Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Excessive glutamate release is associated with neuronal damage. A new strategy for the treatment of neuronal injury involves inhibition of the neuropeptidase glutamate carboxypeptidase II (GCP II), also known as N-acetylated alpha-linked acidic dipeptidase. GCP II is believed to mediate the hydrolysis of N-acetyl-aspartyl-glutamate (NAAG) to glutamate and N-acetyl-aspartate, and inhibition of NAAG peptidase activity (by GCP II and other peptidases) is neuroprotective. Mice were generated in which the Folh1 gene encoding GCP II was disrupted (Folh1-/- mice). No overt behavioral differences were apparent between Folh1-/- mice and wild-type littermates, with respect to their overall performance in locomotion, coordination, pain threshold, cognition and psychiatric behavioral paradigms. Morphological analysis of peripheral nerves, however, showed significantly smaller axons (reduced myelin sheaths and axon diameters) in sciatic nerves from Folh1-/- mice. Following sciatic nerve crush, Folh1-/- mice suffered less injury and recovered faster than wild-type littermates. In a model of ischemic injury, the Folh1-/- mice exhibited a significant reduction (p < 0.05) in infarct volume compared with their wild-type littermates when subjected to middle cerebral artery occlusion, a model of stroke. These findings support the hypothesis that GCP II inhibitors may represent a novel treatment for peripheral neuropathies as well as stroke.
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PMID:Mice lacking glutamate carboxypeptidase II are protected from peripheral neuropathy and ischemic brain injury. 1619 Aug 66

Membrane-bound glutamate carboxypeptidase II (GCPII) is a zinc metalloenzyme that catalyzes the hydrolysis of the neurotransmitter N-acetyl-L-aspartyl-L-glutamate (NAAG) to N-acetyl-L-aspartate and L-glutamate (which is itself a neurotransmitter). Potent and selective GCPII inhibitors have been shown to decrease brain glutamate and provide neuroprotection in preclinical models of stroke, amyotrophic lateral sclerosis, and neuropathic pain. Here, we report crystal structures of the extracellular part of GCPII in complex with both potent and weak inhibitors and with glutamate, the product of the enzyme's hydrolysis reaction, at 2.0, 2.4, and 2.2 A resolution, respectively. GCPII folds into three domains: protease-like, apical, and C-terminal. All three participate in substrate binding, with two of them directly involved in C-terminal glutamate recognition. One of the carbohydrate moieties of the enzyme is essential for homodimer formation of GCPII. The three-dimensional structures presented here reveal an induced-fit substrate-binding mode of this key enzyme and provide essential information for the design of GCPII inhibitors useful in the treatment of neuronal diseases and prostate cancer.
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PMID:Structure of glutamate carboxypeptidase II, a drug target in neuronal damage and prostate cancer. 1646 55

Human glutamate carboxypeptidase II (GCPII) is a transmembrane metallopeptidase found mainly in the brain, small intestine, and prostate. In the brain, it cleaves N-acetyl-L-aspartyl-glutamate, liberating free glutamate. Inhibition of GCPII has been shown to be neuroprotective in models of stroke and other neurodegenerations. In prostate, it is known as prostate-specific membrane antigen, a cancer marker. Recently, human glutamate carboxypeptidase III (GCPIII), a GCPII homolog with 67% amino acid identity, was cloned. While GCPII is recognized as an important pharmaceutical target, no biochemical study of human GCPIII is available at present. Here, we report the cloning, expression, and characterization of recombinant human GCPIII. We show that GCPIII lacks dipeptidylpeptidase IV-like activity, its activity is dependent on N-glycosylation, and it is effectively inhibited by several known inhibitors of GCPII. In comparison to GCPII, GCPIII has lower N-acetyl-L-aspartyl-glutamate-hydrolyzing activity, different pH and salt concentration dependence, and distinct substrate specificity, indicating that these homologs might play different biological roles. Based on a molecular model, we provide interpretation of the distinct substrate specificity of both enzymes, and examine the amino acid residues responsible for the differences by site-directed mutagenesis. These results may help to design potent and selective inhibitors of both enzymes.
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PMID:Biochemical characterization of human glutamate carboxypeptidase III. 1724 Nov 21

Glutamate, first identified in 1866, is the primary excitatory neurotransmitter in the brain. While it is critically important in many highly regulated cortical functions such as learning and memory, glutamate can be much like the magic the Sorcerer's Apprentice used in Goethe's poem: when conjured under unregulated conditions glutamate can get quickly out of control and lead to deleterious consequences. Two broad types of glutamate receptors, the ionotropic and metabotropic, facilitate glutamatergic neurotransmission in the CNS and play key roles in regulating cognitive function. Excessive activation of these receptors leads to excitotoxicity, especially in brain regions that are developmentally and regionally vulnerable to this kind of injury. Dysregulation of glutamate signaling leads to neurodegeneration that plays a role in a number of neuropsychiatric diseases, prompting the development and utilization of novel strategies to balance the beneficial and deleterious potential of this important neurotransmitter. Inhibition of the enzyme glutamate carboxypeptidase II (GCPII) is one method of manipulating glutamate neurotransmission. Positive outcomes (decreased neuronal loss, improved cognition) have been demonstrated in preclinical models of ALS, stroke, and Multiple Sclerosis due to inhibition of GCPII, suggesting this method of glutamate regulation could serve as a therapeutic means for treating neurodegeneration and cognitive impairment.
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PMID:Glutamate in CNS neurodegeneration and cognition and its regulation by GCPII inhibition. 2230 12

The rationale of this case-control study is to ascertain whether glutamate carboxypeptidase II (GCPII) variants serve as determinants of hyperhomocysteinemia and contribute to the etiology of stroke. Hyperhomocysteinemia was observed in stroke cases compared to controls (14.09 +/- 7.62 micromol/L vs. 8.71 +/- 4.35, P < 0.0001). GCPII sequencing revealed two known variants (R190W and H475Y) and six novel variants (V108A, P160S, Y176H, G206R, G245S and D520E). Among the haplotypes of GCPII, all wild-haplotype H0 showed independent association with stroke risk (OR: 9.89, 95% CI: 4.13-23.68), while H2 representing P160S variant showed reduced risk (OR: 0.17, 95% CI: 0.06-0.50). When compared to subjects with H2 haplotype, H0 haplotype showed elevated homocysteine levels (18.26 +/- 4.31 micromol/L vs. 13.66 +/- 3.72 micromol/L, P = 0.002) and reduced plasma folate levels (7.09 +/- 1.19 ng/ml vs. 8.21 +/- 1.14 ng/ml, P = 0.007). Using GCPII genetic variants, dietary folate and gender as predictor variables and homocysteine as outcome variable, a multiple linear regression model was developed. This model explained 36% variability in plasma homocysteine levels. To conclude, GCPII haplotypes influenced susceptibility to stroke by influencing homocysteine levels.
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PMID:Glutamate carboxypeptidase II (GCPII) genetic variants as determinants of hyperhomocysteinemia: implications in stroke susceptibility. 2325 22

N-Acetylaspartylglutamate (NAAG) is the third most prevalent neurotransmitter in the mammalian nervous system, yet its therapeutic potential is only now being fully recognized. Drugs that inhibit the inactivation of NAAG by glutamate carboxypeptidase II (GCPII) increase its extracellular concentration and its activation of its receptor, mGluR3. These drugs warrant attention, as they are effective in animal models of several clinical disorders including stroke, traumatic brain injury and schizophrenia. In inflammatory and neuropathic pain studies, GCPII inhibitors moderated both the primary and secondary pain responses when given systemically, locally or in brain regions associated with the pain perception pathway. The finding that GCPII inhibition also moderated the motor and cognitive effects of ethanol intoxication led to the discovery of their procognitive efficacy in long-term memory tests in control mice and in short-term memory in a mouse model of Alzheimer's disease. NAAG and GCPII inhibitors respectively reduce cocaine self-administration and the rewarding effects of a synthetic stimulant. Most recently, GCPII inhibition also has been reported to be efficacious in a model of inflammatory bowel disease. GCPII was first discovered as a protein expressed by and released from metastatic prostate cells where it is known as prostate specific membrane antigen (PSMA). GCPII inhibitors with high affinity for this protein have been developed as prostate imaging and radiochemical therapies for prostate cancer. Taken together, these data militate in favor of the development and application of GCPII inhibitors in more advanced preclinical research as a prelude to clinical trials.
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PMID:N-acetylaspartylglutamate (NAAG) and glutamate carboxypeptidase II: An abundant peptide neurotransmitter-enzyme system with multiple clinical applications. 3173 Jul 93