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The Role of Glutamine Synthetase and Glutamate Dehydrogenase in Cerebral Ammonia Homeostasis

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Abstract

In the brain, glutamine synthetase (GS), which is located predominantly in astrocytes, is largely responsible for the removal of both blood-derived and metabolically generated ammonia. Thus, studies with [13N]ammonia have shown that about 25 % of blood-derived ammonia is removed in a single pass through the rat brain and that this ammonia is incorporated primarily into glutamine (amide) in astrocytes. Major pathways for cerebral ammonia generation include the glutaminase reaction and the glutamate dehydrogenase (GDH) reaction. The equilibrium position of the GDH-catalyzed reaction in vitro favors reductive amination of α-ketoglutarate at pH 7.4. Nevertheless, only a small amount of label derived from [13N]ammonia in rat brain is incorporated into glutamate and the α-amine of glutamine in vivo. Most likely the cerebral GDH reaction is drawn normally in the direction of glutamate oxidation (ammonia production) by rapid removal of ammonia as glutamine. Linkage of glutamate/α-ketoglutarate-utilizing aminotransferases with the GDH reaction channels excess amino acid nitrogen toward ammonia for glutamine synthesis. At high ammonia levels and/or when GS is inhibited the GDH reaction coupled with glutamate/α-ketoglutarate-linked aminotransferases may, however, promote the flow of ammonia nitrogen toward synthesis of amino acids. Preliminary evidence suggests an important role for the purine nucleotide cycle (PNC) as an additional source of ammonia in neurons (Net reaction: l-Aspartate + GTP + H2O → Fumarate + GDP + Pi + NH3) and in the beat cycle of ependyma cilia. The link of the PNC to aminotransferases and GDH/GS and its role in cerebral nitrogen metabolism under both normal and pathological (e.g. hyperammonemic encephalopathy) conditions should be a productive area for future research.

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Notes

  1. Ammonia free base (NH3) has a pK a of ~9.2. Thus, under normal intracellular physiological conditions (pH 7.2–7.4) ammonia exists predominantly (~99 %) as the conjugate acid, ammonium (NH4 +). For convenience, unless otherwise stated, the term ammonia is used throughout the text to indicate the sum of NH3 plus NH4 +.

  2. This finding appears to have been the basis for the model developed by the Shulman laboratory for the NMR measurement of TCA flux using [13C]glucose cf. [11, 31, 32]. Due to the very rapid exchange of nitrogen in the AAT reaction (considerably faster than carbon flux through the TCA cycle) label in glutamate is a good proxy for that in the much smaller pool of α-ketoglutarate.

Abbreviations

AAT:

Aspartate aminotransferase

AMP:

Adenosine monophosphate

BBB:

Blood–brain barrier

BCA:

Branched-chain amino acid

BUI:

Brain uptake index

cAAT:

Cytosolic aspartate aminotransferase

CSF:

Cerebrospinal fluid

GDH:

Glutamate dehydrogenase

GS:

Glutamine synthetase

HE:

Hepatic encephalopathy

HPLC:

High performance liquid chromatography

IMP:

Inosine monophosphate

mAAAT:

Mitochondrial aspartate aminotransferase

MAS:

Malate-aspartate shuttle

MSKCC:

Memorial Sloan Kettering Cancer center

NMR:

Nuclear magnetic resonance

MSO:

l-Methionine-S,R-sulfoximine

PCS:

Portacaval shunt

PET:

Positron emission tomography

TCA:

Tricarboxylic acid

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Acknowledgments

I thank Dr. Boris Krasnikov (New York Medical College) for his help in preparing this manuscript. I also thank Dr. Kevin Behar (Yale University School of Medicine) for valuable discussion. Part of the work described in this review was supported by NIH grant DK 16739.

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  1. Department of Biochemistry and Molecular Biology, New York Medical College, 15 Dana Road, Valhalla, NY, 10595, USA

    Arthur J. L. Cooper

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Correspondence to Arthur J. L. Cooper.

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Special Issue: in honour of Leif Hertz.

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Cooper, A.J.L. The Role of Glutamine Synthetase and Glutamate Dehydrogenase in Cerebral Ammonia Homeostasis. Neurochem Res 37, 2439–2455 (2012). https://doi.org/10.1007/s11064-012-0803-4

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