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@ARTICLE{Frieg:877684,
      author       = {Frieg, Benedikt and Goerg, Boris and Qvartskhava, Natalia
                      and Jeitner, Thomas and Homeyer, Nadine and Häussinger,
                      Dieter and Gohlke, Holger},
      title        = {{M}echanism of fully-reversible, p{H}-sensitive inhibition
                      of human glutamine synthetase by tyrosine nitration},
      journal      = {Journal of chemical theory and computation},
      volume       = {16},
      number       = {7},
      issn         = {1549-9626},
      address      = {Washington, DC},
      reportid     = {FZJ-2020-02394},
      pages        = {4694–4705},
      year         = {2020},
      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.},
      cin          = {JSC / NIC / IBI-7},
      ddc          = {610},
      cid          = {I:(DE-Juel1)JSC-20090406 / I:(DE-Juel1)NIC-20090406 /
                      I:(DE-Juel1)IBI-7-20200312},
      pnm          = {511 - Computational Science and Mathematical Methods
                      (POF3-511) / Forschergruppe Gohlke $(hkf7_20170501)$},
      pid          = {G:(DE-HGF)POF3-511 / $G:(DE-Juel1)hkf7_20170501$},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:32551588},
      UT           = {WOS:000607532300058},
      doi          = {10.1021/acs.jctc.0c00249},
      url          = {https://juser.fz-juelich.de/record/877684},
}