Glutamate decarboxylase
[3] Together, these two enzymes maintain the major physiological supply of GABA in mammals,[2] though it may also be synthesized from putrescine in the enteric nervous system,[4] brain,[5][6] and elsewhere by the actions of diamine oxidase and aldehyde dehydrogenase 1a1.
PLP is held in place through base-stacking with an adjacent histidine residue, and GABA is positioned such that its carboxyl group forms a salt bridge with arginine and a hydrogen bond with glutamine.
Dimerization is essential to maintaining function as the active site is found at this interface, and mutations interfering with optimal association between the 2 chains has been linked to pathology, such as schizophrenia.
[9][10] Interference of dimerization by GAD inhibitors such as 2-keto-4-pentenoic acid (KPA) and ethyl ketopentenoate (EKP) were also shown to lead to dramatic reductions in GABA production and incidence of seizures.
In GAD67 this loop remains tethered, covering the active site and providing a catalytic environment to sustain GABA production; its mobility in GAD65 promotes a side reaction that results in release of PLP, leading to autoinactivation.
[14][15] GAD derived from Escherichia coli shows additional structural intricacies, including a pH-dependent conformational change.
[32][33] A Cochrane systematic review also examined 1 study showing improvement of C-peptide levels in cases of Latent Autoimmune Diabetes in adults, 5 years following treatment with GAD65.
[34] High titers of autoantibodies to glutamic acid decarboxylase (GAD) are well documented in association with stiff person syndrome (SPS).
[39] GAD67 is a key enzyme involved in the synthesis of inhibitory neurotransmitter GABA and people with schizophrenia have been shown to express lower amounts of GAD67 in the dorsolateral prefrontal cortex compared to healthy controls.
[41] Some have proposed that an immediate early gene, Zif268, which normally binds to the promoter region of GAD67 and increases transcription of GAD67, is lower in schizophrenic patients, thus contributing to decreased levels of GAD67.
The bilateral delivery of glutamic acid decarboxylase (GAD) by an adeno-associated viral vector into the subthalamic nucleus of patients between 30 and 75 years of age with advanced, progressive, levodopa-responsive Parkinson disease resulted in significant improvement over baseline during the course of a six-month study.
[42] Intracerebellar administration of GAD autoantibodies to animals increases the excitability of motoneurons and impairs the production of nitric oxide (NO), a molecule involved in learning.
[45] Antibodies directed against glutamic acid decarboxylase (GAD) are increasingly found in patients with other symptoms indicative of central nervous system (CNS) dysfunction, such as ataxia, progressive encephalomyelitis with rigidity and myoclonus (PERM), limbic encephalitis, and epilepsy.
In Saccharomyces cerevisiae, GAD binds the Ca2+ regulatory protein calmodulin (CaM) and is also involved in responding to oxidative stress.
[50] Unlike vertebrates and invertebrates, the GABA produced by GAD is used in plants to signal abiotic stress by controlling levels of intracellular Ca2+ via CaM.
Binding to CaM opens Ca2+ channels and leads to an increase in Ca2+ concentrations in the cytosol, allowing Ca2+ to act as a secondary messenger and activate downstream pathways.
[50][53] but also significant activity at pH 7.3 in the presence of CaM [16] It is also believed that the control of glutamate decarboxylase has the prospect of improving citrus produce quality post-harvest.
