Glutamate carboxypeptidase III (GCPIII)

Glutamate carboxypeptidase III (GCPIII, also known as NAALAD2) is a type II transmembrane zinc-dependent metallopeptidase closely related to Glutamate carboxypeptidase II (PSMA). Like its homolog, it hydrolyzes C-terminal glutamate from N-acetylated dipeptides, but demonstrates unique substrate specificity—particularly for beta-citrylglutamate—and marked modulation of activity by divalent cations. It is encoded by the NAALAD2 gene on chromosome 11q14.3-q21[3][5]. Structurally, GCPIII forms homodimers via large extracellular domains and is post-translationally N-glycosylated, essential for activity. While the precise physiological and pathological roles of GCPIII remain under study, recent advances have highlighted it as a target for differentiating on-target/off-target effects of PSMA-directed therapies (notably in nuclear medicine), with efforts surrounding the development of selective ligands that block its binding to reduce salivary gland uptake of PSMA radiopharmaceuticals[1][3][4][5][8].

Other names

NAALAD2N-acetylated alpha-linked acidic dipeptidase 2

Inhibitors of GCPIII block the hydrolysis of specific N-acetylated glutamate-containing peptides, notably beta-citrylglutamate, thereby modulating local glutamate metabolism and possibly reducing off-target radio-ligand uptake in tissues like salivary glands[4][3].