Prolyl endopeptidase

Last updated
PREP
Protein PREP PDB 1e5t.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PREP , PE, PEP, prolyl endopeptidase
External IDs OMIM: 600400 MGI: 1270863 HomoloGene: 2042 GeneCards: PREP
Orthologs
SpeciesHumanMouse
Entrez

5550

19072

Ensembl

ENSG00000085377

ENSMUSG00000019849

UniProt

P48147

Q9QUR6

RefSeq (mRNA)

NM_002726

NM_011156

RefSeq (protein)

NP_002717

NP_035286

Location (UCSC) Chr 6: 105.27 – 105.45 Mb n/a
PubMed search [2] [3]
Wikidata
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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]

Contents

Function

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
Search
PMC articles
PubMed articles
NCBI proteins

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:

Related Research Articles

Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group -NH
2 but is rather a secondary amine. The secondary amine nitrogen is in the protonated form (NH2+) under biological conditions, while the carboxyl group is in the deprotonated −COO− form. The "side chain" from the α carbon connects to the nitrogen forming a pyrrolidine loop, classifying it as a aliphatic amino acid. It is non-essential in humans, meaning the body can synthesize it from the non-essential amino acid L-glutamate. It is encoded by all the codons starting with CC (CCU, CCC, CCA, and CCG).

<span class="mw-page-title-main">Angiotensin-converting enzyme</span> Mammalian protein found in humans

Angiotensin-converting enzyme, or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconstrictor angiotensin II. Therefore, ACE indirectly increases blood pressure by causing blood vessels to constrict. ACE inhibitors are widely used as pharmaceutical drugs for treatment of cardiovascular diseases.

In molecular biology, immunophilins are endogenous cytosolic peptidyl-prolyl isomerases (PPI) that catalyze the interconversion between the cis and trans isomers of peptide bonds containing the amino acid proline (Pro). They are chaperone molecules that generally assist in the proper folding of diverse "client" proteins. Immunophilins are traditionally classified into two families that differ in sequence and biochemical characteristics. These two families are: "cyclosporin-binding cyclophilins (CyPs)" and "FK506-binding proteins (FKBPs)". In 2005, a group of dual-family immunophilins (DFI) has been discovered, mostly in unicellular organisms; these DFIs are natural chimera of CyP and FKBPs, fused in either order.

<span class="mw-page-title-main">Dipeptidyl peptidase-4</span> Mammalian protein found in Homo sapiens

Dipeptidyl peptidase-4, also known as adenosine deaminase complexing protein 2 or CD26 is a protein that, in humans, is encoded by the DPP4 gene. DPP4 is related to FAP, DPP8, and DPP9. The enzyme was discovered in 1966 by Hopsu-Havu and Glenner, and as a result of various studies on chemism, was called dipeptidyl peptidase IV [DP IV].

<span class="mw-page-title-main">Neprilysin</span> Mammalian protein found in Homo sapiens

Neprilysin, also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), cluster of differentiation 10 (CD10), and common acute lymphoblastic leukemia antigen (CALLA) is an enzyme that in humans is encoded by the MME gene. Neprilysin is a zinc-dependent metalloprotease that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including glucagon, enkephalins, substance P, neurotensin, oxytocin, and bradykinin. It also degrades the amyloid beta peptide whose abnormal folding and aggregation in neural tissue has been implicated as a cause of Alzheimer's disease. Synthesized as a membrane-bound protein, the neprilysin ectodomain is released into the extracellular domain after it has been transported from the Golgi apparatus to the cell surface.

<span class="mw-page-title-main">Carboxypeptidase E</span> Protein-coding gene in the species Homo sapiens

Carboxypeptidase E (CPE), also known as carboxypeptidase H (CPH) and enkephalin convertase, is an enzyme that in humans is encoded by the CPE gene. This enzyme catalyzes the release of C-terminal arginine or lysine residues from polypeptides.

<span class="mw-page-title-main">PHEX</span> Protein-coding gene in the species Homo sapiens

Phosphate-regulating endopeptidase homolog X-linked also known as phosphate-regulating gene with homologies to endopeptidases on the X chromosome or metalloendopeptidase homolog PEX is an enzyme that in humans is encoded by the PHEX gene. This gene contains 18 exons and is located on the X chromosome.

<span class="mw-page-title-main">Procollagen-proline dioxygenase</span> Enzyme

Procollagen-proline dioxygenase, commonly known as prolyl hydroxylase, is a member of the class of enzymes known as alpha-ketoglutarate-dependent hydroxylases. These enzymes catalyze the incorporation of oxygen into organic substrates through a mechanism that requires alpha-Ketoglutaric acid, Fe2+, and ascorbate. This particular enzyme catalyzes the formation of (2S, 4R)-4-hydroxyproline, a compound that represents the most prevalent post-translational modification in the human proteome.

<span class="mw-page-title-main">Fibroblast activation protein, alpha</span>

Fibroblast activation protein alpha (FAP-alpha) also known as prolyl endopeptidase FAP is an enzyme that in humans is encoded by the FAP gene.

<span class="mw-page-title-main">EGLN1</span> Protein-coding gene in the species Homo sapiens

Hypoxia-inducible factor prolyl hydroxylase 2 (HIF-PH2), or prolyl hydroxylase domain-containing protein 2 (PHD2), is an enzyme encoded by the EGLN1 gene. It is also known as Egl nine homolog 1. PHD2 is a α-ketoglutarate/2-oxoglutarate-dependent hydroxylase, a superfamily non-haem iron-containing proteins. In humans, PHD2 is one of the three isoforms of hypoxia-inducible factor-proline dioxygenase, which is also known as HIF prolyl-hydroxylase.

<span class="mw-page-title-main">THOP1</span> Protein-coding gene in the species Homo sapiens

Thimet oligopeptidase is an enzyme that in humans is encoded by the THOP1 gene.

<span class="mw-page-title-main">NLN (gene)</span> Protein-coding gene in the species Homo sapiens

Neurolysin, mitochondrial is a protein that in humans is encoded by the NLN gene. It is a 78-kDa enzyme, widely distributed in mammalian tissues and found in various subcellular locations that vary with cell type. Neurolysin exemplifies the ability of neuropeptidases to target various cleavage site sequences by hydrolyzing them in vitro, and metabolism of neurotensin is the most important role of neurolysin in vivo. Neurolysin has also been implicated in pain control, blood pressure regulation, sepsis, reproduction, cancer biology pathogenesis of stroke, and glucose metabolism.

<span class="mw-page-title-main">XPNPEP1</span> Protein-coding gene in the species Homo sapiens

Xaa-Pro aminopeptidase 1 is an enzyme that in humans is encoded by the XPNPEP1 gene.

<span class="mw-page-title-main">PREPL</span> Protein-coding gene in the species Homo sapiens

Prolyl endopeptidase-like is an enzyme that in humans is encoded by the PREPL gene.

Dipeptidyl peptidase-4 inhibitors are enzyme inhibitors that inhibit the enzyme dipeptidyl peptidase-4 (DPP-4). They are used in the treatment of type 2 diabetes mellitus. Inhibition of the DPP-4 enzyme prolongs and enhances the activity of incretins that play an important role in insulin secretion and blood glucose control regulation. Type 2 diabetes mellitus is a chronic metabolic disease that results from inability of the β-cells in the pancreas to secrete sufficient amounts of insulin to meet the body's needs. Insulin resistance and increased hepatic glucose production can also play a role by increasing the body's demand for insulin. Current treatments, other than insulin supplementation, are sometimes not sufficient to achieve control and may cause undesirable side effects, such as weight gain and hypoglycemia. In recent years, new drugs have been developed, based on continuing research into the mechanism of insulin production and regulation of the metabolism of sugar in the body. The enzyme DPP-4 has been found to play a significant role.

<span class="mw-page-title-main">S-17092</span> Chemical compound

S-17092 is a drug which acts as a selective inhibitor of the enzyme prolyl endopeptidase. This enzyme is involved in the metabolic breakdown of a number of neuropeptide neurotransmitters in the brain, and so inhibiting the action of the enzyme increases the activity of these neuropeptides. This produces nootropic effects which make S-17092 a promising and novel treatment for neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease.

<span class="mw-page-title-main">Oligopeptidase</span> Enzymes that cleaves peptides but not proteins

An Oligopeptidase is an enzyme that cleaves peptides but not proteins. This property is due to its structure: the active site of this enzyme is located at the end of a narrow cavity which can only be reached by peptides.

<span class="mw-page-title-main">KIAA0922</span> Protein-coding gene in the species Homo sapiens

Transmembrane protein 131-like, alternatively named uncharacterized protein KIAA0922, is an integral transmembrane protein encoded by the human gene KIAA0922 that is significantly conserved in eukaryotes, at least through protists. Although the function of this gene is not yet fully elucidated, initial microarray evidence suggests that it may be involved in immune responses. Furthermore, its paralog, prolyl endopeptidase (PREP) whose function is known, provides clues as to the function of TMEM131L.

<span class="mw-page-title-main">Semax</span> Chemical compound

Semax is a drug which is used mostly in Russia for a broad range of conditions but predominantly for its purported nootropic, neuroprotective, and neurorestorative properties. Semax has not been evaluated, approved for use, or marketed in most other countries. It is prescribed in eastern Europe and Russia for brain trauma.

Hypoxia-inducible factor-proline dioxygenase (EC 1.14.11.29, HIF hydroxylase) is an enzyme with systematic name hypoxia-inducible factor-L-proline, 2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating). This enzyme catalyses the following chemical reaction

References

  1. 1 2 3 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.
  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.
  5. 1 2 "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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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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