glutamate carboxypeptidase 2; glutamate carboxypeptidase-2; membrane glutamate carboxypeptidase; mGCP; N-acetylated-alpha-linked acidic dipeptidase 1; NAALADase 1; pteroylpoly-gamma-glutamate carboxypeptidase; folylpoly-gamma-glutamate carboxypeptidase; FGCP; folate hydrolase 1; prostate-specific membrane antigen; PSMA; PSM (FOLH1, FOLH, NAALAD1, PSM, PSMA, GCP2)
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Function
- folate hydrolase
- acetylated-alpha-linked-acidic dipeptidase (NAALADase)
- preference for tri-alpha-glutamate peptides
- in the intestine, required for uptake of folate
- in brain, modulates excitatory neurotransmission through hydrolysis of the neuropeptide NAAG, endogenous ligand of mGluR3, thus releasing glutamate
- isoforms PSM-4 & PSM-5 would appear to be physiologically irrelevant
- exhibits a dipeptidyl-peptidase IV type activity in vitro, cleaves Gly-Pro-AMC
- release of an unsubstituted, C-terminal glutamyl residue, typically from Ac-Asp-Glu or folylpoly-gamma-glutamates
- the NAALADase activity is inhibited by beta-NAAG, quisqualic acid, 2-(phosphonomethyl) pentanedioic acid (PMPA) & EDTA
- activated by cobalt
pH dependence: stable at pH > 6.5
Structure
- the N-terminus is blocked
- the first two amino acids at the N-terminus of isoform PSMA' appear to be cleaved by limited proteolysis
- the NAALADase activity is found in the central region, the dipeptidyl peptidase IV type activity in the C-terminal
- belongs to the peptidase M28 family, M28B subfamily
Compartment
- cell membrane
- isoform PSMA': cytoplasm
Alternative splicing
named isoforms=6 PSMA-1, PSMA-2, PSMA-3, PSMA-4, PSMA-5, PSMA'
Expression
- highly expressed in prostate epithelium
- also expressed, in the small intestine, brain, kidney, liver, spleen, colon, trachea, spinal cord & the capillary endothelium of a variety of tumors
- expressed specifically in jejunum brush border membranes
- in the brain, highly expressed in the ventral striatum & brain stem
- also expressed in fetal liver & kidney
- in the prostate, the PSMA' cytosolic isoform is the most abundant form in normal tissue, the membrane-bound PSMA-1 form in primary prostate tumors
- the PSMA-2 isoform also found in normal prostate as well as in brain & liver
- in the prostate, up-regulated in response to androgen deprivation
Pathology
- role in prostate tumor progression
- PSMA is used as a diagnostic & prognostic indicator of prostate cancer, & as a possible marker for various neurological disorders including:
Polymorphism
- genetic variation in FOLH1 may be associated with low folate levels & consequent hyperhomocysteinemia