N-Acetylaspartylglutamic Acid - Catabolism

Catabolism

NAAG is catabolized via NAAG peptidase activity. Two enzymes with NAAG peptidase activity have been cloned, glutamate carboxypeptidase II and glutamate carboxypeptidase III. These enzymes mediate the hydrolysis of NAAG to NAA and glutamate. Their inhibition can produce therapeutic benefits. Two main types of inhibitors of this enzyme are known: compounds related to 2-(phosphonomethyl)pentanedioic acid (2-PMPA) and urea-based analogs of NAAG, including ZJ43, ZJ17, and ZJ11. In rat models, ZJ43 and 2-PMPA reduce perception of inflammatory and neuropathic pain when administered systemically, intracerebrally, or locally, suggesting that NAAG modulates neurotrasmission in pain circuits via mGlu3 receptors. The inhibition of NAAG hydrolysis increases the concentration of NAAG in the synaptic space analogous to the effects of SSRIs in increasing the concentration of serotonin. This elevated NAAG gives greater activation of presynaptic mGluR3 receptors, which decrease release of transmitter (glutamate) in the pain signaling pathways of the spinal cord and brain. In the case of traumatic brain injury, the injection of a NAAG peptidase inhibitor reduces neuron and astrocyte death in the hippocampus nearest the site of the injury. In a mouse model of amyotrophic lateral sclerosis (ALS), the chronic inhibition of NAAG peptidase activity delayed the onset of ALS symptoms and slowed the progress of the neuronal death. To model schizophrenia, animals were injected with phencyclidine (PCP) and, therefore, exhibited symptoms of the disorder, such as social withdrawal and motor responses. Upon injection with ZJ43, these behaviors were decreased, suggesting that an increase in NAAG in the synapse — and its subsequent activation of mGluR3 receptors — has potential as a co-therapy for schizophernia. In these cases, NAAG peptidase inhibition reduces the adverse effects in these disorders. Future research focuses on the role of NAAG in pain perception, brain injury, and schizophrenia while developing NAAG peptidase inhibitors with even greater ability to cross the blood–brain barrier.