Metabolism of amino acid neurotransmitters: the synaptic disorder underlying inherited metabolic diseases

AbstractAmino acids are involved in various metabolic pathways and some of them also act as neurotransmitters. Since biosynthesis ofl-glutamate and γ-aminobutyric acid (GABA) requires 2-oxoglutarate while 3-phosphoglycerate is the precursor ofl-glycine andd-serine, evolutionary selection of these amino acid neurotransmitters might have been driven by their capacity to provide important information about the glycolytic pathway and Krebs cycle. Synthesis and recycling of amino acid neurotransmitters as well as composition and function of their receptors are often compromised in inherited metabolic diseases. For instance, increased plasmal-phenylalanine concentrations impair cerebral biosynthesis of protein and bioamines in phenylketonuria, while elevated cerebrall-phenylalanine directly acts via ionotropic glutamate receptors. In succinic semialdehyde dehydrogenase deficiency, the neurotransmitter GABA and neuromodulatory γ-hydroxybutyric acid are elevated. Chronic hyperGABAergic state results in progressive downregulation of GABAA and GABAB receptors and impaired mitophagy. In glycine encephalopathy, the neurological phenotype is precipitated byl-glycine acting both via cortical NMDA receptors and glycine receptors in spinal cord and brain stem neurons. Serine deficiency syndromes are biochemically characterized by decreased biosynthesis ofl-serine, an important neurotrophic factor, and the neurotransmittersd-serine andl-glycine. Supplementation withl-serine andl-glycine has...
Source: Journal of Inherited Metabolic Disease - Category: Internal Medicine Source Type: research