7XH4

Dihydrofolate Reductase-like Protein SacH in safracin biosynthesis complex with safracin A

Summary for 7XH4

• Entry DOI: 10.2210/pdb7xh4/pdb
• Descriptor: Uncharacterized protein sfcH, Safracin A, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (4 entities in total)
• Functional Keywords: reductase, safracin biosynthesis, self-resistance, complex structure., oxidoreductase
• Biological source: Pseudomonas fluorescens
• Total number of polymer chains: 1
• Total formula weight: 23288.87

Authors

Ma, X.,Shao, N.,Zhang, Y.,Yang, D.,Ma, M.,Tang, G. (deposition date: 2022-04-07, release date: 2023-02-08, Last modification date: 2023-11-29)

Primary citation

Shao, N.,Ma, X.,Zhang, Y.Y.,Yang, D.,Ma, M.,Tang, G.L.
Dihydrofolate reductase-like protein inactivates hemiaminal pharmacophore for self-resistance in safracin biosynthesis.
Acta Pharm Sin B, 13:1318-1325, 2023

PubMed Abstract: Dihydrofolate reductase (DHFR), a housekeeping enzyme in primary metabolism, has been extensively studied as a model of acid-base catalysis and a clinic drug target. Herein, we investigated the enzymology of a DHFR-like protein SacH in safracin (SAC) biosynthesis, which reductively inactivates hemiaminal pharmacophore-containing biosynthetic intermediates and antibiotics for self-resistance. Furthermore, based on the crystal structure of SacH-NADPH-SAC-A ternary complexes and mutagenesis, we proposed a catalytic mechanism that is distinct from the previously characterized short-chain dehydrogenases/reductases-mediated inactivation of hemiaminal pharmacophore. These findings expand the functions of DHFR family proteins, reveal that the common reaction can be catalyzed by distinct family of enzymes, and imply the possibility for the discovery of novel antibiotics with hemiaminal pharmacophore.

PubMed: 36970210
DOI: 10.1016/j.apsb.2022.10.005

Experimental method

X-RAY DIFFRACTION (2.2 Å)