Expression of glutamate carboxypeptidase II in human brain

@article{cha2007ExpressionOG,
  title={Expression of glutamate carboxypeptidase II in human brain},
  author={Pavel {\vS}{\'a}cha and Josef Zamecnik and Cyril Bařinka and Kl{\'a}ra Hlouchov{\'a} and Anna Vicha and Petra Mlcochova and Ivan Hilgert and Tom{\'a}{\vs} Eckschlager and Jan Konvalinka},
  journal={Neuroscience},
  year={2007},
  volume={144},
  pages={1361-1372}
}

Glutamate carboxypeptidase II in diagnosis and treatment of neurologic disorders and prostate cancer.

This review offers a summary of GCPII structure, physiological functions in healthy tissues, and its association with various pathologies, and outlines the development of G CPII-specific small-molecule compounds and their use in preclinical and clinical settings.

Mouse glutamate carboxypeptidase II (GCPII) has a similar enzyme activity and inhibition profile but a different tissue distribution to human GCPII

It is found that mouse GCPII possesses lower catalytic efficiency but similar substrate specificity compared with the human protein, and the differences in enzymatic activity and inhibition profile are rather small; therefore, mouse G CPII can approximate human GCP II in drug development and testing.

Dysregulation of glutamate carboxypeptidase II in psychiatric disease

Inhibition of glutamate-carboxypeptidase-II in dorsolateral prefrontal cortex: potential therapeutic target for neuroinflammatory cognitive disorders

Systemic administration of the brain penetrant inhibitor, 2-MPPA, significantly improved working memory performance without apparent side effects, and endorsement of GCPII inhibition as a potential strategy for treating cognitive disorders associated with aging and/or neuroinflammation is endorsed.

Evidence That N-acetylaspartylglutamate Is the Astrocyte-targeted Neurovascular Coupling Agent That Regulates Slow Tonic Control of Brain Blood Flow

Evidence is presented that NAAG is the neurovascular coupling agent that regulates tonic changes in CBF via the astrocyte mGluR3NAAG peptidase connection.

N-Acetyl-Aspartyl-Glutamate in Brain Health and Disease

The main effect of NAAG occurs through increased mGluR3 activation and thereby reduced glutamate release, which is a promising treatment option for many brain disorders where glutamatergic excitotoxicity plays a role.

Structural insight into the evolutionary and pharmacologic homology of glutamate carboxypeptidases II and III

High‐resolution crystal structures of the human GCPIII ectodomain in a ‘pseudo‐unliganded’ state and in a complex with a phosphapeptide transition state mimetic allow us to detail interactions between the enzyme and its ligands and to characterize the functional flexibility of GCP III, which is essential for substrate recognition.

N-Acetylaspartate and N-acetylaspartylglutamate

In conclusion, elucidation of the neurobiology of NAA and NAAG provides insight into the role of these molecules in the pathophysiology of several neurologic disorders and their potential as a therapeutic target for these conditions.
...

References

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Substrate specificity, inhibition and enzymological analysis of recombinant human glutamate carboxypeptidase II

Glutamate carboxypeptidase II (GCPII, EC 3.4.17.21) is a membrane peptidase expressed in a number of tissues such as kidney, prostate and brain. The brain form of GCPII (also known as NAALADase)

Structure of glutamate carboxypeptidase II, a drug target in neuronal damage and prostate cancer

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.

Molecular characterization of human brain N-acetylated alpha-linked acidic dipeptidase (NAALADase).

The form of NAALADase also known as PSMA is expressed in brain and comprises a significant fraction of brain NAALadase activity, which concludes that the human brain and prostate express a common mRNA splice form.

The cloning and characterization of a second brain enzyme with NAAG peptidase activity

Cl cloning and characterization of a mouse enzyme (tentatively identified as glutamate carboxypeptidase III or GCPIII) that is homologous to an enzyme identified in a human lung carcinoma are reported, consistent with the hypothesis that nervous system cells express at least two differentially distributed homologueous enzymes with similar pharmacological properties and affinity for NAAG.

Identification of the N‐glycosylation sites on glutamate carboxypeptidase II necessary for proteolytic activity

It is shown that N‐glycosylation is vital for proper folding and subsequent secretion of human GCPII and glycosylations at sites distant from the putative catalytic domain is critical for the NAAG‐hydrolyzing activity of GCP II calling the validity of previously described structural models of G CPII into question.

Isolation and expression of a rat brain cDNA encoding glutamate carboxypeptidase II.

In situ hybridization histochemistry shows that NAALADase-related mRNAs have an uneven regional distribution in rat brain and are expressed predominantly by astrocytes as demonstrated by their colocalization with theAstrocyte-specific marker glial fibrillary acidic protein.

Deletion of the glutamate carboxypeptidase II gene in mice reveals a second enzyme activity that hydrolyzes N‐acetylaspartylglutamate

A novel membrane‐bound NAAG peptidase activity was discovered in brain, spinal cord and kidney of the GCPII knock out mice and this activity had a similar requirement for metal ions as GCP II.

N‐Acetylaspartylglutamate

It is speculated that one role for NAAG following synaptic release is the activation of metabotropic autoreceptors that inhibit subsequent transmitter release, and a second role is the production of extracellular glutamate following N AAG hydrolysis.

Prostate-specific membrane antigen is a hydrolase with substrate and pharmacologic characteristics of a neuropeptidase.

A PSM-encoded function is demonstrated and a NAALADase-encoding cDNA is identified, suggesting that PSM and/or related molecular species appear to account for NAAG hydrolysis in the nervous system.