Anaplerosis for Glutamate Synthesis in the Neonate and in Adulthood

Abstract

A central task of the tricarboxylic acid (TCA, Krebs, citric acid) cycle in brain is to provide precursors for biosynthesis of glutamate, GABA, aspartate and glutamine. Three of these amino acids are the partners in the intricate interaction between astrocytes and neurons and form the so-called glutamine-glutamate (GABA) cycle. The ketoacids α-ketoglutarate and oxaloacetate are removed from the cycle for this process. When something is removed from the TCA cycle it must be replaced to permit the continued function of this essential pathway, a process termed anaplerosis. This anaplerotic process in the brain is mainly carried out by pyruvate carboxylation performed by pyruvate carboxylase. The present book chapter gives an introduction and overview into this carboxylation and additionally anaplerosis mediated by propionyl-CoA carboxylase under physiological conditions in the adult and in the developing rodent brain. Furthermore, examples are given about pathological conditions in which anaplerosis is disturbed.

Regulation of Neurotransmitters by the Gut Microbiota and Effects on Cognition in Neurological Disorders

“…Glutamate, the most abundant excitatory neurotransmitter in the brain, is responsible for sending signals between nerve cells [ 34 ]. As glutamate cannot pass through the blood–brain barrier, its synthesis in the brain depends on the cooperation between neurons and astrocytes, which utilize the intermediate metabolites of the tricarboxylic acid cycle as precursors [ 35 ]. However, elsewhere in the body—for example, the intestinal tract—cells other than neurons can also produce glutamate.…”

Carbonic Anhydrases: Role in pH Control and Cancer

“…This limits ATP production via oxidative phosphorylation but increases ATP production by glycolysis [ 71 ]. There is evidence that oxidative phosphorylation is supported by anepleurotic reactions particularly through glutamate dehydrogenase, which converts glutamate (derived from glutamine) to α-ketoglutarate another commonly observed metabolic alteration in cancer [ 72 , 73 , 74 ]. Additionally, glycolysis supports the synthesis of phospholipids by providing the glycerol phosphate backbone via the glycolytic intermediate, dihydroxycetone phosphate.…”

Towards an Understanding of Energy Impairment in Huntington’s Disease Brain

“…Their (dys)regulation could contribute to either pathogenic or compensatory shifts in energy production. Astrocyte glutamate synthesis derives from flux through pyruvate carboxylase, an enzyme only found in astrocytes, forming an anaplerotic pathway into TCA [ 97–99 ]. While flux analysis tracing carbon movement through this pathway [ 100 ] has not been done on HD models, pyruvate carboxylase protein levels were found to be elevated in cultured astrocytes from neonatal BACHD cortex [ 101 ], consistent with an increased flux through TCA and increased production of glial glutamate in presymptomatic brain.…”