| Structural highlights
6rbc is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , , |
| Gene: | FOLH1, FOLH, NAALAD1, PSM, PSMA, GIG27 (HUMAN) |
| Activity: | Glutamate carboxypeptidase II, with EC number 3.4.17.21 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[FOLH1_HUMAN] Has both folate hydrolase and N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) activity. Has a preference for tri-alpha-glutamate peptides. In the intestine, required for the uptake of folate. In the brain, modulates excitatory neurotransmission through the hydrolysis of the neuropeptide, N-aceylaspartylglutamate (NAAG), thereby releasing glutamate. Isoform PSM-4 and isoform PSM-5 would appear to be physiologically irrelevant. Involved in prostate tumor progression. Also exhibits a dipeptidyl-peptidase IV type activity. In vitro, cleaves Gly-Pro-AMC.
Publication Abstract from PubMed
Prostate-specific membrane antigen (PSMA) is an excellent biomarker for the early diagnosis of prostate cancer progression and metastasis. The most promising PSMA-targeted agents in the clinical phase are based on the Lys-urea-Glu motif, in which Lys and Glu are alpha-(l)-amino acids. In this study, we aimed to determine the effect of beta- and gamma-amino acids in the S1 pocket on the binding affinity for PSMA. We synthesized and evaluated the beta- and gamma-amino acid analogues with (S)- or (R)-configuration with keeping alpha-(l)-Glu as the S1'-binding pharmacophore. The structure-activity relationship studies identified that compound 13c, a beta-amino acid analogue with (R)-configuration, exhibited the most potent PSMA inhibitory activity with an IC50 value of 3.97 nM. The X-ray crystal structure of PSMA in complex with 13c provided a mechanistic basis for the stereochemical preference of PSMA, which can guide the development of future PSMA inhibitors.
Novel beta- and gamma-Amino Acid-Derived Inhibitors of Prostate-Specific Membrane Antigen.,Kim K, Kwon H, Barinka C, Motlova L, Nam S, Choi D, Ha H, Nam H, Son SH, Minn I, Pomper MG, Yang X, Kutil Z, Byun Y J Med Chem. 2020 Mar 26;63(6):3261-3273. doi: 10.1021/acs.jmedchem.9b02022. Epub , 2020 Mar 9. PMID:32097010[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kim K, Kwon H, Barinka C, Motlova L, Nam S, Choi D, Ha H, Nam H, Son SH, Minn I, Pomper MG, Yang X, Kutil Z, Byun Y. Novel beta- and gamma-Amino Acid-Derived Inhibitors of Prostate-Specific Membrane Antigen. J Med Chem. 2020 Mar 26;63(6):3261-3273. doi: 10.1021/acs.jmedchem.9b02022. Epub , 2020 Mar 9. PMID:32097010 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b02022
|
