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BCAA Metabolism and NH3 Homeostasis

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The Glutamate/GABA-Glutamine Cycle

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 13))

Abstract

The branched chain amino acids (BCAA) are essential amino acids required not only for growth and development, but also as nutrient signals and as nitrogen donors to neurotransmitter synthesis and glutamate/glutamine cycling. Transamination and oxidative decarboxylation of the BCAAs are catalysed by the branched-chain aminotransferase proteins (BCATm, mitochondrial and BCATc, cytosolic) and the branched-chain α-keto acid dehydrogenase enzyme complex (BCKDC), respectively. These proteins show tissue, cell compartmentation, and protein–protein interactions, which call for substrate shuttling or channelling and nitrogen transfer for oxidation to occur. Efficient regulation of these pathways is mediated through the redox environment and phosphorylation in response to dietary and hormonal stimuli. The wide distribution of these proteins allows for effective BCAA utilisation. We discuss how BCAT, BCKDC, and glutamate dehydrogenase operate in supramolecular complexes, allowing for efficient channelling of substrates. The role of BCAAs in brain metabolism is highlighted in rodent and human brain, where differential expression of BCATm indicates differences in nitrogen metabolism between species. Finally, we introduce a new role for BCAT, where a change in function is triggered by oxidation of its redox-active switch. Our understanding of how BCAA metabolism and nitrogen transfer is regulated is important as many studies now point to BCAA metabolic dysregulation in metabolic and neurodegenerative conditions.

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Abbreviations

AGC:

Malate/aspartate carrier

ALT:

Alanine aminotransferase

BCAA:

Branched chain amino acids

BCAT:

Branched chain aminotransferase

BCKA:

Branched chain α-keto acid

BCKDC:

Branched-chain α-keto acid dehydrogenase enzyme complex

E1:

Branched chain α-keto acid dehydrogenase

E2:

Dihydrolpoyl transacylase subunits

E3:

Dihydrolipoyl dehydrogenase

GABA:

Îł-Amino butyric acid

GDH:

Glutamate dehydrogenase

GS:

Glutamine synthetase

GSNO:

S-nitrosoglutathione

KG:

α-Ketoglutarate

KIC:

α-Ketoisocaproate

KIV:

α-Ketoisovalerate

KMV:

α-Keto-β-methylvalerate

MDH:

Malate dehydrogenase

ME:

Malic enzyme

MSUD:

Maple syrup urine disease

mTOR:

The mechanistic target of rapamycin

PLP:

Pyridoxal phosphate

PMP:

Pyridoxamine

TPP:

Thiamine pyrophosphate

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Authors and Affiliations

  1. Department of Applied Sciences, University of the West of England, Coldharbour Lane, Bristol, BS16 1QY, UK

    M. E. Conway

  2. Department of Human Nutrition, Foods and Exercise, Integrated Life Sciences Building (0913), 1981 Kraft Drive, Blacksburg, VA, 24060, USA

    S. M. Hutson

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  1. M. E. Conway
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  2. S. M. Hutson
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Correspondence to M. E. Conway .

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  1. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Arne Schousboe

  2. Department of Neuroscience, Norwegian University of Science and Technology (NTNU), Trondheim, Norway

    Ursula Sonnewald

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Conway, M.E., Hutson, S.M. (2016). BCAA Metabolism and NH3 Homeostasis. In: Schousboe, A., Sonnewald, U. (eds) The Glutamate/GABA-Glutamine Cycle. Advances in Neurobiology, vol 13. Springer, Cham. https://doi.org/10.1007/978-3-319-45096-4_5

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