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 (IC₅₀) values 1 order of magnitude better than diflunisal at 1.32 ± 0.07 μM (22) and 3.10 ± 0.11 μM (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.

中文翻译：

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作为靶向色氨酸-犬尿氨酸途径的 ACMS 脱羧酶调节剂的二氟尼柳衍生物

在色氨酸降解的犬尿氨酸途径中，一种不稳定的代谢中间体 α-氨基-β-羧基粘康酸-ε-半醛 (ACMS) 可以非酶环化形成喹啉酸，这是从头生物合成烟酰胺腺嘌呤二核苷酸 (NAD ⁺ )的前体. 在竞争反应中，ACMS 被 ACMS 脱羧酶 (ACMSD) 脱羧，以进一步代谢和产生能量。因此，抑制 ACMSD 会增加 NAD ⁺水平。在这项研究中，发现食品和药物管理局 (FDA) 批准的药物二氟尼柳可竞争性抑制 ACMSD。ACMSD 与二氟尼柳的复杂结构揭示了一种以前未知的配体结合模式，并且与抑制测定的结果以及构效关系 (SAR) 研究一致。此外，两种合成的二氟尼柳衍生物的半数最大抑制浓度 (IC ₅₀ ) 值分别比二氟尼柳高 1 个数量级，分别为 1.32 ± 0.07 μM ( 22 ) 和 3.10 ± 0.11 μM ( 20 )。结果表明二氟尼柳衍生物具有调节 NAD ⁺水平。这里揭示的配体结合模式为开发ACMSD抑制剂提供了新的方向。