Chelidonic acid and other conformationally restricted substrate analogues as inhibitors of rat brain glutamate decarboxylase.
Chelidonic acid and other conformationally restricted substrate analogues as inhibitors of rat brain glutamate decarboxylase.
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DOI：
10.1016/0006-2952(85)90207-2
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发表时间：
1985-12
影响因子：
5.8
通讯作者：
T. Porter;D. Martin
中科院分区：
文献类型：
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作者：
T. Porter;D. Martin
二十构象限制类似物的谷氨酸盐，包括苯甲酸，羟基苯甲酸，吡啶二羧酸，和吡喃二羧酸作为抑制剂的谷氨酸脱羧酶从大鼠脑进行了测试。白屈菜酸、2，6-吡啶二羧酸、白屈菜酰胺酸、没食子酸和3，4-二羟基苯甲酸是该酶的最有效的抑制剂，并且通常芳香族类似物比它们的脂肪族对应物是更有效的抑制剂。0.75 nm的羧酸间距离似乎是最佳的底物竞争，表明谷氨酸结合到活性位点的扩展构象。至少一个羧基可以被酚羟基取代，而不会大大影响抑制。抑制的程度也受到芳香族结构的影响，特别是相对于桥接二羧酸碳的原子。动力学分析表明，白屈菜酸和白屈菜酰胺酸与谷氨酸具有竞争性抑制作用，Ki值分别为1.2和33 μM。与此结果一致，白屈菜酸也抑制谷氨酸依赖的脱辅基酶的形成。白屈菜酸本身并没有促进形成脱辅基酶，并没有与游离吡哆醛P反应。不同类别的谷氨酸脱羧酶抑制剂的影响进行了讨论，在有关脱辅基酶的形成和吡哆醛-P的再活化。作为已知的谷氨酸脱羧酶的最有效的抑制剂之一，白屈菜酸可能是有价值的γ-氨基丁酸合成的调节研究。
Twenty conformationally restricted analogues of glutamate including benzoic acids, hydroxybenzoic acids, pyridine dicarboxylic acids, and pyran dicarboxylic acids were tested as inhibitors of glutamate decarboxylase from rat brain. Chelidonic acid, 2,6-pyridine dicarboxylic acid, chelidamic acid, gallic acid, and 3,4-dihydroxybenzoic acid were the most potent inhibitors of the enzyme, and generally the aromatic analogues were much more potent inhibitors than their aliphatic counterparts. An intercarboxylate distance of 0.75 nm appears optimal for substrate competition, indicating that glutamate binds to the active site in an extended conformation. At least one carboxyl group can be replaced by a phenolic hydroxyl without greatly affecting inhibition. The degree of inhibition was also influenced by the aromatic structure, particularly with respect to the atom bridging the dicarboxylate carbons. Kinetic analysis of the inhibition by chelidonic acid and chelidamic acid showed that these compounds were competitive with glutamate withKivalues of 1.2 and 33 μM respectively. Consistent with this result, chelidonic acid also inhibited the glutamate-dependent formation of apoenzyme. Chelidonic acid itself did not promote formation of apoenzyme and did not react with free pyridoxal P. The effects of different classes of glutamate decarboxylase inhibitors are discussed in relation to the formation of apoenzyme and its reactivation by pyridoxal-P. As one of the most potent inhibitors of glutamate decarboxylase known, chelidonic acid may be of value in studies of the regulation of γ-aminobutyric acid synthesis.