Role of branched-chain aminotransferase isoenzymes and gabapentin in neurotransmitter metabolism.
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 alpha-ketoglutarate to form the branched-chain alpha-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-14C]glutamate we found that BCKAs, but not BCAAs, stimulate glutamate transamination to alpha-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 alpha-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 alpha-ketoglutarate via BCATm in astrocytes and thereby promote glutamine transfer to neurons, whereas BCATc reaminates the amino acids in neurons for another cycle.
Department of Biochemistry, Wake Forest University Medical School, Winston-Salem, North Carolina 27157, USA.
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Hutson
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Berkich
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Drown
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Xu
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Aschner
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LaNoue
D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D000085:Acetates / Q000494:pharmacology*; D000588:Amines; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology*; D001253:Astrocytes / Q000166:cytology / Q000201:enzymology; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003509:Cyclohexanecarboxylic Acids; D000077206:Gabapentin; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D007658:Ketone Oxidoreductases / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology; D009097:Multienzyme Complexes / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000201:enzymology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D000637:Transaminases / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D000927:Anticonvulsants; D002250:Carbon Radioisotopes; D003509:Cyclohexanecarboxylic Acids; D007527:Isoenzymes; D009097:Multienzyme Complexes; D018377:Neurotransmitter Agents; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D007658:Ketone Oxidoreductases; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D000637:Transaminases; C019798:branched-chain-amino-acid transaminase