7K12

ACMSD in complex with diflunisal

7K12 の概要

• エントリーDOI: 10.2210/pdb7k12/pdb
• 分子名称: 2-amino-3-carboxymuconate 6-semialdehyde decarboxylase, ZINC ION, 5-(2,4-DIFLUOROPHENYL)-2-HYDROXY-BENZOIC ACID, ... (5 entities in total)
• 機能のキーワード: fda-approved drugs, nad+, neuropsychiatric disorders, decarboxylase, lyase
• 由来する生物種: Pseudomonas fluorescens
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 80134.52

構造登録者

Yang, Y.,Liu, A. (登録日: 2020-09-07, 公開日: 2021-01-13, 最終更新日: 2023-10-18)

主引用文献

Yang, Y.,Borel, T.,de Azambuja, F.,Johnson, D.,Sorrentino, J.P.,Udokwu, C.,Davis, I.,Liu, A.,Altman, R.A.
Diflunisal Derivatives as Modulators of ACMS Decarboxylase Targeting the Tryptophan-Kynurenine Pathway.
J.Med.Chem., 64:797-811, 2021

PubMed Abstract: In the kynurenine pathway for tryptophan degradation, an unstable metabolic intermediate, α-amino-β-carboxymuconate-ε-semialdehyde (ACMS), can nonenzymatically cyclize to form quinolinic acid, the precursor for de novo biosynthesis of nicotinamide adenine dinucleotide (NAD). In a competing reaction, ACMS is decarboxylated by ACMS decarboxylase (ACMSD) for further metabolism and energy production. Therefore, the inhibition of ACMSD increases NAD levels. In this study, an Food and Drug Administration (FDA)-approved drug, diflunisal, was found to competitively inhibit ACMSD. The complex structure of ACMSD with diflunisal revealed a previously unknown ligand-binding mode and was consistent with the results of inhibition assays, as well as a structure-activity relationship (SAR) study. Moreover, two synthesized diflunisal derivatives showed half-maximal inhibitory concentration (IC) values 1 order of magnitude better than diflunisal at 1.32 ± 0.07 μM () and 3.10 ± 0.11 μM (), respectively. The results suggest that diflunisal derivatives have the potential to modulate NAD levels. The ligand-binding mode revealed here provides a new direction for developing inhibitors of ACMSD.

PubMed: 33369426
DOI: 10.1021/acs.jmedchem.0c01762

実験手法

X-RAY DIFFRACTION (2.17 Å)