The discovery of human of GLUD2 glutamate dehydrogenase and its implications for cell function in health and disease.
The discovery of human of GLUD2 glutamate dehydrogenase and its implications for cell function in health and disease.
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GLUD2谷氨酸脱氢酶的人类发现及其对健康和疾病中细胞功能的影响。
DOI：
10.1007/s11064-013-1227-5
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发表时间：
2014
影响因子：
4.4
通讯作者：
Plaitakis, Andreas
中科院分区：
文献类型：
--
作者：
Shashidharan, Pullanipally;Plaitakis, Andreas
虽然导致人类独特特征的进化变化尚不清楚，但越来越多的证据表明，通过 DNA 复制过程丰富人类基因组可能有助于双足运动、更高的认知能力和语言等特征。 GLUD2是灵长类动物在大脑发育增强期间通过复制产生的基因之一，它编码在神经和其他组织中表达的谷氨酸脱氢酶的hGDH2亚型。 GDH 是谷氨酸代谢的核心酶，谷氨酸是哺乳动物大脑中主要的兴奋性神经递质，参与多种中枢神经系统功能，包括认知过程。在神经组织中，GDH 在包裹兴奋性突触的星形胶质细胞中表达，人们认为它在兴奋性传递过程中从突触间隙清除的谷氨酸的代谢命运中发挥作用。 GDH 的表达在出生后大脑发育过程中急剧上升，与神经末梢萌芽和突触发生同时发生。与被克雷布斯循环产生的 GTP 有效抑制的原始 hGDH1（由 GLUD1 基因编码）相比，hGDH2 可以独立于该能量开关发挥作用。此外，hGDH2 可以在星形胶质细胞摄取谷氨酸后相对酸性的环境中有效地发挥作用。这种适应被认为通过在强烈的兴奋性神经传递下增强酶催化来提供生物学优势。虽然这种新型蛋白质可能有助于星形胶质细胞处理增加的递质谷氨酸负荷，但 hGDH2 从 GTP 控制中解离可能会使人类容易受到这种酶功能失调的影响。在这里，我们将回顾新型 GLUD2 基因的克隆和表征，以及这一发现对理解允许表达 hGDH2 的大脑和其他器官微调其功能以满足新的挑战性需求的机制的潜在影响。此外，还将考虑 hGDH2 变体功能获得在人类神经退行性过程中的潜在作用。
While the evolutionary changes that led to traits unique to humans remain unclear, there is increasing evidence that enrichment of the human genome through DNA duplication processes may have contributed to traits such as bipedal locomotion, higher cognitive abilities and language. Among the genes that arose through duplication in primates during the period of increased brain development was GLUD2, which encodes the hGDH2 isoform of glutamate dehydrogenase expressed in neural and other tissues. GDH is an enzyme central to the metabolism of glutamate, the main excitatory neurotransmitter in mammalian brain involved in a multitude of CNS functions, including cognitive processes. In nerve tissue GDH is expressed in astrocytes that wrap excitatory synapses, where it is thought to play a role in the metabolic fate of glutamate removed from the synaptic cleft during excitatory transmission. Expression of GDH rises sharply during postnatal brain development, coinciding with nerve terminal sprouting and synaptogenesis. Compared to the original hGDH1 (encoded by the GLUD1 gene), which is potently inhibited by GTP generated by the Krebs cycle, hGDH2 can function independently of this energy switch. In addition, hGDH2 can operate efficiently in the relatively acidic environment that prevails in astrocytes following glutamate uptake. This adaptation is thought to provide a biological advantage by enabling enhanced enzyme catalysis under intense excitatory neurotransmission. While the novel protein may help astrocytes to handle increased loads of transmitter glutamate, dissociation of hGDH2 from GTP control may render humans vulnerable to deregulation of this enzyme’s function. Here we will retrace the cloning and characterization of the novel GLUD2 gene and the potential implications of this discovery in the understanding of mechanisms that permitted the brain and other organs that express hGDH2 to fine-tune their functions in order to meet new challenging demands. In addition, the potential role of gain-of-function of hGDH2 variants in human neurodegenerative processes will be considered.
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AMP激活的蛋白激酶对ULK1（HATG1）的磷酸化将能量传感连接到线粒体。
DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Egan DF;Shackelford DB;Mihaylova MM;Gelino S;Kohnz RA;Mair W;Vasquez DS;Joshi A;Gwinn DM;Taylor R;Asara JM;Fitzpatrick J;Dillin A;Viollet B;Kundu M;Hansen M;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
5.3
作者：
Levy, LM;Warr, O;Attwell, D
通讯作者：
Attwell, D
DOI：
10.1073/pnas.0911239106
发表时间：
2009-12-08
影响因子：
11.1
作者：
Goodman, Morris;Sterner, Kirstin N.;Wildman, Derek E.
通讯作者：
Wildman, Derek E.
影响因子：
9.8
作者：
GABRIEL, JL;ZERVOS, PR;PLAUT, GWE
通讯作者：
PLAUT, GWE
影响因子：
4.8
作者：
Borompokas, Nikolas;Papachatzaki, Maria-Martha;Plaitakis, Andreas
通讯作者：
Plaitakis, Andreas