Glutamate CarboxypeptidaseII

Abstract

Glutamate carboxypeptidase II (GCP II) is a homodimeric, dinuclear zinc carboxypeptidase that catalyzes the cleavage of two endogenous substrates carrying L ‐glutamate at the C‐terminal P1′ position, namely N ‐acetyl‐ L ‐aspartyl‐α‐ L ‐glutamate (α‐NAAG) and folylpoly‐γ‐ L ‐glutamate (folylpolyglutamate). Former synonyms for GCP II, a type‐II membrane glycoprotein that belongs to the transferrin receptor family of proteins, include prostate‐specific membrane antigen (PSMA), folylpoly‐γ‐glutamate carboxypeptidase (FGCP), and N ‐acetylated α‐linked acidic dipeptidase (NAALADase). GCP II predominantly occurs in nearly all types of glial cells and is drastically overproduced in endothelial cells of tumor‐associated neovasculature and in prostate cancer tissue. The particular role of PSMA, a folylpolyglutamate hydrolase, in prostate cancer is poorly understood. In the brain, GCP II catalyzes the cleavage of the abundant neuropeptide α‐NAAG that acts as an agonist for the metabotropic (i.e. G‐protein‐coupled) glutamate receptor‐3 (mGluR3), and as a mixed agonist/antagonist for N ‐methyl‐ D ‐aspartate (NMDA) receptors. The liberated L ‐glutamate acts as a downstream neurotransmitter that is excitotoxic at high concentrations, harming retina and brain. Accordingly, inhibitory compounds of GCP II have been shown to provide neuroprotection. In addition, they may prove useful, through the binding to PSMA, for the imaging and possible treatment of certain forms of cancer.

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

“…A comparison of CeGCP2.1 isoforms revealed that isoform CeGCP2.1b lacks the predicted intracellular domain. Isoform CeGCP2.1c completely lacks the C-terminal domain, which implies the loss or significant changes in the catalytic function, given that in its human homolog GCP2, the C-terminal domain is involved in substrate recognition [ 69 , 70 ]. No biological functions associated with these isoforms of GCP2.1 protein have been described so far, so we can only conclude homology to other isoforms and GCP2-like proteins of Caenorhabditis species, NAAG and transferrin receptors.…”

Uncovering the essential roles of human GCP 2 orthologs inCaenorhabditis elegans

“…A comparison of CeGCP2.1 isoforms revealed that isoform CeGCP2.1b lacks the predicted intracellular domain. Isoform CeGCP2.1c completely lacks the C-terminal domain, which implies the loss or significant changes in the catalytic function, given that in its human homolog GCP2, the C-terminal domain is involved in substrate recognition (Barinka et al , 2007; Mesters & Hilgenfeld, 2008). No biological functions associated with these isoforms of GCP2.1 protein have been described so far, so we can only conclude homology to other isoforms and GCP2-like proteins of Caenorhabditis species, NAAG and transferrin receptors.…”

Glutamate carboxypeptidase II

“…According DFT calculation-based studies, in transition state-1 (Figure 1), the hydrogen of the hydroxyl group of Glu24 is in the near-attack conformation and the Zn─Zn distance is elongated (from 3.3 A to 3.5 A). The carbonyl oxygen of the peptide bond is stabilised by Zn (1). Following the transition state-1, the system evolves towards the formation of the intermediate, which is structurally characterised by i) the elongated Zn─Zn distance, ii) a newly formed C─O bond between the oxygen atom of the bridging hydroxide and the carbon atom of the peptide bond of the substrate, iii) the stabilisation of the carbonyl oxygen of the substrate by Zn(1) and Tyr552, iv) the repositioning of the protonated hydroxyl group of Glu424 (Figure 1).…”

“…The type-II membrane glycoprotein glutamate carboxypeptidase II (EC 3.4.17.21), known as GCP II, is a homodimeric dinuclear zinc carboxypeptidase with the highest expression levels found in the nervous and prostatic tissue [1,2].…”

“…Glutamate carboxypeptidase II is also known as prostate-specific membrane antigen (PSMA). It is worth remembering that this membrane-bound exopeptidase (EC 3.4.17.21) is different from the prostate specific antigen (PSA, EC 3.4.21.77), which refers to kallikrein-related peptidase 3 [1,3].…”