Alternative titles; symbols
HGNC Approved Gene Symbol: PREP
Cytogenetic location: 6q21 Genomic coordinates (GRCh38): 6:105,273,218-105,403,082 (from NCBI)
Prolyl endopeptidase (EC 3.4.21.26) is a large cytosolic enzyme that belongs to a distinct class of serine peptidases. The enzyme is involved in the maturation and degradation of peptide hormones and neuropeptides. PREP cleaves peptide bonds at the C-terminal side of proline residues. Its activity is confined to action on oligopeptides of less than 10 kD and it has an absolute requirement for the trans-configuration of the peptide bond preceding proline. Vanhoof et al. (1994) sequenced the human cDNA encoding prolyl endopeptidase. A complete cDNA was 2,562 nucleotides long and contained an open reading frame coding for a protein of 710 amino acids. Comparison of the sequences from human lymphocyte PREP and that of pig brain showed 97% identity. Also known as prolyl oligopeptidase, this enzyme shows sequence similarity with dipeptidyl peptidase IV (102720) and acylaminoacyl peptidase (102645) (Goossens et al., 1996).
Crystal Structure
Fulop et al. (1998) reported the 1.4-angstrom resolution crystal structure of the porcine PREP enzyme. The enzyme contains a peptidase domain with an alpha/beta hydrolase fold, and its catalytic triad (ser554, his680, asp641) is covered by the central tunnel of an unusual beta propeller. This domain makes PREP an oligopeptidase by excluding large structured peptides from the active site. In this way, the propeller protects larger peptides and proteins from proteolysis in the cytosol.
Using fluorimetric analysis of PREP and pyroglutamyl peptidase I (PGPEP1; 610694) enzyme activity in seminal fractions from fertile men and subfertile patients, Valdivia et al. (2004) showed increased specific activities of both enzymes in necrozoospermic semen (defined as having more that 50% dead spermatozoa) in comparison to normozoospermic semen. PGEP1 activity was highest in the particulate sperm fraction, whereas PREP activity was highest in the soluble sperm fraction. Valdivia et al. (2004) hypothesized that PGPEP1 and PREP may play a role in mediating sperm death by regulating the levels of thyrotropin-releasing hormone (TRH; 613879) analogs and in mediating sperm death associated with necrozoospermia.
By fluorescence in situ hybridization, Goossens et al. (1996) mapped the PREP gene to 6q22.
Fulop, V., Bocskei, Z., Polgar, L. Prolyl oligopeptidase: an unusual beta-propeller domain regulates proteolysis. Cell 94: 161-170, 1998. [PubMed: 9695945] [Full Text: https://doi.org/10.1016/s0092-8674(00)81416-6]
Goossens, F. J., Wauters, J. G., Vanhoof, G. C., Bossuyt, P. J., Schatteman, K. A., Loens, K., Scharpe, S. L. Subregional mapping of the human lymphocyte prolyl oligopeptidase gene (PREP) to human chromosome 6q22. Cytogenet. Cell Genet. 74: 99-101, 1996. [PubMed: 8893811] [Full Text: https://doi.org/10.1159/000134391]
Valdivia, A., Irazusta, J., Fernandez, D., Mugica, J., Ochoa, C., Casis, L. Pyroglutamyl peptidase I and prolyl endopeptidase in human semen: increased activity in necrozoospermia. Regulatory Peptides 122: 79-84, 2004. [PubMed: 15380924] [Full Text: https://doi.org/10.1016/j.regpep.2004.05.005]
Vanhoof, G., Goossens, F., Hendriks, L., De Meester, I., Hendriks, D., Vriend, G., Van Broeckhoven, C., Scharpe, S. Cloning and sequence analysis of the gene encoding human lymphocyte prolyl endopeptidase. Gene 149: 363-366, 1994. [PubMed: 7959018] [Full Text: https://doi.org/10.1016/0378-1119(94)90177-5]