7k12
ACMSD in complex with diflunisalACMSD in complex with diflunisal
Structural highlights
FunctionPublication Abstract from PubMedIn the kynurenine pathway for tryptophan degradation, an unstable metabolic intermediate, alpha-amino-beta-carboxymuconate-epsilon-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 (IC50) values 1 order of magnitude better than diflunisal at 1.32 +/- 0.07 muM (22) and 3.10 +/- 0.11 muM (20), 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. Diflunisal Derivatives as Modulators of ACMS Decarboxylase Targeting the Tryptophan-Kynurenine Pathway.,Yang Y, Borel T, de Azambuja F, Johnson D, Sorrentino JP, Udokwu C, Davis I, Liu A, Altman RA J Med Chem. 2020 Dec 28. doi: 10.1021/acs.jmedchem.0c01762. PMID:33369426[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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