Carboxylation and anaplerosis in neurons and glia

Mol Neurobiol. Aug-Dec 2000;22(1-3):21-40. doi: 10.1385/MN:22:1-3:021.


Anaplerosis, or de novo formation of intermediates of the tricarboxylic acid (TCA) cycle, compensates for losses of TCA cycle intermediates, especially alpha-ketoglutarate, from brain cells. Loss of alpha-ketoglutarate occurs through release of glutamate and GABA from neurons and through export of glutamine from glia, because these amino acids are alpha-ketoglutarate derivatives. Anaplerosis in the brain may involve four different carboxylating enzymes: malic enzyme, phosphoenopyruvate carboxykinase (PEPCK), propionyl-CoA carboxylase, and pyruvate carboxylase. Anaplerotic carboxylation was for many years thought to occur only in glia through pyruvate carboxylase; therefore, loss of transmitter glutamate and GABA from neurons was thought to be compensated by uptake of glutamine from glia. Recently, however, anaplerotic pyruvate carboxylation was demonstrated in glutamatergic neurons, meaning that these neurons to some extent can maintain transmitter synthesis independently of glutamine. Malic enzyme, which may carboxylate pyruvate, was recently detected in neurons. The available data suggest that neuronal and glial pyruvate carboxylation could operate at as much as 30% and 40-60% of the TCA cycle rate, respectively. Cerebral carboxylation reactions are probably balanced by decarboxylation reactions,, because cerebral CO2 formation equals O2 consumption. The finding of pyruvate carboxylation in neurons entails a major revision of the concept of the glutamine cycle.

Publication types

  • Review

MeSH terms

  • Acyl Coenzyme A / metabolism
  • Adenosine Triphosphate / metabolism
  • Animals
  • Artifacts
  • Brain / metabolism*
  • Carbon Dioxide / metabolism
  • Carbon-Carbon Ligases / metabolism
  • Carboxy-Lyases / metabolism
  • Citric Acid Cycle*
  • Fatty Acids / metabolism
  • Glutamic Acid / biosynthesis
  • Glutamine / metabolism
  • Humans
  • Isotope Labeling
  • Ketoglutaric Acids / metabolism
  • Magnetic Resonance Spectroscopy
  • Malate Dehydrogenase / metabolism
  • Methylmalonyl-CoA Decarboxylase
  • Nerve Tissue Proteins / metabolism*
  • Neuroglia / metabolism*
  • Neurons / metabolism*
  • Phosphoenolpyruvate Carboxykinase (ATP) / metabolism
  • Protein Processing, Post-Translational
  • Pyruvate Carboxylase / metabolism
  • Pyruvic Acid / metabolism
  • gamma-Aminobutyric Acid / biosynthesis


  • Acyl Coenzyme A
  • Fatty Acids
  • Ketoglutaric Acids
  • Nerve Tissue Proteins
  • Glutamine
  • Carbon Dioxide
  • propionyl-coenzyme A
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Pyruvic Acid
  • Adenosine Triphosphate
  • Malate Dehydrogenase
  • Carboxy-Lyases
  • Phosphoenolpyruvate Carboxykinase (ATP)
  • Carbon-Carbon Ligases
  • glutamyl carboxylase
  • Pyruvate Carboxylase
  • Methylmalonyl-CoA Decarboxylase