9JML

NADP-dependent oxidoreductase complexed with NADP and substrate 1

This is a non-PDB format compatible entry.

Summary for 9JML

• Entry DOI: 10.2210/pdb9jml/pdb
• Descriptor: NADP-dependent oxidoreductase, (1Z,3Z,5Z,7S,8R,9S,10S,11R,13R,15R,16Z,18Z,24S)-11-ethyl-2,7-dihydroxy-10-methyl-21,25-diazatetracyclo[22.2.1.08,15.09,13]heptacosa-1,3,5,16,18-pentaene-20,26,27-trione, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (4 entities in total)
• Functional Keywords: alcohol dehydrogenase, complex, biosynthetic protein
• Biological source: Lysobacter enzymogenes
• Total number of polymer chains: 2
• Total formula weight: 80362.72

Authors

Li, Y.,Zhu, D.,Xie, X.,Li, F.,Lu, M. (deposition date: 2024-09-20, release date: 2025-06-18)

Primary citation

Xie, X.,Li, F.,Mu, Y.,Lu, M.,Luo, J.,Wang, H.,Shen, Y.,Du, L.,Zhu, D.,Li, Y.
Structural Basis for Medium-Chain Dehydrogenase/Reductase-Catalyzed Reductive Cyclization in Polycyclic Tetramate Macrolactam Biosynthesis.
J.Am.Chem.Soc., 147:19253-19261, 2025

PubMed Abstract: Few enzymes are known to catalyze reductive cyclizations via nucleophile-mediated C-C bond formation. Medium-chain dehydrogenases/reductases (MDRs) typically function as dehydrogenases or reductases. However, a distinct subclass of MDRs involved in polycyclic tetramate macrolactam (PoTeM) biosynthesis catalyzes reductive cyclizations via hydride-mediated C-C bond formation. Here, we present the apo and substrate-bound structures of OX4 and CftD, two enzymes responsible for the third ring formation in PoTeMs biosynthesis. Structural and mutational analysis reveal a catalytic mechanism wherein OX4 initiates a NADPH-dependent 1,6-reduction, followed by cyclization to form the C11-C22 bond, water-mediated protonation of the C7-carbonyl oxygen, and a final tautomerization to produce the cyclized product. Precise substrate positioning and stabilization of the enolate intermediate by the conserved residue W260 are critical for catalysis. These findings represent the first structural and mechanistic understanding of this newly identified cyclase subgroup and offer promising new avenues for enzyme engineering and natural product biosynthesis.

PubMed: 40406958
DOI: 10.1021/jacs.5c04971

Experimental method

X-RAY DIFFRACTION (2.02 Å)