Prolyl endopeptidase

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PubMed	articles
NCBI	proteins

prolyl oligopeptidase
prolyl oligopeptidase
Identifiers
EC no.	3.4.21.26
CAS no.	72162-84-6
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
PMC
Search
PMC	articles
PubMed	articles
NCBI	proteins

PREP
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	3DDU
Identifiers
Aliases	PREP, PE, PEP, prolyl endopeptidase
External IDs	OMIM: 600400; MGI: 1270863; HomoloGene: 2042; GeneCards: PREP; OMA:PREP - orthologs
Gene location (Human)
Chr.	Chromosome 6 (human)
End	105,454,062 bp
RNA expression pattern
	Top expressed in
	secondary oocyte; ; gastrocnemius muscle; ; mucosa of transverse colon; ; rectum; ; triceps brachii muscle; ; muscle of thigh; ; Skeletal muscle tissue of rectus abdominis; ; glutes; ; mucosa of sigmoid colon; ; biceps brachii;
	n/a
	More reference expression data
	; ;
	More reference expression data
Gene ontology
Molecular function	serine-type exopeptidase activity; peptidase activity; serine-type peptidase activity; serine-type endopeptidase activity; protein binding; hydrolase activity; endopeptidase activity; oligopeptidase activity;
Cellular component	membrane; nucleus; cytoplasm; cytosol;
Biological process	proteolysis;
	Sources:Amigo / QuickGO
Orthologs
	5550
	19072
	ENSG00000085377
	ENSMUSG00000019849
	P48147
	Q9QUR6
	NM_002726
	NM_011156
	NP_002717
	NP_035286
	Wikidata
View/Edit Human	View/Edit Mouse

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]

Function

Prolyl 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

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]

Clinical significance

Altered 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

Several prolyl endopeptidase inhibitors are known,^[15]^[16] and have been suggested as possible nootropic and antidepressant drugs.^[17]^[18] Notable compounds include:

References

^ ^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.
^ Fülöp V, Böcskei Z, Polgár 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.
^ 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. 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, 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. PMC 1190193. 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. PMC 3107327. 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. PMC 6741683. PMID 12070525.

External links

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

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000085377 – Ensembl, May 2017

[2] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[3] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid7959018-4] 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.

[entrez-5] "Entrez Gene: PREP prolyl endopeptidase".

[6] 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_1998-7] Fülöp V, Böcskei Z, Polgár 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.

[Fülöp_2002-8] 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. PMC 1083722. PMID 11256612.

[Castellani_2023-9] 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.

[10] 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. PMC 1190193. PMID 15932649.

[11] 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.

[12] 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.

[13] 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.

[pmid21576491-14] 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.

[15] 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.

[16] 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.

[17] 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.

[18] 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.

[pmid3330562-19] 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.

[pmid18650094-20] 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.

[pmid9683325-21] 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.

[pmid17244263-22] 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.

[pmid12070525-23] 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.

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v t e Endopeptidases: serine proteases/serine endopeptidases (EC 3.4.21)
Digestive enzymes	Enteropeptidase Trypsin Chymotrypsin Elastase Neutrophil Pancreatic
Coagulation	factors: Thrombin Factor VIIa Factor IXa Factor Xa Factor XIa Factor XIIa Kallikrein PSA KLK1 KLK2 KLK3 KLK4 KLK5 KLK6 KLK7 KLK8 KLK9 KLK10 KLK11 KLK12 KLK13 KLK14 KLK15 fibrinolysis: Plasmin Plasminogen activator Tissue plasminogen activator Urinary plasminogen activator
Complement system	Factor B Factor D Factor I MASP MASP1 MASP2 C3-convertase
Other immune system	Chymase Granzyme Tryptase Proteinase 3/Myeloblastin
Venombin	Ancrod Batroxobin
Other	Acrosin Prolyl endopeptidase Pronase Proprotein convertases 1 2 Prostasin Reelin Subtilisin/Furin/S1P4 Sedolisin/TPP1 Streptokinase Cathepsin A G

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)