Allosteric regulation of glutamate dehydrogenase deamination activity

Glutamate dehydrogenase (GDH) is a key enzyme interlinking carbon and nitrogen metabolism. Recent discoveries of the GDH specific role in breast cancer, hyperinsulinism/hyperammonemia (HI/HA) syndrome, and neurodegenerative diseases have reinvigorated interest on GDH regulation, which remains poorly...

Celý popis

Uloženo v:

Podrobná bibliografie
Vydáno v:	Scientific reports Ročník 10; číslo 1; s. 16523
Hlavní autoři:	Bera, Soumen, Rashid, Mubasher, Medvinsky, Alexander B., Sun, Gui-Quan, Li, Bai-Lian, Acquisti, Claudia, Sljoka, Adnan, Chakraborty, Amit
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 05.10.2020 Nature Publishing Group
Témata:	631/114 631/57 631/57/2265 631/57/2266 631/57/2272 Active sites Adenosine Diphosphate - metabolism Allosteric properties Allosteric Regulation - physiology Biophysics - methods Breast cancer Computational Biology - methods Cryoelectron Microscopy - methods Deamination Dehydrogenase Dehydrogenases Electron microscopy Enzymatic activity Glutamate dehydrogenase Glutamate Dehydrogenase - metabolism Glutamate Dehydrogenase - ultrastructure Guanosine Triphosphate - metabolism Humanities and Social Sciences Hyperammonemia Hyperammonemia - genetics Models, Molecular Molecular Docking Simulation - methods multidisciplinary Mutagenesis Mutation - drug effects NAD - metabolism NADH Neurodegenerative diseases Protein Conformation Regulation Science Science (multidisciplinary) Structural analysis
ISSN:	2045-2322, 2045-2322
On-line přístup:	Získat plný text
Tagy:	Přidat tag Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!

Popis
Shrnutí:	Glutamate dehydrogenase (GDH) is a key enzyme interlinking carbon and nitrogen metabolism. Recent discoveries of the GDH specific role in breast cancer, hyperinsulinism/hyperammonemia (HI/HA) syndrome, and neurodegenerative diseases have reinvigorated interest on GDH regulation, which remains poorly understood despite extensive and long standing studies. Notwithstanding the growing evidence of the complexity of allosteric network behind GDH regulation, identifications of allosteric factors and associated mechanisms are paramount to deepen our understanding of the complex dynamics that regulate GDH enzymatic activity. Combining structural analyses of cryo-electron microscopy data with molecular dynamic simulations, here we show that the cofactor NADH is a key player in the GDH regulation process. Our structural analysis indicates that, binding to the regulatory sites in proximity of the antenna region, NADH acts as a positive allosteric modulator by enhancing both the affinity of the inhibitor GTP binding and inhibition of GDH catalytic activity. We further show that the binding of GTP to the NADH-bound GDH activates a triangular allosteric network, interlinking the inhibitor with regulatory and catalytic sites. This allostery produces a local conformational rearrangement that triggers an anticlockwise rotational motion of interlinked alpha-helices with specific tilted helical extension. This structural transition is a fundamental switch in the GDH enzymatic activity. It introduces a torsional stress, and the associated rotational shift in the Rossmann fold closes the catalytic cleft with consequent inhibition of the deamination process. In silico mutagenesis examinations further underpin the molecular basis of HI/HA dominant mutations and consequent over-activity of GDH through alteration of this allosteric communication network. These results shed new light on GDH regulation and may lay new foundation in the design of allosteric agents.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-020-73743-4