Glutamate carboxypeptidase II (GCPII) (GCPII)

Glutamate carboxypeptidase II (GCPII), widely known in oncology as prostate-specific membrane antigen (PSMA) and in neurobiology as N-acetylated alpha-linked acidic dipeptidase (NAALADase), is a type II transmembrane zinc-dependent metallopeptidase [5, 10]. In the central nervous system, it hydrolyzes the neuropeptide N-acetylaspartylglutamate (NAAG) into N-acetylaspartate and glutamate, serving as a key regulator of glutamatergic signaling and a target for neuroprotective therapies [6, 15]. In the intestinal brush border, the enzyme functions as a folate hydrolase to facilitate the absorption of dietary folates [10, 17]. GCPII is highly overexpressed on the cell surface of virtually all prostate cancer cells and the neovasculature of many other solid tumors, while having limited expression in most normal tissues [1, 4]. This unique expression profile has enabled the development of theranostic agents, where radiolabeled ligands are used for both high-sensitivity PET imaging and targeted radionuclide therapy (e.g., Pluvicto) [2, 13]. Clinical challenges include the accumulation of these agents in the salivary glands and kidneys, which can lead to adverse effects like dry mouth and renal toxicity [13, 14]. Ongoing research continues to explore GCPII inhibitors for treating chronic pain, inflammatory bowel disease, and various cognitive disorders [7, 21].

Other names

Prostate-specific membrane antigenPSMAN-acetylated alpha-linked acidic dipeptidaseNAALADase IFolate hydrolase 1FOLH1Glutamate carboxypeptidase 2GCP2Folylpoly-gamma-glutamate carboxypeptidaseFGCP

Drugs targeting this molecule generally act through two main pathways: targeted radioligand therapy, where radionuclides are delivered to PSMA-expressing cancer cells to induce DNA damage via beta radiation [1, 12], and competitive enzymatic inhibition, where small molecules block the catalytic site to prevent the hydrolysis of NAAG into glutamate, thereby reducing excitotoxic neuronal damage in neurological conditions [6, 15].