Glutamate carboxypeptidase 2 (GCPII) (GCPII)

Glutamate carboxypeptidase 2 (GCPII), also known as prostate-specific membrane antigen (PSMA) or brush border folate conjugase, is a type II transmembrane zinc metalloenzyme with diverse physiological roles [1]. In the small intestine, it acts as a folylpoly-gamma-glutamate carboxypeptidase (FGCP), which is essential for the absorption of dietary folates by hydrolyzing polyglutamated forms into monoglutamates [2]. In the nervous system, it functions as N-acetylated-alpha-linked acidic dipeptidase I (NAALADase I), regulating glutamatergic signaling by hydrolyzing the neurotransmitter N-acetylaspartylglutamate (NAAG) [3]. GCPII is highly overexpressed in the plasma membrane of prostate cancer cells and the neovasculature of various solid tumors, making it a highly effective target for diagnostic imaging and therapeutic intervention [4]. Modern clinical applications primarily utilize PSMA-targeted radioligands, such as Lutetium (177Lu) vipivotide tetraxetan, to deliver targeted radiation to metastatic cancer sites, while small-molecule inhibitors are being explored for treating neurological disorders like neuropathic pain [5, 6]. The enzyme's expression in non-target tissues like the salivary glands and kidneys presents specific safety challenges, such as xerostomia and potential renal toxicity, which must be managed during therapy [5].

Other names

Prostate-specific membrane antigenPSMABrush border folate conjugaseFolylpoly-gamma-glutamate carboxypeptidaseFGCPN-acetylated-alpha-linked acidic dipeptidase INAALADase IFolate hydrolase 1FOLH1Dihydrofolate-related enzyme

Targeted delivery of radionuclides for imaging or therapy; inhibition of enzymatic hydrolysis of polyglutamated folates or NAAG.