Role of Branched‐Chain Aminotransferase Isoenzymes and Gabapentin in Neurotransmitter Metabolism
Abstract
Abstract: Because it is well known that excess branched‐chain amino acids (BCAAs) have a profound influence on neurological function, studies were conducted to determine the impact of BCAAs on neuronal and astrocytic metabolism and on trafficking between neurons and astrocytes. The first step in the metabolism of BCAAs is transamination with α‐ketoglutarate to form the branched‐chain α‐keto acids (BCKAs). The brain is unique in that it expresses two separate branched‐chain aminotransferase (BCAT) isoenzymes. One is the common peripheral form [mitochondrial (BCATm)], and the other [cytosolic (BCATc)] is unique to cerebral tissue, placenta, and ovaries. Therefore, attempts were made to define the isoenzymes' spatial distribution and whether they might play separate metabolic roles. Studies were conducted on primary rat brain cell cultures enriched in either astroglia or neurons. The data show that over time BCATm becomes the predominant isoenzyme in astrocyte cultures and that BCATc is prominent in early neuronal cultures. The data also show that gabapentin, a structural analogue of leucine with anticonvulsant properties, is a competitive inhibitor of BCATc but that it does not inhibit BCATm. Metabolic studies indicated that BCAAs promote the efflux of glutamine from astrocytes and that gabapentin can replace leucine as an exchange substrate. Studying astrocyte‐enriched cultures in the presence of [U‐14 C]glutamate we found that BCKAs, but not BCAAs, stimulate glutamate transamination to α‐ketoglutarate and thus irreversible decarboxylation of glutamate to pyruvate and lactate, thereby promoting glutamate oxidative breakdown. Oxidation of glutamate appeared to be largely dependent on the presence of an α‐keto acid acceptor for transamination in astrocyte cultures and independent of astrocytic glutamate dehydrogenase activity. The data are discussed in terms of a putative BCAA/BCKA shuttle, where BCATs and BCAAs provide the amino group for glutamate synthesis from α‐ketoglutarate via BCATm in astrocytes and thereby promote glutamine transfer to neurons, whereas BCATc reaminates the amino acids in neurons for another cycle.
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Cooper, A. J. L., Bruschi, S. A., Conway, M. E., & Hutson, S. M. (2002) · Biochemical Pharmacology · doi:10.1016/s0006-2952(02)01513-7 · Cited by 29 · see citing works
Self-citationDrug safety evaluation of pregabalin
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“In vitro, gabapentinoids modulate the concentrations of GABA, without effect on the enzyme glutamic acid decarboxylase (GAD), but with effect on the glutamate synthesizing enzyme, branched-chain amino acid transaminase (cytosolic form) [35,36].”
BackgroundMammalian Branched-Chain Aminotransferases
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“The hBCATm is expressed in body tissues, whereas hBCATc was localized primarily in the central nervous system (11, 25, 61).”
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“The activity of LDH (E.C. 1.1.1.27) was performed by means of the nitroblue tetrazolium technique described by Jacobsen (1969) and modified by Borowsky and Collins (1989).”
MethodInfluentialAnanieva, E. A., Horn, C. G. V., Jones, M. R., & Hutson, S. M. (2016) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2016.10.014 · Cited by 24 · see citing works
“Additionally, BCAAs contribute nitrogen to the Glu-Gln shuttle between neurons and astrocytes in the brain and Glu and Ala metabolism between skeletal muscle and liver [3,16].”
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Prophylactic use of gabapentin for prevention of succinylcholine-induced fasciculation and myalgia
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Emerging Moonlighting Functions of the Branched-Chain Aminotransferase Proteins
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“A vast body of work has supported a role for these proteins in amino acid metabolism and whole-body nitrogen shuttling (74).”
Branched-Chain Amino Acids and Seizures: A Systematic Review of the Literature
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Altered Metabolic Profiles Associate with Toxicity in SOD1G93A Astrocyte-Neuron Co-Cultures
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Proteomic Studies of Pediatric Medulloblastoma Tumors with 17p Deletion
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“The importance of investigating BCAAs as amino-group nitrogen donors for synthesis of vesicular glutamate is supported by the fact that gabapentin, an anticonvulsant drug used to treat epilepsy and neuropathic pain, inhibits neuronal cytosolic branched-chain aminotransferase (BCATcyt; Hutson et al., 1998; Goto et al.,…”
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- Authors
- Hutson, S. M., Berkich, D., Drown, P., Xu, B., Aschner, M., & LaNoue, K. F.
- Affiliations
- Wake Forest University Health Sciences (US)
- Pennsylvania State University (US)
- Corresponding author
- Hutson, S. M.
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 1998-08
- Volume
- 71
- Issue
- 2
- Pages
- 863-874
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W1976456720
- Cited by
- 171
- References
- 0
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 4 · 2023: 5 · 2022: 4 · 2020: 6 · 2019: 7 · 2018: 7 · 2017: 7 · 2016: 8 · 2015: 5 · 2014: 6 · 2013: 8 · 2012: 8
- FWCI
- 3.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK34738)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- branched-chain amino acid aminotransferase, branched-chain amino acids, branched-chain α-keto acids, gabapentin, glutamate metabolism, astrocytes, neurons, alpha-ketoglutarate, leucine, neurotransmitter metabolism, isoenzyme distribution
- MeSH terms
- Gabapentin, Acetates, Amines, Transaminases, Animals, Animals, Newborn, Anticonvulsants, Astrocytes, Carbon Radioisotopes, Cells, Cultured, Cerebral Cortex, Cyclohexanecarboxylic Acids, gamma-Aminobutyric Acid, Humans, Isoenzymes, Ketone Oxidoreductases, Mitochondria, Multienzyme Complexes, Neurons, Oxidation-Reduction, Rats, Sprague-Dawley, Neurotransmitter Agents, Glutamic Acid, 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide), Rats
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