Prolyl endopeptidase

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]

PREP
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPREP, PE, PEP, prolyl endopeptidase
External IDsOMIM: 600400; MGI: 1270863; HomoloGene: 2042; GeneCards: PREP; OMA:PREP - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_002726

NM_011156

RefSeq (protein)

NP_002717

NP_035286

Location (UCSC)Chr 6: 105.27 – 105.45 Mbn/a
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

Function

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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
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

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

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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

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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

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

References

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