Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich GmbH, D-52425 Jülich, Germany.
Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University Düsseldorf, D-40225 Düsseldorf, Germany.
Biol Chem. 2021 May 7;402(9):1063-1072. doi: 10.1515/hsz-2021-0166. Print 2021 Aug 26.
Glutamine synthetase (GS) in the liver is expressed in a small perivenous, highly specialized hepatocyte population and is essential for the maintenance of low, non-toxic ammonia levels in the organism. However, GS activity can be impaired by tyrosine nitration of the enzyme in response to oxidative/nitrosative stress in a pH-sensitive way. The underlying molecular mechanism as investigated by combined molecular simulations and experiments indicates that tyrosine nitration can lead to a fully reversible and pH-sensitive regulation of protein function. This approach was also used to understand the functional consequences of several recently described point mutations of human GS with clinical relevance and to suggest an approach to restore impaired GS activity.
肝组织中的谷氨酰胺合成酶（GS）表达于小静脉周围的一小部分高度特化的肝细胞中，对于维持机体内低水平、无毒的氨至关重要。然而，GS 酶的活性可因氧化/硝化应激导致的酪氨酸硝化而受到抑制，这种抑制作用具有 pH 敏感性。通过组合分子模拟和实验研究的方法，我们研究了潜在的分子机制，结果表明酪氨酸硝化可以导致蛋白功能的完全可逆且 pH 敏感的调节。该方法还被用于研究与临床相关的人类 GS 基因的几个最近报道的点突变的功能后果，并提出了一种恢复受损 GS 活性的方法。
