Glutamine synthetase as a central element in hepatic glutamine and ammonia metabolism: novel aspects

Abstract

Glutamine synthetase (GS) in the liver is expressed in a small perivenous, highly specialized hepatocyte population and is essential for the maintenance of low, non-toxic ammonia levels in the organism. However, GS activity can be impaired by tyrosine nitration of the enzyme in response to oxidative/nitrosative stress in a pH-sensitive way. The underlying molecular mechanism as investigated by combined molecular simulations and in vitro experiments indicates that tyrosine nitration can lead to a fully reversible and pH-sensitive regulation of protein function. This approach was also used to understand the functional consequences of several recently described point mutations of human GS with clinical relevance and to suggest an approach to restore impaired GS activity.

Protein Tyrosine Nitration in Plant Nitric Oxide Signaling

“…These enzymes enable the initial N incorporation to the amino acids Gln, Glu, Asn, and Asp assimilation, but also GS has been identified as targets of nitration (Lozano-Juste et al, 2011). GS enzymes from mammals and fungi seem to be nitrated and inactivated, thus affecting the metabolism of Glu and ammonia in liver (Frieg et al, 2021) and the secondary metabolism in fungi (Zhu et al, 2021), respectively. Plant GDH seem to be involved mainly in Glu oxidation to supply cells with carbon skeletons under carbon limiting conditions (Robinson et al, 1991).…”

Asparagine protects pericentral hepatocytes during acute liver injury

“…Hepatic glutamine metabolism represents another highly zonated process where glutamine synthesis occurs through the catalytic action of glutamate-ammonia ligase (GLUL, also known as glutamine synthetase, [GS]), an enzyme whose expression is confined to a layer of hepatocytes surrounding the central veins, known as scavenger cells (reviewed in ref. 11 ). While glutamine synthesis from glutamate appears to be an efficient and required mechanism to capture ammonia ( 12 ), the fate of glutamine synthesized at high rates in the pericentral zone is unclear.…”

Overweight/Obesity Increases the Risk of Overt Hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt in Cirrhotic Patients

“…While the pathophysiology of HE is not entirely understood, ammonia and inflammation are considered two major pathogeneses of HE. The capacity of hepatocytes to eliminate ammonia is impaired in liver cirrhosis, and hyperammonemia ensues, leading to excess ammonia across the blood-brain barrier, the accumulation of intra-astrocytic glutamine, and low-grade cerebral oedema [13][14][15]. Inflammatory factors and hyperammonemia synergistically contribute to astrocytic and neuronal dysfunction, leading to alterations in synaptic plasticity and oscillatory networks; thus, HE-related neurologic symptoms occur [16,17].…”