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

Benedikt Frieg,Dieter Häussinger,Holger Gohlke,Boris Görg

doi:10.1515/hsz-2021-0166

Benedikt Frieg, Dieter Häussinger + Show 2 more

Open Access

https://doi.org/10.1515/hsz-2021-0166

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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.

Highlights

There is a sophisticated structural and functional organization of ammonia and glutamine metabolizing pathways in the liver acinus (Häussinger 1983)
In the liver acinus, glutamine is hydrolyzed in periportal hepatocytes, whereas it is resynthesized by perivenous hepatocytes from the ammonia left over by periportal urea synthesis (Figure 1)
This is the so-called intercellular glutamine cycle, whose regulation is essential for the maintenance of bicarbonate and ammonia homeostasis in the organism

Summary

Introduction

There is a sophisticated structural and functional organization of ammonia and glutamine metabolizing pathways in the liver acinus (Häussinger 1983) (for review see Häussinger 1990). In the liver acinus, glutamine is hydrolyzed in periportal hepatocytes, whereas it is resynthesized by perivenous hepatocytes from the ammonia left over by periportal urea synthesis (Figure 1) This is the so-called intercellular glutamine cycle, whose regulation is essential for the maintenance of bicarbonate and ammonia homeostasis in the organism. Perivenous scavenger cells are well equipped for their task to eliminate ammonia with high affinity through glutamine synthesis They are the only hepatocytes expressing the ammonium transporter RhBG, the glutamate/aspartate transporter Glt, ornithine aminotransferase (OAT), and take up glutamate and related dicarboxylates (Cadoret et al 2002; Ginguay et al 2017; Kuo et al 1991; Stoll and Häussinger 1991; Weiner et al 2003) (Figure 1). This study suggested that GS-positive hepatocytes may not be uniform, but may comprise subpopulations, because immunohistochemistry showed that only 50–70% of the GS-expressing hepatocytes expressed Hsp and BTF3 (Paluschinski et al 2021)

Liver glutamine synthesis and ammonium homeostasis

GS and protein tyrosine nitration

Congenital GS deficiency

Concluding remarks