Glutamate carboxypeptidase II (PSMA) (PSMA)

Glutamate carboxypeptidase II (GCPII), widely known as Prostate-specific membrane antigen (PSMA), is a zinc-dependent type II transmembrane metallopeptidase [1]. It is encoded by the FOLH1 gene and exhibits distinct enzymatic activities depending on its tissue localization: in the central nervous system, it acts as NAALADase to hydrolyze the neurotransmitter N-acetylaspartylglutamate (NAAG) into N-acetylaspartate and glutamate, while in the small intestine, it functions as a folate hydrolase to facilitate dietary folate absorption [1,2]. GCPII is significantly upregulated in prostate cancer, especially in high-grade, metastatic, and hormone-refractory cases, where its expression correlates with disease progression and poor prognosis [3]. This high tumor-to-normal tissue expression ratio has established PSMA as a critical target for both diagnostic PET imaging and radioligand therapy, such as Lutetium-177 vipivotide tetraxetan [4]. Beyond oncology, GCPII inhibitors are being investigated for neuroprotective effects in conditions like neuropathic pain and stroke by preventing excessive glutamate accumulation and subsequent excitotoxicity [5].

Other names

Prostate-specific membrane antigenN-acetylated-alpha-linked acidic dipeptidase INAALADase IFolate hydrolase 1FOLH1Folylpolygamma-glutamate carboxypeptidaseFGCPGlutamate carboxypeptidase 2

Targeted delivery of cytotoxic radionuclides (e.g., Beta-emitters) to PSMA-expressing cells for radioligand therapy; use of radiolabeled ligands for PET/SPECT diagnostic imaging; competitive inhibition of enzymatic activity to reduce glutamate-mediated excitotoxicity in neurological conditions.