Alternative titles; symbols
HGNC Approved Gene Symbol: DPEP1
Cytogenetic location: 16q24.3 Genomic coordinates (GRCh38): 16:89,613,308-89,641,540 (from NCBI)
DPEP1 (EC 3.4.13.11) is a kidney membrane enzyme that hydrolyzes a variety of dipeptides and is implicated in renal metabolism of glutathione and its conjugates, e.g., leukotriene D4 (Kozak and Tate, 1982). DPEP1 is responsible for hydrolysis of the beta-lactam ring of antibiotics, such as penem and carbapenem (Campbell et al., 1984). Earlier, beta-lactamase enzymes were thought to occur only in bacteria, where their probable function was in protecting the organisms against the action of beta-lactam antibiotics. These antibiotics exhibit selective toxicity against bacteria but virtual inertness against many eukaryotic cells (Adachi et al., 1990).
Adachi et al. (1990) isolated and characterized cDNA clones for human DPEP1, which they called RDP. DNA and RNA blot analysis indicated the existence of a single gene.
To isolate potential tumor/growth suppressor genes involved in Wilms tumor, Austruy et al. (1993) constructed a cDNA library by cloning a mature kidney cDNA subtracted with an excess of Wilms tumor mRNA. Clones were selected according to a differential pattern of expression, i.e., positive with RNA from mature kidney and negative with RNA from several Wilms tumors. By comparison of sequences of these clones with database sequences, 1 clone was identified as DPEP1.
Nitanai et al. (2002) stated that RDP is a homodimer of identical 369-amino acid subunits. Each subunit has a calculated molecular mass of about 42 kD, but N-glycosylation at 4 possible sites results in a highly glycosylated peptide of about 63 kD. In addition, each RDP subunit has a C-terminal glycosylphosphatidylinositol membrane anchor.
Habib et al. (2003) cloned mouse Dpep1, which they designated Mbd1. Northern blot analysis detected 3 transcripts that were differentially expressed in heart, lung, skeletal muscle, kidney, liver, and testis. No Mbd1 expression was detected in brain and spleen. The transcripts likely arise from the use of alternate poly(A) sites and variations in the 5-prime UTR.
Nitanai et al. (2002) determined the crystal structure of human RDP. Each subunit appears to assume a barrel shape made up of 8 alpha helix and beta sheet pairs. Each monomer requires 2 zinc ions that are ligated to the catalytic residues (glu125, his198, and his219) at the bottom of the enzymatic pocket. His152 is not ligated to zinc, but it is responsible for recognition of a substrate or inhibitor. The pocket is reinforced by 2 adjacent disulfide bonds and by 3 proline residues. Cys361 is involved in a disulfide bridge between monomers.
Kera et al. (1999) measured dipeptidase activity in several human postmortem tissues and in rat tissues using glycyl-D-alanine as substrate. Highest activity in human tissues was detected in kidney cortex, pancreas, and testis. Much lower activity was detected in adrenal gland and liver, and very low activity was detected in lung, spleen, cerebrum, and cerebellum. The enzyme was also found in serum and urine from healthy volunteers. Activity in rats was similar, but was much higher in lung. The distribution of enzyme activity in various tissues changed in postnatal rats up to 8 weeks of age.
Habib et al. (2003) demonstrated that COS-7 cells transfected with mouse Mbd1 were able to convert leukotriene D4 to leukotriene E4 and could hydrolyze cystinyl-bis-glycine (cys-bis-gly) and beta-lactam. Inhibition of Mbd1 by penicillamine indicated that it is a metallopeptidase.
Satoh et al. (1993) determined that the DPEP1 gene contains 10 exons and spans about 6 kb.
By FISH, Nakagawa et al. (1991) mapped the RDP gene to chromosome 16q24.
Austruy et al. (1993) used somatic cell hybrids carrying either different human chromosomes or chromosome 16 segments to confirm and refine the physical mapping of DPEP1 to 16q24.3. Two RFLPs were described and used to show linkage of DPEP1 to D16S7; maximum lod score was 5.8 at theta of 0.03.
Habib et al. (1998) found that Mbd1-deficient mice retained partial ability to degrade cys-bis-gly and to convert leukotriene D4 to leukotriene E4 depending on the tissue examined. Habib et al. (2003) suggested that tissue- and substrate-specific activities of Mbd2 (DPEP2; 609925) and Mbd3 (DPEP3; 609926) partially compensate for the loss of Mbd1 in these mice.
Adachi, H., Tawaragi, Y., Inuzuka, C., Kubota, I., Tsujimoto, M., Nishihara, T., Nakazato, H. Primary structure of human microsomal dipeptidase deduced from molecular cloning. J. Biol. Chem. 265: 3992-3995, 1990. [PubMed: 2303490]
Austruy, E., Jeanpierre, C., Antignac, C., Whitmore, S. A., Van Cong, N., Bernheim, A., Callen, D. F., Junien, C. Physical and genetic mapping of the dipeptidase gene DPEP1 to 16q24.3. Genomics 15: 684-687, 1993. [PubMed: 7682195] [Full Text: https://doi.org/10.1006/geno.1993.1126]
Campbell, B. J., Forrester, L. J., Zahler, W. L., Burks, M. Beta-lactamase activity of purified and partially characterized human renal dipeptidase. J. Biol. Chem. 259: 14586-14590, 1984. [PubMed: 6334084]
Habib, G. M., Shi, Z.-Z., Cuevas, A. A., Lieberman, M. W. Identification of two additional members of the membrane-bound dipeptidase family. FASEB J. 17: 1313-1315, 2003. [PubMed: 12738806] [Full Text: https://doi.org/10.1096/fj.02-0899fje]
Habib, G. M., Shi, Z. Z., Cuevas, A. A., Guo, Q., Matzuk, M. M., Lieberman, M. W. Leukotriene D4 and cystinyl-bis-glycine metabolism in membrane-bound dipeptidase-deficient mice. Proc. Nat. Acad. Sci. 95: 4859-4863, 1998. [PubMed: 9560193] [Full Text: https://doi.org/10.1073/pnas.95.9.4859]
Kera, Y., Liu, Z., Matsumoto, T., Sorimachi, Y., Nagasaki, H., Yamada, R. Rat and human membrane dipeptidase: tissue distribution and developmental changes. Comp. Biochem. Physiol. Part B 123: 53-58, 1999.
Kozak, E. M., Tate, S. S. Glutathione-degrading enzymes of microvillus membranes. J. Biol. Chem. 257: 6322-6327, 1982. [PubMed: 6122685]
Nakagawa, H., Inazawa, J., Inoue, K., Misawa, S., Kashima, K., Adachi, H., Nakazato, H., Abe, T. Assignment of the human renal dipeptidase gene (DPEP1) to band q24 of chromosome 16. (Abstract) Cytogenet. Cell Genet. 58: 2002 only, 1991.
Nitanai, Y., Satow, Y., Adachi, H., Tsujimoto, M. Crystal structure of human renal dipeptidase involved in beta-lactam hydrolysis. J. Molec. Biol. 321: 177-184, 2002. [PubMed: 12144777] [Full Text: https://doi.org/10.1016/s0022-2836(02)00632-0]
Satoh, S., Kusunoki, C., Konta, Y., Niwa, M., Kohsaka, M. Cloning and structural analysis of genomic DNA for human renal dipeptidase. Biochim. Biophys. Acta 1172: 181-183, 1993. [PubMed: 8439558] [Full Text: https://doi.org/10.1016/0167-4781(93)90289-p]