Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism
Maleylacetoacetate isomerase (MAAI/GSTZ)-deficient mice reveal a glutathione-dependent nonenzymatic bypass in tyrosine catabolism
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DOI：
10.1128/mcb.22.13.4943-4951.2002
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发表时间：
2002-07-01
影响因子：
5.3
通讯作者：
Grompe, M
中科院分区：
文献类型：
--
作者：
Fernández-Cañón, JM;Baetscher, MW;Grompe, M
在哺乳动物中，苯丙氨酸和酪氨酸的分解代谢途径在肝脏(肝细胞)和肾脏(近端肾小管细胞)中被发现。除了顺丁烯二酰乙酰乙酸酯异构酶(MAAI)，它将顺丁烯二酰乙酰乙酸酯(MAA)转化为延胡索乙酸乙酯(FAA)外，还有一些众所周知的人类疾病与这一途径中所有酶的缺乏有关。MAAI又称谷胱甘肽转移酶Zeta(GSTZ1)。在这里，我们描述了MAAI(GSTZ1)基因定向缺失的小鼠的表型。MAAI基因缺陷的小鼠在尿液中积累了FAA和琥珀酸丙酮，但在其他方面看起来很健康。这一观察结果表明，积累MAA要么是无毒的，要么是存在MAA代谢的替代途径。可以排除MAAI的完全冗余，因为酪氨酸分解代谢途径的底物过载(给予同种异丙酸、苯丙氨酸或酪氨酸)会导致肾和肝脏损伤。然而，也发现了部分绕过MAAI活性的证据。MAAI和富马酸乙酰乙酸酯水解酶(FAH)的双重突变小鼠在正常饮食下迅速死亡，这表明在没有MAAI的情况下，MAA可以异构化为FAA。双突变体表现出明显的肾脏损伤，表明该器官是MAAI缺乏所致累积化合物(S)的主要靶点。体外实验证明，谷胱甘肽介导的MAA异构化反应不依赖于MAAI酶。这种非酶旁路可能是导致非应激MAAI突变小鼠缺乏表型的原因。
In mammals, the catabolic pathway of phenylalanine and tyrosine is found in liver (hepatocytes) and kidney (proximal tubular cells). There are well-described human diseases associated with deficiencies of all enzymes in this pathway except for maleylacetoacetate isomerase (MAAI), which converts maleylacetoacetate (MAA) to fumarylacetoacetate (FAA). MAAI is also known as glutathione transferase zeta (GSTZ1). Here, we describe the phenotype of mice with a targeted deletion of the MAAI (GSTZ1) gene. MAAI-deficient mice accumulated FAA and succinylacetone in urine but appeared otherwise healthy. This observation suggested that either accumulating MAA is not toxic or an alternate pathway for MAA metabolism exists. A complete redundancy of MAAI could be ruled out because substrate overload of the tyrosine catabolic pathway (administration of homogentisic acid, phenylalanine, or tyrosine) resulted in renal and hepatic damage. However, evidence for a partial bypass of MAAI activity was also found. Mice doubly mutant for MAAI and fumarylacetoacetate hydrolase (FAH) died rapidly on a normal diet, indicating that MAA could be isomerized to FAA in the absence of MAAI. Double mutants showed predominant renal injury, indicating that this organ is the primary target for the accumulated compound(s) resulting from MAAI deficiency. A glutathione-mediated isomerization of MAA to FAA independent of MAAI enzyme was demonstrated in vitro. This nonenzymatic bypass is likely responsible for the lack of a phenotype in nonstressed MAAI mutant mice.