Katson geeneistä PREP ja PREPL jotain niiden vaikutuksista.

Tämä on vasta bulk-alkuhakua. Katson ajan mittaan vähän vähemmäksi tämän artikkelin  sisällön. Kyse on prolyyliä pilkkova entsyymi. se pilkkoo oligopeptidin C_terminaalista. PREPL ei pilko   arginiinin tai lysiinin jälkeen (R tai K)  ja se on muutenkin  erilainen hieman rakennepiirteiltään, kuten esim  sisältää runsaasti  cysteinejä (C) ihan  riittäisi sinkkisormeksikin ja rakenne on miltei  puolipropellinen.  Toimivatkohan nuo peräkanaa?

 

(*) TÄSTÄ KIRJOITTAA DUODECIM  11/23

Katson GENECARDS lähteestä : “PREP” ja sen jälkeen PREP

Tekstit mainitsevat että se jollain tavalla osallistuu inositolin aineenvaihduntaan, joten katson tarkemmin. Lisäksi se puuttuu QPPAQP etc. sisältävien peptidien pilkkoutumiseen. Joita uodostuss gluteenipitoisesta ravinnosta. Huomaan että se on selektiivisesstio peptidien C-terminaalisen proliinin pilkkoja ja tuotaa oligopeptidilopputuotteita eikä esim. erillisiä proliineja tai erillisiäaminohappoja. Sen rakenteessa ei näy tavallisia Znf sinkkisormimahdollisuuksia. Se on aika järjestäytynyt beetanauhojensa ja alfahelixiensä suhteen.Se ei vaikuta suoraan sigannlivälittäjään IP3 itse vaan sen kinaasisäätelyjärjestelmään, joka on saateaa olla laaja. Siitä tietoisuus on kasvanut nyt vuosituhannen vaihteen jälkeen.

* HAKU GENE CARDS “PREP Showing 25 of 2,755 results for PREP Search Time: 0 ms.

PREP (6q21).  Prolyl oligoendopeptidases                    GENECARDS haku 12.6. 2023 .

Aliases for PREP Gene

• GeneCards Symbol: PREP 2

• Prolyl Endopeptidase 2 3 4 5

• Post-Proline Cleaving Enzyme 3 4

• Prolyl Oligopeptidase 2 3

• EC 3.4.21.26 4 48

• PEP 3 4

• PE 3 4

• DJ355L5.1 (Prolyl Endopeptidase) 3

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. Prolyl endopeptidases have been reported to be involved in the maturation and degradation of peptide hormones and neuropeptides. [provided by RefSeq, Jul 2008]

GeneCards Summary for PREP Gene: PREP (Prolyl Endopeptidase) is a Protein Coding gene. Diseases associated with PREP include Amnestic Disorder and Post-Traumatic Stress Disorder. Gene Ontology (GO) annotations related to this gene include serine-type endopeptidase activity and serine-type exopeptidase activity. An important paralog of this gene is PREPL. 

  UniProtKB/Swiss-Prot Summary for PREP Gene: Cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long. ( PPCE_HUMAN,P48147 )

Show:

		Symbol	Description	Category	UniProt ID	GIFtS	GC id	Score ▼
1		PREP	Prolyl Endopeptidase	Protein Coding	P48147	49	GC06M105277	43.35
Header Symbol: PREP Publications (5/19) See All Prolyl oligopeptidase enhances α-synuclein...protein-protein interaction. (PMID: 25555914) Abstract: ...oligopeptidase (PREP) accelerates the aggregation of α-synuclein (aSyn)...of Parkinson disease and other synucleinopathies. PREP inhibitors reduce aSyn aggregation, but the mechanism...microscale thermophoresis in parallel to show that PREP interacts directly with aSyn in both intact cells...split luciferase-based PCA, we first showed that PREP enhances the formation of soluble aSyn dimers in live Neuro-2A neuroblastoma cells. A PREP inhibitor, KYP-2047, reduced aSyn dimerization in PREP-expressing cells but not in cells lacking PREP expression. aSyn dimerization was also enhanced by PREP(S554A), an enzymatically inactive PREP mutant, but this was not affected by KYP-2047. PCA...thermophoresis studies showed that aSyn interacts with both PREP and PREP... Prolyl oligopeptidase inhibition reduces...phosphatase 2A. (PMID: 33838285) Abstract: ...oligopeptidase (PREP) is a serine protease that is linked to neurodegeneration, as endogenous PREP inhibits autophagy and induces the accumulation of...detrimental protein aggregates. As such, inhibition of PREP by a small-molecular inhibitor has provided neuroprotection...models of neurodegenerative diseases. In addition, PREP inhibition has been shown to reduce production of...reactive oxygen species (ROS) and the absence of PREP blocks stress-induced ROS production. However, the mechanism behind PREP-related ROS regulation is not known. As we recently discovered PREP's physiological role as a protein phosphatase 2A (PP2A) regulator, we wanted to characterize PREP inhibition as an approach to reduce OS. We studied the impact of a PREP inhibitor, KYP-2047, on hydrogen peroxide and ferrous...and SH-SY5Y cells. In addition, we used HEK-2... Distribution of prolyl oligopeptidase in...colorectal tumors. (PMID: 22740343) Abstract: ...oligopeptidase (PREP) is a serine protease that hydrolyzes peptides shorter...multiple physiological and pathological conditions. PREP has been mostly studied in the brain, but significant PREP activities have been measured in peripheral tissues. Moreover, increased PREP activities have been found in tumors. In this study...authors studied the immunohistochemical distribution of PREP protein in human peripheral tissues and in ovarian and colorectal tumors. PREP was found to be widely distributed in human peripheral...and specifically in certain cells. The most intense PREP expression was seen in the testis, ovaries, liver...some parts of the skin. At the cellular level, high PREP levels were seen as a rule in secreting epithelial...cells and cells involved in reproduction. Increased PREP expression was seen in most of the tumors studied. PREP expression was high... (x) Prolyl oligopeptidase inhibition activates...phosphatase 2A. (PMID: 31759088) Abstract: Prolyl endopeptidase is involved in cellular...SH-SY5Y cells. (PMID: 21487212) Abstract: Prolyl endopeptidase (PREP), probably acting through the inositol cycle, has been implicated in memory and learning. However, the physiological role of PREP is unknown. It has been shown that PREP expression, regulated in cerebellar granule cells...report the levels and subcellular distribution of PREP in human neuroblastoma SH-SY5Y cells in proliferating conditions and under differentiation induced by retinoic acid (RA). We analysed the levels of cell signalling intermediates, growth behavior and gene expression, and differentiation morphology changes, upon PREP inhibition. After induction of differentiation,PREP activity was found decreased in the nucleus but increased to high levels in the cytoplasm, due in part to increased PREP transcription. The levels of inositol (1,4,5)-trisphosphate revealed no correlation with PREP activity, but phosphorylated extracellular signal-regulated kinases 1 and 2 were decreased by PREP inhibition during early stages of differentiation. Morphological evaluation indicated that PREP inhibition retarded the onset of differentiation. PREP activity regulated gene expression of protein synthesis machinery, intracellular transport and kinase complexes. We conclude that PREP is a regulatory target and a regulatory element in cell signalling. This is the first report of a direct influence of a cell signalling molecule, RA, on PREP expression. Function Phenotypes (5/10) See All homeostasis/metabolism phenotype: Alleles: Prep PrepGt(RRM213)Byg / Prep Preptm1b(KOMP)Wtsi - MP:0005376 behavior/neurological phenotype: Alleles: Prep Preptm1b(KOMP)Wtsi / Prep Preptm1Dgen - MP:0005386 renal/urinary system phenotype: Alleles: Prep PrepGt(RRM213)Byg - MP:0005367 liver/biliary system phenotype: Alleles: Prep PrepGt(RRM213)Byg - MP:0005370 adipose tissue phenotype: Alleles: Prep PrepGt(RRM213)Byg - MP:0005375

(x)  Pharmacol Res

• 2020 Jan;151:104558. doi: 10.1016/j.phrs.2019.104558. Epub 2019 Nov 20.Prolyl oligopeptidase inhibition activates autophagy via protein phosphatase 2A Reinis Svarcbahs  1 , Maria Jäntti  1 , Tommi Kilpeläinen  1 , Ulrika H Julku  1 , Lauri Urvas  1 , Saara Kivioja  1 , Susanna Norrbacka  1 , Timo T Myöhänen  DOI: 10.1016/j.phrs.2019.104558 
• Abstract. Prolyl oligopeptidase (PREP) is a serine protease that has been studied particularly in the context of neurodegenerative diseases for decades but its physiological function has remained unclear. We have previously found that PREP negatively regulates beclin1-mediated macroautophagy (autophagy), and that PREP inhibition by a small-molecule inhibitor induces clearance of protein aggregates in Parkinson's disease models. Since autophagy induction has been suggested as a potential therapy for several diseases, we wanted to further characterize how PREP regulates autophagy. We measured the levels of various kinases and proteins regulating beclin1-autophagy in HEK-293 and SH-SY5Y cell cultures after PREP inhibition, PREP deletion, and PREP overexpression and restoration, and verified the results in vivo by using PREP knock-out and wild-type mouse tissue where PREP was restored or overexpressed, respectively. We found that PREP regulates autophagy by interacting with protein phosphatase 2A (PP2A) and its endogenous inhibitor, protein phosphatase methylesterase 1 (PME1), and activator (protein phosphatase 2 phosphatase activator, PTPA), thus adjusting its activity and the levels of PP2A in the intracellular pool. PREP inhibition and deletion increased PP2A activity, leading to activation of death-associated protein kinase 1 (DAPK1), beclin1 phosphorylation and induced autophagy while PREP overexpression reduced this. Lowered activity of PP2A is connected to several neurodegenerative disorders and cancers, and PP2A activators would have enormous potential as drug therapy but development of such compounds has been a challenge. The concept of PREP inhibition has been proved safe, and therefore, our study supports the further development of PREP inhibitors as PP2A activators.Keywords: Alzheimer’s disease; Bafilomycin A1 (PubChem CID: 6436223); FTY-720 (fingolimod, PubChem CID: 107970); KYP-2047 (PubChem CID: 11198569); Neurodegeneration; Okadaic acid (PubChem CID: 446512); PP242 (PubChem CID: 135565635); Parkinson’s disease; Protein phosphatase 2 phosphatase activator; Protein phosphatase methylesterase 1; Rapamycin (sirolimus, PubChem CID: 5284616); Serine protease. Copyright © 2019 Elsevier Ltd. All rights reserved.

Similar articles

• Deletion or inhibition of prolyl oligopeptidase blocks lithium-induced phosphorylation of GSK3b and Akt by activation of protein phosphatase 2A. Myöhänen TT, Mertens F, Norrbacka S, Cui H. Basic Clin Pharmacol Toxicol. 2021 Oct;129(4):287-296. doi: 10.1111/bcpt.13632. Epub 2021 Jul 20. PMID: 34196102

  Prolyl oligopeptidase inhibition reduces oxidative stress via reducing NADPH oxidase activity by activating protein phosphatase 2A. Eteläinen T, Kulmala V, Svarcbahs R, Jäntti M, Myöhänen TT. Free Radic Biol Med. 2021 Jun;169:14-23. doi: 10.1016/j.freeradbiomed.2021.04.001. Epub 2021 Apr 7. PMID: 33838285

• The effect of prolyl oligopeptidase inhibitors on alpha-synuclein aggregation and autophagy cannot be predicted by their inhibitory efficacy. Kilpeläinen TP, Hellinen L, Vrijdag J, Yan X, Svarcbahs R, Vellonen KS, Lambeir AM, Huttunen H, Urtti A, Wallen EAA, Myöhänen TT. Biomed Pharmacother. 2020 Aug;128:110253. doi: 10.1016/j.biopha.2020.110253. Epub 2020 May 22. PMID: 32447211

• New tricks of prolyl oligopeptidase inhibitors - A common drug therapy for several neurodegenerative diseases. Svarcbahs R, Julku U, Kilpeläinen T, Kyyrö M, Jäntti M, Myöhänen TT. Biochem Pharmacol. 2019 Mar;161:113-120. doi: 10.1016/j.bcp.2019.01.013. Epub 2019 Jan 17. PMID: 30660495 Review.

• 'How can I halt thee?' The puzzles involved in autophagic inhibition. Vinod V, Padmakrishnan CJ, Vijayan B, Gopala S. Pharmacol Res. 2014 Apr;82:1-8. doi: 10.1016/j.phrs.2014.03.005. Epub 2014 Mar 21. PMID: 24657238 Review. Abstract

The strategy for interpreting the role of autophagy on the basis of evidence obtained through autophagic inhibition sounds logical, but is beset with practical constraints. The knock down of autophagy-related (ATG) gene(s) or blockage of class III PI3-Kinase are the most common approaches for inhibiting autophagy. However, during stressful conditions, autophagy may operate in synchrony with other processes such as apoptosis; autophagy-related genes, unlike what their name implies, exert their regulation on apoptosis as well. Knocking down such genes not only blocks autophagy but also renders apoptosis defective, making the interpretation of autophagic roles unreliable. Similarly, class III PI3-Kinase aids in initiating autophagy but it is not a quintessential autophagic regulator. Class III PI3-Kinase also has a role in regulating almost all membrane transport in cells. Blocking it not only inhibits autophagy, but also hampers all the membrane trades, including endosomal transport. The pharmacological inhibitors used to block autophagy by blocking class III PI3-Kinase further compound these limitations with their off-target effects. Knowing the limitations involved in blocking a target or using an autophagy-blocking tool is a prerequisite for designing the experiments meant for analyzing autophagic functions. This review attempts to provide a detailed overview about the practical constraints involved in using autophagic inhibition as a strategy to understand autophagy.Keywords: 3-Methyladenine; 3-Methyladenine (PubChem CID: 1673); Ammonium chloride (PubChem CID: 25517); Apoptosis; Atg5; Autophagy; Bafilomycin A1 (PubChem CID: 6436223); Beclin1; Chloroquine (PubChem CID: 2719); E64d (PubChem CID: 393035); KU55933 (PubChem CID: 5278396); Monensin (PubChem CID: 28263); Wortmannin (PubChem CID: 312145). Copyright © 2014 Elsevier Ltd. All rights reserved.

See all similar articles

(*) Toinen HAKU “PREPL”(2p21)

Selected DME Specific Peptides for PREP Gene

P48147:

• KQHFEWL
• LCAEFPDEPKWMGGAELSDDGRYVLLSI
• TNEGTVFTFKTNR
• VFREVTVKGIDA
• AYGLSASGSDWVTIKFMKVDGAKEL
• TKIPMFI
• IYHCDLTKEELEP
• NQRPDLF
• RGGGEYG
• GGSNGGLL
• GILKWVKLIDNFEGEYDY
• FKKGKRYFYFYNTGLQNQRVLYVQDSLEGEARV
• QDYHGHK
• EIFYQFTSFLSPG
• TIGHAWTTDYGCSD
• AAEYLIKE
• YPQQDGKSDGTETSTNLHQKL
• YHGHKICDPY
• TGALLKTFPL
• YGGFNIS
• KYSPLHNVKLPEADDIQYPSMLLLTADHDDRVVPLHS
• VGVMDML
• See less «

 

b) ( PARALOG GENE Tässä paralogissa on useita cysteiinejä, rakenne on puoli propellimainen verattuna edelliseen ja se katsotaan solunsisäiseksi, osallistu retrogradisen suunnan liikutteluun. Endosomi Golgi, Golgi PM, ja lopulta Ja lopulta mm synaptisen vesikkelin erityksiin)

Aliases for PREPL Gene 2p21.

• GeneCards Symbol: PREPL ²

• Prolyl Endopeptidase Like ^{2 3 5}

• Prolyl Endopeptidase-Like ^{2 3 4}

• KIAA0436 ^{2 4 5}

• Putative Prolyl Oligopeptidase ³

• Prolylendopeptidase-Like ⁴

• EC 3.4.21.83 ⁴⁸

• EC 3.4.21.- ⁴

• EC 3.4.21 ⁴⁸

• CMS22 ³

Gene Families for PREPL Gene

IUPHAR :S9: Prolyl oligopeptidase

Human Protein Atlas (HPA):

• Disease related genes

• Enzymes

• Human disease related genes

• Potential drug targets

• Predicted intracellular proteins

Protein Domains for PREPL Gene

InterPro:

• AB_hydrolase

• Peptidase_S9

• Pept_S9A_N

• Peptidase_S9A

Blocks:

• Prolyl oligopeptidase serine protease (S9A) signature

Suggested Antigen Peptide Sequences for PREPL Gene

GenScript: Design optimal peptide antigens:

• Prolylendopeptidase-like (PPCEL_HUMAN)

  Graphical View of Domain Structure for InterPro EntryQ4J6C6 UniProtKB/Swiss-Prot:PPCEL_HUMAN :

• Belongs to the peptidase S9A family.

Molecular function for PREPL Gene according to UniProtKB/Swiss-Prot

Function:

• Serine peptidase whose precise substrate specificity remains unclear (PubMed:16143824, 16385448, 28726805).
  Does not cleave peptides after a arginine (R)  or lysine (K) residue (PubMed:16143824).
  Regulates trans-Golgi network morphology and sorting by regulating the membrane binding of the AP-1 complex (PubMed:23321636).
  May play a role in the regulation of synaptic vesicle exocytosis (PubMed:24610330). PPCEL_HUMAN,Q4J6C6

EnzymeRegulation:

• Inhibited by PMSF and Prefabloc, as well as leupeptin at high concentrations (PubMed:16385448).
  Partially inhibited by TPCK, a chymotrypsin inhibitor and E64, a cysteine protease inhibitor (PubMed:16385448).
  Not affected by 4-amidinophenyl-methanesulfonyl fluoride (APMSF), pepstatin or EDTA (PubMed:16385448).
  Inhibited by 1-isobutyl-3-oxo-3,5,6,7-tetrahydro-2H-cyclopenta[c]pyridine-4-carbonitrile (PubMed:28726805). PPCEL_HUMAN,Q4J6C6

Phenotypes for PREPL Gene MGI mutant phenotypes for PREPL:

inferred from 2 alleles

• nervous system phenotype

• vision/eye phenotype

• growth/size/body region phenotype

• behavior/neurological phenotype

• muscle phenotype

• skeleton phenotype

• mortality/aging

GenomeRNAi human phenotypes for PREPL:

• Increased vaccinia virus (VACV) infection

• no effect

• Decreased viability

• Increased shRNA abundance (Z-score > 2)

• Decreased HPV16-GFP infection

• Decreased shRNA abundance (Z-score < -2)

Gluteenin ruoansulatuspätkistä tulee paljon QP-rakenteisiä peptidejä. proly -glutamyl- prolyl ym oligopeptidejä

Uusi  Duodecim 2023 ; 139;841.kertoo  artikkelissa  Prolyylioligopeptidaasien estäjistä apua muistisairauksien  pysäyttämiseen?

 AJATUKSIANI 10.6. 2023.

 Jos on entsyymivajetta siinä vaiheesas, missä näitä proliinj-proliini, (PP)    proliiniglutamiini (PQ)ja glutamiiniglutamiini (QQ)  ja glutamiiniproliini (QP)  sidoskohtia ei pilkkoudukaan ja  jää  eräänlaisia  T-solujen havaitsemia   oligopeptidejä ja ne ovat  antigeenejä. 

 Neuronaalinen signalointi vaatii yksittäisten  glutamiinista (Q) muodostuvien glutamiinihappojen (E) tai  GABA  gamma-aminovoihappojen  hyvää mudostumista ja sykliä.  GLU on excitatorinen, GABA inhibitorine ja GLN  antaa  vapaata  sidosenergiaa kohdissa, missaä  ei ole mahdollista käyttää isoja ATP  tai  pienempiäkään rikastuneita inositoliperäisiä  fosfaatteja  energialähteinä.  Siis Q on se ilmainen energialähde, E on  stimuloiva ja GABA inhiboiva.   Tähän ydinmoduliin reseptorisettiensä kanssa  perustuu neuronien muistin lataustoiminta ja muistin esiinhakemistoiminta.

Haitallinen rakenne on Hungington-viruksessa, sillä siinä on näitä PPP ja QP jaksoja, joita  keho ei pysty kaikilla kai  pilkkomaan proteosomissa ja  immuunivasteessa.Jptkut  virusrakenteet vehnän tapaan  suosivat näitä aminohappoja.  https://www.mdpi.com/biomolecules/biomolecules-10-01458/article_deploy/html/images/biomolecules-10-01458-g001.png

  https://www.mdpi.com/biomolecules/biomolecules-10-01458/article_deploy/html/images/biomolecules-10-01458-g001.png

Nyt on hiirillä huomattu että  muistin latauksessa ja esiinotossa tärkeät  aivojen etuosat hiirillä voivat  olla  muistihäiriön ayntyalue ja  siten kun on  tällaisia haittapeptidejä  paljon siihen on keksitty entsyymin estäjä. ja hiirien muisti paranee.

 

 Varmaan hieno asia , mutta tuohon järjestelmään pitää asettaa  eliminaatiodieetti:jolloin  samaan  heikkoon aineenvaihdunnalliseen linkkiin  tulisi tukea  tiukasta ( gluteenittomasta  dieetistä, jolloin näitä  oligopeptidejä ei jäisi sulamatta  niin suunnattomia määriä kehoon, mikä säätää tuollaista sekundääristi entsyymiä ylös.  Se onkin  siten paradigma, joka vain pitäisi ottaa huomioon. 

Sen sijaan että keksitään  esim  desensitoimisteitä kuten  vähemmän gluteenisen ( aveniiniprolamiinityyppisen)  kauran  palauttamista   laajalti keliakiadieettiin, voisi  löytää sen entsyymin, josta  ytimissä on kysymys primääristi. ja siten voi esikäsitellä ne sidokset ja jos  se ei auta, tekijä on myös jokin toinenkin, lektiinitaso tms. 

Toistaiseksi  suosittelen englantilaista linja, jossa ei  palautteta  kauraa vielä, koska kerran ei tiedetä primääriä  entsyymivajetta.  

 

Uusi  Duodecim 2023 ; 139;841.kertoo  artikkelissa  Prolyylioligopeptidaasien estäjistä apua muistisairauksien  pysäyttämiseen?