Glutamate carboxypeptidase II (GCPII) is a membrane-bound binuclear zinc metallopeptidase with the highest expression levels found in the nervous and prostatic tissue. Throughout the nervous system, glia-bound GCPII is intimately involved in the neuron-neuron and neuron-glia signaling via the hydrolysis of N-acetylaspartylglutamate (NAAG), the most abundant mammalian peptidic neurotransmitter. The inhibition of the GCPII-controlled NAAG catabolism has been shown to attenuate neurotoxicity associated with enhanced glutamate transmission and GCPII-specific inhibitors demonstrate efficacy in multiple preclinical models including traumatic brain injury, stroke, neuropathic and inflammatory pain, amyotrophic lateral sclerosis, and schizophrenia. The second major area of pharmacological interventions targeting GCPII focuses on prostate carcinoma; GCPII expression levels are highly increased in androgen-independent and metastatic disease. Consequently, the enzyme serves as a potential target for imaging and therapy. This review offers a summary of GCPII structure, physiological functions in healthy tissues, and its association with various pathologies. The review also outlines the development of GCPII-specific small-molecule compounds and their use in preclinical and clinical settings.

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Popik P, Kozela E, Wrobel M, Wozniak KM, Slusher BS. Morphine tolerance and reward but not expression of morphine dependence are inhibited by the selective glutamate carboxypeptidase II (GCP II, NAALADase) inhibitor, 2-PMPA. Neuropsychopharmacology. 2003;28:457–467. PubMed

Lumley LA, Robison CL, Slusher BS, Wozniak K, Dawood M, Meyerhoff JL. Reduced isolation-induced aggressiveness in mice following NAALADase inhibition. Psychopharmacology (Berl) 2004;171:375–381. PubMed

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Ghadge GD, Slusher BS, Bodner A, Canto MD, Wozniak K, Thomas AG, Rojas C, Tsukamoto T, Majer P, Miller RJ, Monti AL, Roos RP. Glutamate carboxypeptidase II inhibition protects motor neurons from death in familial amyotrophic lateral sclerosis models. Proc. Natl. Acad. Sci. U. S. A. 2003;100:9554–9559. PubMed PMC

Zhang W, Murakawa Y, Wozniak KM, Slusher B, Sima AA. The preventive and therapeutic effects of GCPII (NAALADase) inhibition on painful and sensory diabetic neuropathy. J Neurol Sci. 2006;247:217–223. PubMed

Slusher BS, Thomas A, Paul M, Schad CA, Ashby CR., Jr Expression and acquisition of the conditioned place preference response to cocaine in rats is blocked by selective inhibitors of the enzyme N-acetylated-alpha-linked-acidic dipeptidase (NAALADASE) Synapse. 2001;41:22–28. PubMed

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Uncovering the essential roles of glutamate carboxypeptidase 2 orthologs in Caenorhabditis elegans

Targeting Prostate Cancer Using Bispecific T-Cell Engagers against Prostate-Specific Membrane Antigen

Combination of In Silico and In Vitro Screening to Identify Novel Glutamate Carboxypeptidase II Inhibitors

Characterization of glutamate carboxypeptidase 2 orthologs in trematodes

Phosphonates and Phosphonate Prodrugs in Medicinal Chemistry: Past Successes and Future Prospects

Glycoforms of human prostate-specific membrane antigen (PSMA) in human cells and prostate tissue

Engineered Fragments of the PSMA-Specific 5D3 Antibody and Their Functional Characterization

Cellular Delivery of Bioorthogonal Pretargeting Therapeutics in PSMA-Positive Prostate Cancer

Enhanced Oral Bioavailability of 2-(Phosphonomethyl)-pentanedioic Acid (2-PMPA) from its (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl (ODOL)-Based Prodrugs

The calcium-binding site of human glutamate carboxypeptidase II is critical for dimerization, thermal stability, and enzymatic activity

Enhanced Brain Delivery of 2-(Phosphonomethyl)pentanedioic Acid Following Intranasal Administration of Its γ-Substituted Ester Prodrugs

Discovery of a para-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain

Novel Monoclonal Antibodies Recognizing Human Prostate-Specific Membrane Antigen (PSMA) as Research and Theranostic Tools

Design of composite inhibitors targeting glutamate carboxypeptidase II: the importance of effector functionalities

Structural and biochemical characterization of the folyl-poly-γ-l-glutamate hydrolyzing activity of human glutamate carboxypeptidase II

Structural characterization of P1'-diversified urea-based inhibitors of glutamate carboxypeptidase II

Development of a high-throughput fluorescence polarization assay to identify novel ligands of glutamate carboxypeptidase II