|Topic:||γ-Aminobutyric Acid (GABA) from Glutamate .|
|Details:||The amino acid derivative, γ-aminobutyrate (GABA; also called 4-aminobutyrate) is a major inhibitory neurotransmitter responsible for the regulation of presynaptic transmission in the CNS, and also in the retina. Neurons that secrete GABA are termed GABAergic. GABA cannot cross the blood-brain-barrier and as such must be synthesized within neurons in the CNS. The synthesis of GABA in the brain occurs via a metabolic pathway referred to as the GABA shunt. Glucose is the principal precursor for GABA production via its conversion to α-ketoglutarate in the TCA cycle. Within the context of the GABA shunt the α-ketoglutarate is transaminated to the amino acid glutamate by GABA α-oxoglutarate transaminase (GABA-T). Glutamic acid decarboxylase (GAD) catalyzes the decarboxylation of glutamic acid to form GABA. There are two GAD genes in humans identified as GAD1 and GAD2. The GAD isoforms produced by these two genes are identified as GAD67 (GAD1 gene: GAD67) and GAD65 (GAD2 gene: GAD65) which is reflective of their molecular weights. Both the GAD1 and GAD2 genes are expressed in the brain and GAD2 expression also occurs in the pancreas. The activity of GAD requires pyridoxal phosphate (PLP) as a cofactor. PLP is generated from the B6 vitamins (pyridoxine, pyridoxal, and pyridoxamine) through the action of pyridoxal kinase. Pyridoxal kinase itself requires zinc for activation. A deficiency in zinc or defects in pyridoxal kinase can lead to seizure disorders, particularly in seizure-prone pre-eclamptic patients (hypertensive condition in late pregnancy). The presence of anti-GAD antibodies (both anti-GAD65 and anti-GAD67) is a strong predictor of the future development of type 1 diabetes in high-risk populations.|
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