Glutamate dehydrogenase: structure, allosteric regulation, and role in insulin homeostasis.
Glutamate dehydrogenase: structure, allosteric regulation, and role in insulin homeostasis.
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DOI：
10.1007/s11064-013-1173-2
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发表时间：
2014
影响因子：
4.4
通讯作者：
Smith TJ
中科院分区：
文献类型：
--
作者：
Li M;Li C;Allen A;Stanley CA;Smith TJ
谷氨酸脱氢酶 (GDH) 是一种同源六聚酶，可催化 L-谷氨酸可逆氧化脱氨基为 2-酮戊二酸。只有在动物界，这种酶才受到多种代谢物的严格变构调节。主要激活剂是 ADP 和亮氨酸，抑制剂包括 GTP、棕榈酰辅酶 A 和 ATP。 GTP 抑制位点的自发突变导致高胰岛素血症/高氨血症 (HHS) 综合征，这揭示了为什么哺乳动物 GDH 受到如此严格的调控。 HHS 患者在消耗蛋白质后表现出胰岛素分泌过多，并伴有血清中极高水平的铵。与 GDH 复合物复合的四种新型抑制剂的原子结构已确定了三个不同的变构结合位点。使用表达人类 HHS 形式的 GDH 的转基因小鼠模型，这些化合物中的至少三种可以阻断胰腺组织中失调的 GDH 形式。绿茶中的 EGCG 可以防止整个动物对氨基酸的过度反应，并改善基础血糖水平。 ECG-GDH 复合物的原子结构和诱变研究正在指导使用这些多酚作为基础支架进行基于结构的药物设计。此外，所有这些变构抑制剂都在阐明这种复杂酶中变构的原子机制。
Glutamate dehydrogenase (GDH) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of l-glutamate to 2-oxoglutarate. Only in the animal kingdom is this enzyme heavily allosterically regulated by a wide array of metabolites. The major activators are ADP and leucine and inhibitors include GTP, palmitoyl CoA, and ATP. Spontaneous mutations in the GTP inhibitory site that lead to the hyperinsulinism/hyperammonemia (HHS) syndrome have shed light as to why mammalian GDH is so tightly regulated. Patients with HHS exhibit hypersecretion of insulin upon consumption of protein and concomitantly extremely high levels of ammonium in the serum. The atomic structures of four new inhibitors complexed with GDH complexes have identified three different allosteric binding sites. Using a transgenic mouse model expressing the human HHS form of GDH, at least three of these compounds blocked the dysregulated form of GDH in pancreatic tissue. EGCG from green tea prevented the hyper-response to amino acids in whole animals and improved basal serum glucose levels. The atomic structure of the ECG–GDH complex and mutagenesis studies is directing structure-based drug design using these polyphenols as a base scaffold. In addition, all of these allosteric inhibitors are elucidating the atomic mechanisms of allostery in this complex enzyme.
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影响因子：
2.9
作者：
Banerjee, S;Schmidt, T;Smith, TJ
通讯作者：
Smith, TJ
DOI：
10.1111/j.1550-7408.1973.tb03600.x
发表时间：
1973-01-01
期刊：
JOURNAL OF PROTOZOOLOGY
影响因子：
--
作者：
BLUM, JJ
通讯作者：
BLUM, JJ
影响因子：
3.9
作者：
FAHIEN, LA;KMIOTEK, E
通讯作者：
KMIOTEK, E
DOI：
10.1016/j.bbrc.2007.10.188
发表时间：
2008-03-28
影响因子：
3.1
作者：
Filling, Charlotta;Keller, Brigitte;Oppermann, Udo
通讯作者：
Oppermann, Udo
影响因子：
11.4
作者：
Herrero-Yraola, A;Bakhit, SMA;Ziegler, M
通讯作者：
Ziegler, M