ArticlePLoS computational biology2016
Molecular Mechanisms of Glutamine Synthetase Mutations that Lead to Clinically Relevant Pathologies.
Article in PLoS computational biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 38 citations in OpenAlex.
- Product-stabilized filamentation by human glutamine synthetase allosterically tunes metabolic activity.eLife · 2026Article
- Cancer-associated TRF1 mutations alter PARP1 interaction dynamics: an in silico study.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Article
- Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy.Scientific reports · 2025Article
- Improving effects of melatonin on memory and synaptic potentiation in a mouse model of Alzheimer's-like disease: the involvement of glutamate homeostasis and mGluRs receptors.Behavioral and brain functions : BBF · 2025Article
- [Integrative transcriptomics-metabolomics approach to identify metabolic pathways regulated by glutamine synthetase activity].Se pu = Chinese journal of chromatography · 2025Article
- Glutamine Synthetase: Diverse Regulation and Functions of an Ancient Enzyme.Biochemistry · 2025Review
- SARS-CoV-2 Rapidly Infects Peripheral Sensory and Autonomic Neurons, Contributing to Central Nervous System Neuroinvasion before Viremia.International journal of molecular sciences · 2024Article
- Cryo-EM structures of lipidic fibrils of amyloid-β (1-40).Nature communications · 2024Article
- TMT-based comprehensive proteomic profiling identifies serum prognostic signatures of acute myeloid leukemia.Open medicine (Warsaw, Poland) · 2023Article
- The 3D structure of lipidic fibrils of α-synuclein.Nature communications · 2022Article
- Heliorhodopsin binds and regulates glutamine synthetase activity.PLoS biology · 2022Article
- Biophysical and pharmacokinetic characterization of a small-molecule inhibitor of RUNX1/ETO tetramerization with anti-leukemic effects.Scientific reports · 2022Article
- Aqueous ionic liquids redistribute local enzyme stability via long-range perturbation pathways.Computational and structural biotechnology journal · 2021Article
- Characterization of the nucleotide-binding domain NsrF from the BceAB-type ABC-transporter NsrFP from the human pathogen Streptococcus agalactiae.Scientific reports · 2020Article
- Article
- Amino acid synthesis deficiencies.Journal of inherited metabolic disease · 2017Review
- Complementary transcriptomic and proteomic analyses reveal regulatory mechanisms of milk protein production in dairy cows consuming different forages.Scientific reports · 2017Article
- Article
- Minireview on Glutamine Synthetase Deficiency, an Ultra-Rare Inborn Error of Amino Acid Biosynthesis.Biology · 2016Review
- Glutamine Synthetase Drugability beyond Its Active Site: Exploring Oligomerization Interfaces and Pockets.Molecules (Basel, Switzerland) · 2016Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Glutamine synthetase (GS) catalyzes ATP-dependent ligation of ammonia and glutamate to glutamine. Two mutations of human GS (R324C and R341C) were connected to congenital glutamine deficiency with severe brain malformations resulting in neonatal death. Another GS mutation (R324S) was identified in a neurologically compromised patient. However, the molecular mechanisms underlying the impairment of GS activity by these mutations have remained elusive. Molecular dynamics simulations, free energy calculations, and rigidity analyses suggest that all three mutations influence the first step of GS catalytic cycle. The R324S and R324C mutations deteriorate GS catalytic activity due to loss of direct interactions with ATP. As to R324S, indirect, water-mediated interactions reduce this effect, which may explain the suggested higher GS residual activity. The R341C mutation weakens ATP binding by destabilizing the interacting residue R340 in the apo state of GS. Additionally, the mutation is predicted to result in a significant destabilization of helix H8, which should negatively affect glutamate binding. This prediction was tested in HEK293 cells overexpressing GS by dot-blot analysis: Structural stability of H8 was impaired through mutation of amino acids interacting with R341, as indicated by a loss of masking of an epitope in the glutamate binding pocket for a monoclonal anti-GS antibody by L-methionine-S-sulfoximine; in contrast, cells transfected with wild type GS showed the masking. Our analyses reveal complex molecular effects underlying impaired GS catalytic activity in three clinically relevant mutants. Our findings could stimulate the development of ATP binding-enhancing molecules by which the R324S mutant can be repaired extrinsically.
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