Effect of arylformamidase (kynurenine formamidase) gene inactivation in mice on enzymatic activity, kynurenine pathway metabolites and phenotype
Effect of arylformamidase (kynurenine formamidase) gene inactivation in mice on enzymatic activity, kynurenine pathway metabolites and phenotype
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DOI：
10.1016/j.bbagen.2005.03.010
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发表时间：
2005-06-20
影响因子：
3
通讯作者：
Casida, JE
中科院分区：
文献类型：
--
作者：
Dobrovolsky, VN;Bowyer, JF;Casida, JE
通过去除调节 Afmid 和胸苷激酶 (Tk) 基因表达的共享双向启动子区域，使小鼠体内编码芳基甲酰胺酶（Afmid，也称为犬尿氨酸甲酰胺酶）的基因失活。已知 Afmid/Tk 缺陷小鼠会出现肾小球硬化并具有异常的免疫系统。 Afmid 催化的 N-甲酰基犬尿氨酸水解是色氨酸代谢和犬尿氨酸衍生产物（包括犬尿酸、喹啉酸、烟酰胺、NAD 和 NADP）生物合成的关键步骤。这些途径的破坏与神经毒性和免疫毒性有关。在野生型 (WT) 小鼠中，肝脏中的 Afmid 特异性活性（通过甲酰基犬尿氨酸水解测量）比肾脏中高 2 倍。在 Afmid/Tk 杂合子 (HZ) 小鼠中，甲酰基犬尿氨酸水解减少了约 50%，在 Afmid/Tk 敲除 (KO) 小鼠中几乎完全消除。然而，KO 小鼠的肾脏中有 13% 残留的甲酰基犬尿氨酸水解，表明除 Afmid 之外还存在甲酰胺酶。 WT、HZ 和 KO 小鼠中烟酰胺加 NAD/NADP 的肝脏和肾脏水平保持相同。相对于 WT 小鼠，KO 小鼠（但 HZ 小鼠）甲酰基犬尿氨酸、犬尿氨酸和犬尿酸的血浆浓度升高，这进一步表明除了 Afmid（可能在肾脏中）之外，一定还有其他酶能够将甲酰基犬尿氨酸代谢为犬尿氨酸。 KO 小鼠的肾脏逐渐恶化和随后的衰竭与 WT 小鼠肾脏中高水平的组织特异性 Afmid 表达一致，但与 KO 小鼠不同。在此基础上，小鼠中犬尿氨酸途径和 Afmid 最重要的功能可能是消除有毒代谢物，并在较小程度上为其他过程提供中间体。由 Elsevier B.V. 出版
The gene coding for arylformamidase (Afmid, also known as kynurenine formamidase) was inactivated in mice through the removal of a shared bidirectional promoter region regulating expression of the Afmid and thymidine kinase (Tk) genes. Afmid/Tk-deficient mice are known to develop sclerosis of glomeruli and to have an abnormal immune system. Afmid-catalyzed hydrolysis of N-fonnyl-kynurenine is a key step in tryptophan metabolism and biosynthesis of kynurenine-derived products including kynurenic acid, quinolinic acid, nicotinamide, NAD, and NADP. A disruption of these pathways is implicated in neurotoxicity and immunotoxicity. In wild-type (WT) mice, Afmid-specific activity (as measured by formyl-kynurenine hydrolysis) was 2-fold higher in the liver than in the kidney. Formyl-kynurenine hydrolysis was reduced by similar to 50% in mice heterozygous (HZ) for Afmid/Tk and almost completely eliminated in Afmid/Tk knockout (KO) mice. However, there was 13% residual formyl-kynurenine hydrolysis in the kidney of KO mice, suggesting the existence of a formamidase other than Afmid. Liver and kidney levels of nicotinamide plus NAD/NADP remained the same in WT, HZ and KO mice. Plasma concentrations of formyl-kynurenine, kynurenine, and kynurenic acid were elevated in KO mice (but not HZ mice) relative to WT mice, further suggesting that there must be enzymes other than Afmid (possibly in the kidney) capable of metabolizing formyl-kynurenine into kynurenine. Gradual kidney deterioration and subsequent failure in KO mice is consistent with high levels of tissue-specific Afmid expression in the kidney of WT but not KO mice. On this basis, the most significant function of the kynurenine pathway and Afmid in mice may be in eliminating toxic metabolites and to a lesser extent in providing intermediates for other processes. Published by Elsevier B.V.