PATHOPHYSIOLOGY IN HYPERAMMONEMIC SYNDROMES: THE MANY FACES OF GLUTAMINE
Roger F Butterworth PhD DSc.
Dept. of Medicine, University of Montreal and Neuroscience Research Unit, Hopital St-Luc (CHUM), 1058
St-Denis, Montreal, Qc, Canada H2X 3J4
The absence of effective hepatic clearance of excess ammonia in the form of urea, as occurs in urea
cycle enzymopathies (UCDs) and in several types of liver failure leads to increases in circulating and
tissue concentrations of glutamine. Studies using classical biochemical approaches or, more recently, 1H-NMR spectroscopy demonstrate a positive correlation between brain glutamine increases and the
severity of neurological symptoms in these disorders. These findings have led to the assumption that
increased brain glutamine synthesis rates are predictive of the severity of neurological complications as
a result of the osmotic effects of the amino acid on astrocyte cell volume regulation. Studies using
1H/13C NMR spectroscopy provide evidence of increased de novo synthesis of glutamine in brain in
acute hyperammonemia ; but increases of synthesis do not correlate with either the severity of
encephalopathy or with the presence of brain edema (Chatauret et al., Gastroenterol., 125, 815, 2003).
These findings led to the suggestion that the capacity of the brain to synthesize glutamine is limited in
hyperammonemic syndromes, and studies show that the mechanism responsible for this limitation
involves tyrosine nitration of the glutamine sythetase (GS) gene and protein involving NMDA receptoractivated nitric oxide production (Schliess et al., FASEB J., 16, 739, 2002).
In UCDs and in liver failure, skeletal muscle becomes the organ primarily responsible for removal of
excess ammonia and this adaptation results from post-translational induction of the GS gene and
protein in muscle (Chatauret et al., J Hepatol., 44, 1083, 2006). 13C-NMR studies confirm that the
increase in muscle glutamine synthesis involves both the pyruvate carboxylase and dehydrogenase
metabolic pathways. These alterations of inter-organ trafficking of ammonia and the particular
importance of muscle in its removal in conditions of urea cycle deficiency accounts for the current
resurgence of interest in (1) maintaining adequate dietary protein and (2) the use of L-ornithine Laspartate whose ammonia-lowering action involves primarily the stimulation of muscle glutamine
synthesis (Rose et al., Metab Brain Dis., 13, 24, 1998).
It is important to bear in mind that other metabolic and regulatory pathways may impact on ammonia
and/or glutamine homeostasis, particularly in the brain. These pathways include (1) glutamine
deamination by glutaminase, an enzyme with a predominantly neuronal localization, (2) glutamine
transaminase leading to the production of the neurotoxic metabolite, alpha-ketoglutaramate (AKGM),
and (3) recently cloned and characterized neuronal and astrocytic high affinity glutamate transporters
(SNATs). Surprisingly little attention has been given to date to the possibility that increases in circulating
and/or brain glutamine in hyperammonemic disorders could result from inhibition of glutaminase by its
product despite the fact that it has been demonstrated that neomycin lowers circulating ammonia levels
by inhibition of glutaminase rather than an action at the GI tract. One proposed new theory related to
the glutaminase pathway suggests that the accumulation of glutamine (“A Trojan Horse”) by the
astrocyte could afford an indirect pathway whereby ammonia is generated via the action of glutaminase
in the astrocyte (Albrecht and Norenberg, Hepatol., 44, 788, 2006). However, the theory has been
challenged on multiple grounds. The transaminase pathway has not been further investigated even
though concentrations of AKGM are increased in UCDs and in liver failure. On the other hand, findings of
a selective reduction in expression of the glutamine transporter SNAT-5 (responsible for glutamine exit
from the astrocyte) in a liver failure model has raised the issue of “glutamine trapping “within these cells
in hyperammonemia (Desjardins et al., ref). Such a trapping mechanism could explain the phenomenon
of cytotoxic brain edema and, given the key role that glutamine from the astrocyte plays as precursor of
neurotransmitter amino acids, could also contribute to the imbalance between excitatory and inhibitory
neurotransmission that is considered to occur in both UCDs and in liver failure.
Funded by the Canadian Institutes of Health Research