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In humans, prolyl endopeptidase is encoded by the ''PREP'' [[gene]].<ref name="pmid7959018">{{cite journal | author = Vanhoof G, Goossens F, Hendriks L, De Meester I, Hendriks D, Vriend G, Van Broeckhoven C, Scharpe S | title = [[Cloning]] and sequence analysis of the gene encoding human [[lymphocyte]] prolyl endopeptidase | journal = Gene | volume = 149 | issue = 2 | pages = 363–6 | year = 1994 | month = Dec | pmid = 7959018 | pmc = | doi =10.1016/0378-1119(94)90177-5 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: PREP prolyl endopeptidase| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5550| accessdate = }}</ref> The protein encoded by this gene 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 acid]]s 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.<ref name="Fulop 1998">{{cite journal | title = Prolyl Oligopeptidase: An Unusual b-Propeller Domain Regulates Proteolysis | author = V. Fulop, Z. Bocskei, L. Polgar | journal = Cell | volume = 94 | year = 1998 | page = 161 | url = http://ac.els-cdn.com/S0092867400814166/1-s2.0-S0092867400814166-main.pdf?_tid=34c234b2473fd5aef9b0fb87faa3111d&acdnat=1336601668_816a9e212f80d61785a0f7ff460d982b}}</ref><ref name ="Fulop 2002">{{cite journal | author = V. Fulop, Z. Szeltner, L. Polgar | journal = EMBO Rep. | volume = 1 | year = 2000 | page = 277 | title = Catalysis of serine oligopeptidases is controlled by a gating filter mechanism | url = http://www.nature.com.ezp2.lib.umn.edu/embor/journal/v1/n3/full/embor589.html | issue=3}}</ref> Prolyl endopeptidases have been reported to be involved in the maturation and degradation of peptide [[hormone]]s and [[neuropeptide]]s.<ref name="entrez"/> There's an indication that altered PREP activity is associated with [[autism spectrum disorder]]s and various psychological diseases such as [[schizophrenia]], [[mania]] and [[clinical depression]].<ref>{{cite journal |author=Momeni N, Nordström BM, Horstmann V, Avarseji H, Sivberg BV |title=Alterations of prolyl endopeptidase activity in the plasma of children with autistic spectrum disorders |journal=BMC Psychiatry |volume=5 |pages=27 |year=2005 |pmid=15932649 |pmc=1190193 |doi=10.1186/1471-244X-5-27 }}</ref>
In humans, prolyl endopeptidase is encoded by the ''PREP'' [[gene]].<ref name="pmid7959018">{{cite journal | author = Vanhoof G, Goossens F, Hendriks L, De Meester I, Hendriks D, Vriend G, Van Broeckhoven C, Scharpe S | title = [[Cloning]] and sequence analysis of the gene encoding human [[lymphocyte]] prolyl endopeptidase | journal = Gene | volume = 149 | issue = 2 | pages = 363–6 | year = 1994 | month = Dec | pmid = 7959018 | pmc = | doi =10.1016/0378-1119(94)90177-5 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: PREP prolyl endopeptidase| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5550| accessdate = }}</ref> The protein encoded by this gene 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 acid]]s 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.<ref name="Fulop 1998">{{cite journal | title = Prolyl Oligopeptidase: An Unusual b-Propeller Domain Regulates Proteolysis | author = V. Fulop, Z. Bocskei, L. Polgar | journal = Cell | volume = 94 | year = 1998 | page = 161 | url = http://ac.els-cdn.com/S0092867400814166/1-s2.0-S0092867400814166-main.pdf?_tid=34c234b2473fd5aef9b0fb87faa3111d&acdnat=1336601668_816a9e212f80d61785a0f7ff460d982b}}</ref><ref name ="Fulop 2002">{{cite journal | author = V. Fulop, Z. Szeltner, L. Polgar | journal = EMBO Rep. | volume = 1 | year = 2000 | page = 277 | title = Catalysis of serine oligopeptidases is controlled by a gating filter mechanism | url = http://www.nature.com.ezp2.lib.umn.edu/embor/journal/v1/n3/full/embor589.html | issue=3}}</ref> Prolyl endopeptidases have been reported to be involved in the maturation and degradation of peptide [[hormone]]s and [[neuropeptide]]s.<ref name="entrez"/> There's an indication that altered PREP activity is associated with [[autism spectrum disorder]]s and various psychological diseases such as [[schizophrenia]], [[mania]] and [[clinical depression]].<ref>{{cite journal |author=Momeni N, Nordström BM, Horstmann V, Avarseji H, Sivberg BV |title=Alterations of prolyl endopeptidase activity in the plasma of children with autistic spectrum disorders |journal=BMC Psychiatry |volume=5 |pages=27 |year=2005 |pmid=15932649 |pmc=1190193 |doi=10.1186/1471-244X-5-27 }}</ref>
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. <ref>{{cite journal |author=Maes M, Goossens F, Scharpé S, Calabrese J, Desnyder R, Meltzer HY |title=Alterations in plasma prolyl endopeptidase activity in depression, mania, and schizophrenia: effects of antidepressants, mood stabilizers, and antipsychotic drugs. |journal=Psychiatry Res. |volume=58 |pages=9 |year=1995 |pmid=8570777 |pmc=1190193 |doi=10.1186/1471-244X-5-27 }}</ref>
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. <ref>{{cite journal |author=Maes M, Goossens F, Scharpé S, Calabrese J, Desnyder R, Meltzer HY |title=Alterations in plasma prolyl endopeptidase activity in depression, mania, and schizophrenia: effects of antidepressants, mood stabilizers, and antipsychotic drugs. |journal=Psychiatry Res. |volume=58 |pages=9 |year=1995 |pmid=8570777 |pmc=1190193 |doi=10.1186/1471-244X-5-27 }}</ref><ref>{{cite journal |author=Khlebnikova NN, Krupina NA, Kushnareva EY, Zolotov NN, Kryzhanovskii GN |title=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. |journal=Bull Exp Biol Med. |volume=152 |pages=4 |year=2012 |pmid=22803098 }}</ref>


==Inhibitors==
==Inhibitors==

Revision as of 15:15, 2 September 2013

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prolyl oligopeptidase
Identifiers
EC no.3.4.21.26
CAS no.72162-84-6
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
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Gene OntologyAmiGO / QuickGO
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PMCarticles
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Prolyl endopeptidase (PREP) or prolyl oligopeptidase, sometimes post-proline cleaving enzyme) 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.[1] 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.

Some types of prolyl endopeptidase have been used in studies to decrease the propensity of gluten-containing wheat products to aggravate coeliac disease.[2] However, orally administered enzymes are potentially subject to inactivation in the gastrointestinal tract.[3]

In humans, prolyl endopeptidase is encoded by the PREP gene.[4][5] The protein encoded by this gene 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.[6][7] Prolyl endopeptidases have been reported to be involved in the maturation and degradation of peptide hormones and neuropeptides.[5] There's an indication that altered PREP activity is associated with autism spectrum disorders and various psychological diseases such as schizophrenia, mania and clinical depression.[8] 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. [9][10]

Inhibitors

Several prolyl endopeptidase inhibitors are known,[11][12] and have been suggested as possible nootropic and antidepressant drugs.[13][14] Notable compounds include

References

  1. ^ Oliveira EB, Martins AR, Camargo ACM (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ Stepniak D, Spaenij-Dekking L, Mitea C; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Fuhrmann G, Leroux JC (2011) In vivo fluorescence imaging of exogenous enzyme activity in the gastrointestinal tract. Proceedings of the National Academy of Sciences, 108, 9032-9037 [1]
  4. ^ Vanhoof G, Goossens F, Hendriks L, De Meester I, Hendriks D, Vriend G, Van Broeckhoven C, Scharpe S (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ a b "Entrez Gene: PREP prolyl endopeptidase".
  6. ^ V. Fulop, Z. Bocskei, L. Polgar (1998). "Prolyl Oligopeptidase: An Unusual b-Propeller Domain Regulates Proteolysis" (PDF). Cell. 94: 161.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ V. Fulop, Z. Szeltner, L. Polgar (2000). "Catalysis of serine oligopeptidases is controlled by a gating filter mechanism". EMBO Rep. 1 (3): 277.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  9. ^ 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: 9. doi:10.1186/1471-244X-5-27. PMC 1190193. PMID 8570777.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  10. ^ 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. PMID 22803098.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Jarho EM, Venäläinen JI, Poutiainen S; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Kánai K, Arányi P, Böcskei Z; et al. (2008). "Prolyl oligopeptidase inhibition by N-acyl-pro-pyrrolidine-type molecules". J. Med. Chem. 51 (23): 7514–22. doi:10.1021/jm800944x. PMID 19006380. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ Khlebnikova NN, Krupina NA, Bogdanova NG, Zolotov NN, Kryzhanovskii GN (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. PMID 19526123. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  15. ^ Yoshimoto T, Kado K, Matsubara F, Koriyama N, Kaneto H, Tsura D. "Pramiracetam, a nootropic drug, is a prolyl oligopeptidase inhibitor". J Pharmacobiodyn.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ Tarragó T, Kichik N, Claasen B, Prades R, Teixidó M, Giralt E (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ 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. PMID 9683325.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Jalkanen AJ, Puttonen KA, Venäläinen JI, Sinervä V, Mannila A, Ruotsalainen S, Jarho EM, Wallén EA, Männistö PT (2007). "Beneficial effect of prolyl oligopeptidase inhibition on spatial memory in young but not in old scopolamine-treated rats". Basic Clin. Pharmacol. Toxicol. 100 (2): 132–8. doi:10.1111/j.1742-7843.2006.00021.x. PMID 17244263. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  19. ^ 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. PMID 12070525.{{cite journal}}: CS1 maint: multiple names: authors list (link)

Further reading

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