Glutamate carboxypeptidase II (GCPII), also known as prostate-specific membrane antigen (PSMA) or folate hydrolase, is a metallopeptidase expressed predominantly in the human brain and prostate. GCPII expression is considerably increased in prostate carcinoma, and the enzyme also participates in glutamate excitotoxicity in the brain. Therefore, GCPII represents an important diagnostic marker of prostate cancer progression and a putative target for the treatment of both prostate cancer and neuronal disorders associated with glutamate excitotoxicity. For the development of novel therapeutics, mouse models are widely used. However, although mouse GCPII activity has been characterized, a detailed comparison of the enzymatic activity and tissue distribution of the mouse and human GCPII orthologs remains lacking. In this study, we prepared extracellular mouse GCPII and compared it with human GCPII. We found that mouse GCPII possesses lower catalytic efficiency but similar substrate specificity compared with the human protein. Using a panel of GCPII inhibitors, we discovered that inhibition constants are generally similar for mouse and human GCPII. Furthermore, we observed highest expression of GCPII protein in the mouse kidney, brain, and salivary glands. Importantly, we did not detect GCPII in the mouse prostate. Our data suggest that the differences in enzymatic activity and inhibition profile are rather small; therefore, mouse GCPII can approximate human GCPII in drug development and testing. On the other hand, significant differences in GCPII tissue expression must be taken into account when developing novel GCPII-based anticancer and therapeutic methods, including targeted anticancer drug delivery systems, and when using mice as a model organism.

Department of Normal Pathological and Clinical Physiology 3rd Faculty of MedicineCharles UniversityPragueCzech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of SciencesPragueCzech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of SciencesPragueCzech Republic 1st Faculty of MedicineCharles UniversityPragueCzech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of SciencesPragueCzech Republic 1st Faculty of MedicineCharles UniversityPragueCzech Republic Department of Genetics and MicrobiologyFaculty of ScienceCharles UniversityPragueCzech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of SciencesPragueCzech Republic Department of BiochemistryFaculty of ScienceCharles UniversityPragueCzech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of SciencesPragueCzech Republic Department of BiochemistryFaculty of ScienceCharles UniversityPragueCzech Republic Present address Donnelly Centre for Cellular and Biomolecular ResearchUniversity of TorontoTorontoONCanada

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