Journal Article

FZJ-2020-02394

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Mechanism of fully-reversible, pH-sensitive inhibition of human glutamine synthetase by tyrosine nitration

Frieg, B.FZJ* ; Goerg, B. ; Qvartskhava, N. ; Jeitner, T. ; Homeyer, N. ; Häussinger, D. ; Gohlke, H. (Corresponding author)FZJ*

2020
Washington, DC

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Please use a persistent id in citations: http://hdl.handle.net/2128/25278  doi:10.1021/acs.jctc.0c00249

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. pKa computations of nitrated Y336 within GS predict a pKa 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 pH 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.

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Contributing Institute(s):

1. Jülich Supercomputing Center (JSC)
2. John von Neumann - Institut für Computing (NIC)
3. Strukturbiochemie (IBI-7)

Research Program(s):

1. 511 - Computational Science and Mathematical Methods (POF3-511) (POF3-511)
2. Forschergruppe Gohlke (hkf7_20170501) (hkf7_20170501)

Appears in the scientific report 2020

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Database coverage:
; ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; Essential Science Indicators ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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