The role of glutamine synthetase and glutamate dehydrogenase in cerebral ammonia homeostasis.
The role of glutamine synthetase and glutamate dehydrogenase in cerebral ammonia homeostasis.
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DOI：
10.1007/s11064-012-0803-4
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发表时间：
2012-11
影响因子：
4.4
通讯作者：
Cooper, Arthur J. L.
中科院分区：
文献类型：
--
作者：
Cooper, Arthur J. L.
关键词：
在大脑中，谷氨酰胺合成酶（GS）主要位于星形胶质细胞中，在清除血液来源的和代谢产生的氨方面起主要作用。因此，利用[13N]氨进行的研究表明，约25%的血液来源的氨在单次通过大鼠大脑时被清除，并且这些氨主要在星形胶质细胞中被整合到谷氨酰胺（酰胺）中。大脑中产生氨的主要途径包括谷氨酰胺酶反应和谷氨酸脱氢酶（GDH）反应。体外谷氨酸脱氢酶催化反应的平衡位置在pH 7.4时有利于α - 酮戊二酸的还原胺化。然而，在大鼠大脑中，只有少量来自[13N]氨的标记物在体内被整合到谷氨酸和谷氨酰胺的α - 胺中。很可能大脑中的谷氨酸脱氢酶反应通常由于氨作为谷氨酰胺被快速清除而朝着谷氨酸氧化（产生氨）的方向进行。利用谷氨酸/α - 酮戊二酸的转氨酶与谷氨酸脱氢酶反应相联系，将多余的氨基酸氮导向氨以用于谷氨酰胺合成。然而，在高氨水平和/或当谷氨酰胺合成酶被抑制时，谷氨酸脱氢酶反应与谷氨酸/α - 酮戊二酸相关的转氨酶相结合，可能会促进氨氮向氨基酸合成的流动。初步证据表明，嘌呤核苷酸循环（PNC）作为神经元中氨的额外来源（净反应：L - 天冬氨酸+ GTP + H₂O → 富马酸+ GDP + Pi + NH₃）以及在室管膜纤毛的搏动周期中具有重要作用。嘌呤核苷酸循环与转氨酶以及谷氨酸脱氢酶/谷氨酰胺合成酶的联系，及其在正常和病理（例如高氨血症性脑病）条件下大脑氮代谢中的作用，应该是未来研究的一个有成效的领域。
In the brain, glutamine synthetase (GS), which is located predominantly in astrocytes, is largely responsible for the removal of both blood-derived and metabolically generated ammonia. Thus, studies with [13N]ammonia have shown that about 25% of blood-derived ammonia is removed in a single pass through the rat brain and that this ammonia is incorporated primarily into glutamine (amide) in astrocytes. Major pathways for cerebral ammonia generation include the glutaminase reaction and the glutamate dehydrogenase (GDH) reaction. The equilibrium position of the GDH-catalyzed reaction in vitro favors reductive amination of α-ketoglutarate at pH 7.4. Nevertheless, only a small amount of label derived from [13N]ammonia in rat brain is incorporated into glutamate and the α-amine of glutamine in vivo. Most likely the cerebral GDH reaction is drawn normally in the direction of glutamate oxidation (ammonia production) by rapid removal of ammonia as glutamine. Linkage of glutamate/α-ketoglutarate-utilizing aminotransferases with the GDH reaction channels excess amino acid nitrogen toward ammonia for glutamine synthesis. At high ammonia levels and/or when GS is inhibited the GDH reaction coupled with glutamate/α-ketoglutarate-linked aminotransferases may, however, promote the flow of ammonia nitrogen toward synthesis of amino acids. Preliminary evidence suggests an important role for the purine nucleotide cycle (PNC) as an additional source of ammonia in neurons (Net reaction: L-Aspartate + GTP + H2O → Fumarate + GDP + Pi + NH3) and in the beat cycle of ependyma cilia. The link of the PNC to aminotransferases and GDH/GS and its role in cerebral nitrogen metabolism under both normal and pathological (e.g. hyperammonemic encephalopathy) conditions should be a productive area for future research.
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影响因子：
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