Prolyl endopeptidase (PE) also known as prolyl oligopeptidase or post-proline cleaving enzyme is an enzyme that in humans is encoded by the PREPgene.[4][5]
Prolyl endopeptidases are involved in the maturation and degradation of peptide hormones and neuropeptides.[5]
Structure
Prolyl endopeptidase is a cytosolic prolyl endopeptidase that cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long. Only short protein residues are able to enter the active site of prolyl endopeptidase due to the distinct beta-propeller region that acts as a gating filter mechanism.[7][8]
Prolyl endopeptidase was also found to be involved in the metabolism of VHL-PROTACs in in vitro studies.[9]
However, there is conflicting information as to the exact role that prolyl endopeptidase plays in the pathophysiology of depression, with earlier studies documenting a decreased activity of the enzyme in depressed patients, but more recent studies demonstrating that inhibition of the same enzyme actually results in alleviation of depressive symptoms.[11][12]
Some types of prolyl endopeptidase have been used in studies to decrease the propensity of gluten-containing wheat products to aggravate coeliac disease.[13] However, orally administered enzymes are potentially subject to inactivation in the gastrointestinal tract.[14]
Inhibitors
Several prolyl endopeptidase inhibitors are known,[15][16] and have been suggested as possible nootropic and antidepressant drugs.[17][18] Notable compounds include:
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Vanhoof G, Goossens F, Hendriks L, De Meester I, Hendriks D, Vriend G, Van Broeckhoven C, Scharpe S (Dec 1994). "Cloning and sequence analysis of the gene encoding human lymphocyte prolyl endopeptidase". Gene. 149 (2): 363–6. doi:10.1016/0378-1119(94)90177-5. PMID7959018.
^Oliveira EB, Martins AR, Camargo AC (May 1976). "Isolation of brain endopeptidases: Influence of size and sequence of substrates structurally related to bradykinin". Biochemistry. 15 (9): 1967–74. doi:10.1021/bi00654a026. PMID5120.
^Castellani B, Eleuteri M, Di Bona S, Cruciani G, Desantis J, Goracci L (September 2023). "VHL-Modified PROteolysis TArgeting Chimeras (PROTACs) as a Strategy to Evade Metabolic Degradation in In Vitro Applications". Journal of Medicinal Chemistry. 66 (18): 13148–71. doi:10.1021/acs.jmedchem.3c01144. PMID37699425. S2CID261704865.
^Maes M, Goossens F, Scharpé S, Calabrese J, Desnyder R, Meltzer HY (1995). "Alterations in plasma prolyl endopeptidase activity in depression, mania, and schizophrenia: effects of antidepressants, mood stabilizers, and antipsychotic drugs". Psychiatry Res. 58 (3): 217–25. doi:10.1016/0165-1781(95)02698-V. PMID8570777. S2CID42691937.
^Khlebnikova NN, Krupina NA, Kushnareva EY, Zolotov NN, Kryzhanovskii GN (2012). "Effect of imipramine and prolyl endopeptidase inhibitor benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine on activity of proline-specific peptidases in the brain of rats with experimental anxious-depressive syndrome". Bull Exp Biol Med. 152 (4): 409–12. doi:10.1007/s10517-012-1540-z. PMID22803098. S2CID15088734.
^Stepniak D, Spaenij-Dekking L, Mitea C, et al. (Oct 2006). "Highly efficient gluten degradation with a newly identified prolyl endoprotease: implications for celiac disease". Am J Physiol Gastrointest Liver Physiol. 291 (4): G621–9. doi:10.1152/ajpgi.00034.2006. PMID16690904.
^Jarho EM, Venäläinen JI, Poutiainen S, et al. (March 2007). "2(S)-(Cycloalk-1-enecarbonyl)-1-(4-phenyl-butanoyl)pyrrolidines and 2(S)-(aroyl)-1-(4-phenylbutanoyl)pyrrolidines as prolyl oligopeptidase inhibitors". Bioorg. Med. Chem. 15 (5): 2024–31. doi:10.1016/j.bmc.2006.12.036. PMID17215128.
^Kánai K, Arányi P, Böcskei Z, et al. (December 2008). "Prolyl oligopeptidase inhibition by N-acyl-pro-pyrrolidine-type molecules". J. Med. Chem. 51 (23): 7514–22. doi:10.1021/jm800944x. PMID19006380.
^Morain P, Boeijinga PH, Demazières A, De Nanteuil G, Luthringer R (2007). "Psychotropic profile of S 17092, a prolyl endopeptidase inhibitor, using quantitative EEG in young healthy volunteers". Neuropsychobiology. 55 (3–4): 176–83. doi:10.1159/000107070. PMID17700042. S2CID27856130.
^Khlebnikova NN, Krupina NA, Bogdanova NG, Zolotov NN, Kryzhanovskii GN (January 2009). "Effects of prolylendopeptidase inhibitor benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine on experimental depressive syndrome development in rats". Bull. Exp. Biol. Med. 147 (1): 26–30. doi:10.1007/s10517-009-0458-6. PMID19526123. S2CID25448235.
^Tarragó T, Kichik N, Claasen B, Prades R, Teixidó M, Giralt E (August 2008). "Baicalin, a prodrug able to reach the CNS, is a prolyl oligopeptidase inhibitor". Bioorg. Med. Chem. 16 (15): 7516–24. doi:10.1016/j.bmc.2008.04.067. PMID18650094.
^Toide K, Shinoda M, Miyazaki A (1998). "A novel prolyl endopeptidase inhibitor, JTP-4819--its behavioral and neurochemical properties for the treatment of Alzheimer's disease". Rev Neurosci. 9 (1): 17–29. doi:10.1515/revneuro.1998.9.1.17. PMID9683325. S2CID24450362.
