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]
Structureedit
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]
Inhibitorsedit
Several prolyl endopeptidase inhibitors are known,[15][16] and have been suggested as possible nootropic and antidepressant drugs.[17][18] Notable compounds include:
^ abcGRCh38: Ensembl release 89: ENSG00000085377 - Ensembl, May 2017
^"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. PMID 7959018.
^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. PMID 5120.
^Fülöp V, Szeltner Z, Polgár L (September 2000). "Catalysis of serine oligopeptidases is controlled by a gating filter mechanism". EMBO Rep. 1 (3): 277–81. doi:10.1093/embo-reports/kvd048. PMC1083722. PMID 11256612.
^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. PMID 37699425. S2CID 261704865.
^Momeni N, Nordström BM, Horstmann V, Avarseji H, Sivberg BV (2005). "Alterations of prolyl endopeptidase activity in the plasma of children with autistic spectrum disorders". BMC Psychiatry. 5: 27. doi:10.1186/1471-244X-5-27. PMC1190193. PMID 15932649.
^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. PMID 8570777. S2CID 42691937.
^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. PMID 22803098. S2CID 15088734.
^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. PMID 16690904.
^Fuhrmann G, Leroux JC (May 2011). "In vivo fluorescence imaging of exogenous enzyme activity in the gastrointestinal tract". Proc. Natl. Acad. Sci. U.S.A. 108 (22): 9032–7. Bibcode:2011PNAS..108.9032F. doi:10.1073/pnas.1100285108. PMC3107327. PMID 21576491.
^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. PMID 17215128.
^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. PMID 19006380.
^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. PMID 17700042. S2CID 27856130.
^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. PMID 19526123. S2CID 25448235.
^Yoshimoto T, Kado K, Matsubara F, Koriyama N, Kaneto H, Tsura D (December 1987). "Specific inhibitors for prolyl endopeptidase and their anti-amnesic effect". J. Pharmacobio-Dyn. 10 (12): 730–5. doi:10.1248/bpb1978.10.730. PMID 3330562.
^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. PMID 18650094.
^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. PMID 9683325. S2CID 24450362.
^Jalkanen AJ, Puttonen KA, Venäläinen JI, Sinervä V, Mannila A, Ruotsalainen S, Jarho EM, Wallén EA, Männistö PT (February 2007). "Beneficial effect of prolyl oligopeptidase inhibition on spatial memory in young but not in old scopolamine-treated rats". Basic & Clinical Pharmacology & Toxicology. 100 (2): 132–8. doi:10.1111/j.1742-7843.2006.00021.x. PMID 17244263.
^Morain P, Lestage P, De Nanteuil G, Jochemsen R, Robin JL, Guez D, Boyer PA (2002). "S 17092: a prolyl endopeptidase inhibitor as a potential therapeutic drug for memory impairment. Preclinical and clinical studies". CNS Drug Rev. 8 (1): 31–52. doi:10.1111/j.1527-3458.2002.tb00214.x. PMC6741683. PMID 12070525.
External linksedit
prolyl+endopeptidase,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Prolyl Endopeptidase entry at the National Center for Biotechnology Information
PDBe-KB provides an overview of all the structure information available in the PDB for Human Prolyl endopeptidase
prolyl, endopeptidase, also, known, prolyl, oligopeptidase, post, proline, cleaving, enzyme, enzyme, that, humans, encoded, prep, gene, prepavailable, structurespdbortholog, search, pdbe, rcsblist, codes3dduidentifiersaliasesprep, prolyl, endopeptidaseexternal. Prolyl endopeptidase PE also known as prolyl oligopeptidase or post proline cleaving enzyme is an enzyme that in humans is encoded by the PREP gene 4 5 PREPAvailable structuresPDBOrtholog search PDBe RCSBList of PDB id codes3DDUIdentifiersAliasesPREP PE PEP prolyl endopeptidaseExternal IDsOMIM 600400 MGI 1270863 HomoloGene 2042 GeneCards PREPGene location Human Chr Chromosome 6 human 1 Band6q21Start105 273 218 bp 1 End105 454 062 bp 1 RNA expression patternBgeeHumanMouse ortholog Top expressed insecondary oocytegastrocnemius musclerectumtriceps brachii musclebiceps brachiistromal cell of endometriumskin of abdomenmonocyteduodenummiddle temporal gyrusn aMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functionserine type exopeptidase activity peptidase activity serine type peptidase activity serine type endopeptidase activity protein binding hydrolase activity endopeptidase activity oligopeptidase activityCellular componentmembrane nucleus cytoplasm cytosolBiological processproteolysisSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez555019072EnsemblENSG00000085377ENSMUSG00000019849UniProtP48147Q9QUR6RefSeq mRNA NM 002726NM 011156RefSeq protein NP 002717NP 035286Location UCSC Chr 6 105 27 105 45 Mbn aPubMed search 2 3 WikidataView Edit HumanView Edit Mouse Contents 1 Function 2 Structure 3 Clinical significance 4 Inhibitors 5 References 6 External linksFunction editprolyl oligopeptidaseIdentifiersEC no 3 4 21 26CAS no 72162 84 6DatabasesIntEnzIntEnz viewBRENDABRENDA entryExPASyNiceZyme viewKEGGKEGG entryMetaCycmetabolic pathwayPRIAMprofilePDB structuresRCSB PDB PDBe PDBsumGene OntologyAmiGO QuickGOSearchPMCarticlesPubMedarticlesNCBIproteinsProlyl endopeptidase is a large cytosolic enzyme that belongs to a distinct class of serine peptidases It was first described in the cytosol of rabbit brain as an oligopeptidase which degrades the nonapeptide bradykinin at the Pro Phe bond 6 The enzyme is involved in the maturation and degradation of peptide hormones and neuropeptides such as alpha melanocyte stimulating hormone luteinizing hormone releasing hormone LH RH thyrotropin releasing hormone angiotensin neurotensin oxytocin substance P and vasopressin 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 Prolyl endopeptidases are involved in the maturation and degradation of peptide hormones and neuropeptides 5 Structure editProlyl 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 Clinical significance editAltered PREP activity may be associated with autism spectrum disorders and various psychological diseases such as schizophrenia mania and clinical depression 10 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 editSeveral prolyl endopeptidase inhibitors are known 15 16 and have been suggested as possible nootropic and antidepressant drugs 17 18 Notable compounds include Pramiracetam 19 Baicalin 20 JTP 4819 21 KYP 2047 22 S 17092 23 BerberineReferences edit a b c GRCh38 Ensembl release 89 ENSG00000085377 Ensembl May 2017 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 PMID 7959018 a b Entrez Gene PREP prolyl endopeptidase 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 PMID 5120 Fulop V Bocskei Z Polgar L July 1998 Prolyl oligopeptidase an unusual beta propeller domain regulates proteolysis Cell 94 2 161 70 doi 10 1016 S0092 8674 00 81416 6 PMID 9695945 S2CID 17074611 Fulop V Szeltner Z Polgar L September 2000 Catalysis of serine oligopeptidases is controlled by a gating filter mechanism EMBO Rep 1 3 277 81 doi 10 1093 embo reports kvd048 PMC 1083722 PMID 11256612 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 PMID 37699425 S2CID 261704865 Momeni N Nordstrom BM Horstmann V Avarseji H Sivberg BV 2005 Alterations of prolyl endopeptidase activity in the plasma of children with autistic spectrum disorders BMC Psychiatry 5 27 doi 10 1186 1471 244X 5 27 PMC 1190193 PMID 15932649 Maes M Goossens F Scharpe 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 PMID 8570777 S2CID 42691937 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 PMID 22803098 S2CID 15088734 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 PMID 16690904 Fuhrmann G Leroux JC May 2011 In vivo fluorescence imaging of exogenous enzyme activity in the gastrointestinal tract Proc Natl Acad Sci U S A 108 22 9032 7 Bibcode 2011PNAS 108 9032F doi 10 1073 pnas 1100285108 PMC 3107327 PMID 21576491 Jarho EM Venalainen 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 PMID 17215128 Kanai K Aranyi P Bocskei 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 PMID 19006380 Morain P Boeijinga PH Demazieres 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 PMID 17700042 S2CID 27856130 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 PMID 19526123 S2CID 25448235 Yoshimoto T Kado K Matsubara F Koriyama N Kaneto H Tsura D December 1987 Specific inhibitors for prolyl endopeptidase and their anti amnesic effect J Pharmacobio Dyn 10 12 730 5 doi 10 1248 bpb1978 10 730 PMID 3330562 Tarrago T Kichik N Claasen B Prades R Teixido 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 PMID 18650094 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 PMID 9683325 S2CID 24450362 Jalkanen AJ Puttonen KA Venalainen JI Sinerva V Mannila A Ruotsalainen S Jarho EM Wallen EA Mannisto PT February 2007 Beneficial effect of prolyl oligopeptidase inhibition on spatial memory in young but not in old scopolamine treated rats Basic amp Clinical Pharmacology amp Toxicology 100 2 132 8 doi 10 1111 j 1742 7843 2006 00021 x PMID 17244263 Morain P Lestage P De Nanteuil G Jochemsen R Robin JL Guez D Boyer PA 2002 S 17092 a prolyl endopeptidase inhibitor as a potential therapeutic drug for memory impairment Preclinical and clinical studies CNS Drug Rev 8 1 31 52 doi 10 1111 j 1527 3458 2002 tb00214 x PMC 6741683 PMID 12070525 External links editprolyl endopeptidase human at the U S National Library of Medicine Medical Subject Headings MeSH Prolyl Endopeptidase entry at the National Center for Biotechnology Information PDBe KB provides an overview of all the structure information available in the PDB for Human Prolyl endopeptidase Portal nbsp Biology Retrieved from https en wikipedia org w index php title Prolyl endopeptidase amp oldid 1191166394, wikipedia, wiki, book, books, library,
