当前位置： SCI文献检索 > Scientific Reports期刊下所有文献 > Allosteric regulation of glutamate dehydrogenase deamination activity.

Allosteric regulation of glutamate dehydrogenase deamination activity.

Abstract：

: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.

journal_name

Sci Rep

journal_title

Scientific reports

authors

Bera S,Rashid M,Medvinsky AB,Sun GQ,Li BL,Acquisti C,Sljoka A,Chakraborty A

doi

10.1038/s41598-020-73743-4

subject

Has Abstract

pub_date

2020-10-05 00:00:00

pages

16523

issue

issn

2045-2322

pii

10.1038/s41598-020-73743-4

journal_volume

pub_type

杂志文章

在线工具

Allosteric regulation of glutamate dehydrogenase deamination activity.