem-oxygenase-like diiron oxidases, converting the desaturated L-isoleucine to polyoximic acid via an intramolecular C-N cyclization. Remarkably, we also establish that PolF exhibits dual functionality, orchestrating the sequential desaturation and cyclization with L-isoleucine as the initial substrate. Finally, our combined structural and quantum-mechanics/molecular-mechanics studies show that the PolF enzyme employs an extraordinary mechanism for the construction of the azetidine-containing moiety. These findings expand our knowledge on the catalysis of metalloenzymes and open the way for rational access of more azetidine-related molecules.

PubMed: 41028918
DOI: 10.1038/s41557-025-01949-y

Experimental method

X-RAY DIFFRACTION (2.3 Å)