Mechanism of Fully Reversible, pH-Sensitive Inhibition of Human Glutamine Synthetase by Tyrosine Nitration.,Journal of Chemical Theory and Computation

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Mechanism of Fully Reversible, pH-Sensitive Inhibition of Human Glutamine Synthetase by Tyrosine Nitration.
Journal of Chemical Theory and Computation ( IF 5.7 ) Pub Date : 2020-06-17 , DOI: 10.1021/acs.jctc.0c00249
Benedikt Frieg _{1,

2} , Boris Görg ₃ , Natalia Qvartskhava ₃ , Thomas Jeitner ₄ , Nadine Homeyer ₁ , Dieter Häussinger ₃ , Holger Gohlke _{1,

2}

Affiliation

Glutamine synthetase (GS) catalyzes an ATP-dependent condensation of glutamate and ammonia to form glutamine. This reaction—and therefore GS—are indispensable for the hepatic nitrogen metabolism. Nitration of tyrosine 336 (Y336) inhibits human GS activity. GS nitration and the consequent loss of GS function are associated with a broad range of neurological diseases. The mechanism by which Y336 nitration inhibits GS, however, is not understood. Here, we show by means of unbiased MD simulations, binding, and configurational free energy computations that Y336 nitration hampers ATP binding but only in the deprotonated and negatively charged state of residue 336. By contrast, for the protonated and neutral state, our computations indicate an increased binding affinity for ATP. pK_a computations of nitrated Y336 within GS predict a pK_a of ∼5.3. Thus, at physiological pH, nitrated Y336 exists almost exclusively in the deprotonated and negatively charged state. In vitro experiments confirm these predictions, in that, the catalytic activity of nitrated GS is decreased at pH 7 and 6 but not at pH 4. These results indicate a novel, fully reversible, pH-sensitive mechanism for the regulation of GS activity by tyrosine nitration.

中文翻译：

酪氨酸硝化完全可逆，pH敏感性抑制人谷氨酰胺合成酶的机理。

谷氨酰胺合成酶（GS）催化谷氨酸和氨的ATP依赖性缩合反应，形成谷氨酰胺。该反应以及因此的GS对于肝氮代谢是必不可少的。酪氨酸336（Y336）的硝化抑制人GS活性。GS硝化和随之而来的GS功能丧失与多种神经系统疾病有关。然而，尚不清楚Y336硝化抑制GS的机理。在这里，我们通过无偏的MD模拟，结合和构型自由能计算表明，Y336硝化会阻碍ATP结合，但仅在残基336的去质子化和带负电荷的状态下发生。相反，对于质子化和中性状态，我们的计算表明对ATP的结合亲和力增加。p ķ_一GS中硝化Y336的计算预测ap K _a约为5.3。因此，在生理pH下，硝化的Y336几乎仅以去质子且带负电荷的状态存在。体外实验证实了这些预测，因为在pH 7和6时硝化GS的催化活性会降低，而在pH 4时不会降低。这些结果表明，酪氨酸调节GS活性的新的，完全可逆的，pH敏感的机制。硝化作用

更新日期：2020-07-14

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