NYMC Faculty Publications
Mechanism of Fully Reversible, pH-Sensitive Inhibition of Human Glutamine Synthetase by Tyrosine Nitration
DOI
10.1021/acs.jctc.0c00249
Journal Title
Journal of Chemical Theory and Computation
First Page
4694
Last Page
4705
Document Type
Article
Publication Date
7-14-2020
Department
Biochemistry and Molecular Biology
Abstract
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. p
Recommended Citation
Frieg, B., Görg, B., Qvartskhava, N., Jeitner, T., Homeyer, N., Häussinger, D., & Gohlke, H. (2020). Mechanism of Fully Reversible, pH-Sensitive Inhibition of Human Glutamine Synthetase by Tyrosine Nitration. Journal of Chemical Theory and Computation, 16 (7), 4694-4705. https://doi.org/10.1021/acs.jctc.0c00249
