MME(3q25.2) NEP ( Neprilysiini) , CD10 , membraanimetalloendopeptidaasi

Olen kertaamassa  RAAS- järjestelmää ja siinä on neprilysiinillä (NEP)  myös osa. 

ACE2 ja neprilysiini kehkeyttävät  angiotensiiniä Ang -(1-7)  . ACE2 tekee   sitä muodosta Ang-(1-8), joka on Angiotensiini-II.  Neprilysiini muodostaa sitä  Ang-(1-10).stä,  joka on Angiotensiini-I.  Ang-(1-7)  toimii renoprotektiivisesti ja kardioprotektiivisesti  ja käyttää GPCR-MAS aktivaatiotietä, joka  tie  opponoi ja vaimentaa   ACE- Angiotensiini II- välitteisen   verenpaineen säätelytien  monipuolisia reseptorivaikutuksia ja täten molemmat tiet osallistuvat verenpaineen säätelynhomeostaasiin. 

 

MME-geenin koodama neprilysiini (NEP) on tyypin II transmembraaniglykoproteiini ja  se tunnetaan myös  tavallisena akuutin leukemian antigeenina (CALLA) tärkeänä solupintamerkitsijänä diagnosoitaessa  akuuttia lymfaattista leukemiaa. koodautunutta proteiinia on  pre-B-fenotyyppisissä leukemisissa soluissa, joita on  85% ALL-solusita. Proteiini ei ole kutienkaan rajoittunut leukemisiin soluihin vaan sitä löytyy useissa normaalikudoksissa. proteiini on neutraali endopeptidaasi, joka  pilkkoo peptidejä hydrofobisten aminohappojen  aminopuoellta ja pystyy inaktivoimaan useita peptidihormoneja8 glukagonia, enkefaliineja, P-substanssia, neurotensiiniä, oksytosiinia, bradykiniiniä (BK). Geeniä ilmenee duodenumissa, munuaisessa ja 8 muussa kudoksessa. Neprilysiinillä on vaihtoehtoisia nimiä monta, mutta  suositeltu nimi on neprilysiini(NEP). Se tunnetaan  myös mm.  atriolysiininä,   yleisenä  akuuttin lymfosyyttileukemian antigeenina (CALLA)

kalvon metallo-endopeptidaasina (MME), neutraalina endopeptidaasina (NEP), enkefalinaasina, CD 10 (Cluster of Differentiation 10), iho-fibriblastielastaasina (SFE)  ja muitakin nimiä on ( kts. alla)

PubMed:

Official Symbol MME

  membrane metalloendopeptidase

Also known as

NEP; SFE; CD10; CALLA; CMT2T; SCA43

Summary

The protein encoded by this gene is a type II transmembrane glycoprotein and a common acute lymphocytic leukemia antigen that is an important cell surface marker in the diagnosis of human acute lymphocytic leukemia (ALL). The encoded protein is present on leukemic cells of pre-B phenotype, which represent 85% of cases of ALL. This protein is not restricted to leukemic cells, however, and is found on a variety of normal tissues. The protein is a neutral endopeptidase that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including glucagon, enkephalins, substance P, neurotensin, oxytocin, and bradykinin. [provided by RefSeq, Aug 2017]

Expression

Biased expression in duodenum (RPKM 88.5), kidney (RPKM 83.7) and 8 other tissues See more

Preferred Names

neprilysin

Names

atriopeptidase

common acute lymphocytic leukemia antigen

membrane metallo-endopeptidase (neutral endopeptidase, enkephalinase, CALLA, CD10)

membrane metallo-endopeptidase variant 1

membrane metallo-endopeptidase variant 2

neprilysin-390

neprilysin-411

neutral endopeptidase 24.11

skin fibroblast elastase

Neprilysiiniin  liittyvää lisätietoa PubMed artikkeleista.

Related articles in PubMed

1. Discovery of a CD10-negative B-progenitor in human fetal life identifies unique ontogeny-related developmental programs. O'Byrne S, et al. Blood, 2019 Sep 26. PMID 31383639
2. Tumorous CD10 Is More Strongly Related to the Progression of Urothelial Carcinoma than Stromal CD10. Kumagai-Togashi A, et al. Anticancer Res, 2019 Feb. PMID 30711939
3. Characterising the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations. Lupo V, et al. J Med Genet, 2018 Dec. PMID 30415211
4. High expression of CD10 in anaplastic thyroid carcinomas. Nakazawa T, et al. Histopathology, 2018 Sep. PMID 29791034
5. CD10 inhibits cell motility but expression is associated with advanced stage disease in colorectal cancer. Raposo TP, et al. Exp Mol Pathol, 2018 Jun. PMID 29653092

See all (304) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGe

 GeneRIF

1. Almost one-third of fetal B-progenitors are CD10-ve PreProB-progenitors, whereas, by contrast, PreProB-progenitors are almost undetectable (0.53% +/- 0.24%) in adult Bone Marrow.
2. our findings confirm that MME does represent the most common causative gene responsible for late-onset AR-CMT2 in our population, but they do not provide support for the hypothesis that heterozygous mutations in MME are a direct cause of CMT.
3. receptor signaling and NEP are involved in the resistance of CNP to human mesangial proliferation and Col-IV expression.
4. Urinary ACE2, neprilysin, and ADAM17 are increased in patients with diabetes and could be used as early biomarkers to predict the incidence or progression of CKD at early stages among individuals with type 2 diabetes.   Abstract
   Angiotensin converting enzyme 2 (ACE2) and neprilysin (NEP) are metalloproteases that are highly expressed in the renal proximal tubules. ACE2 and NEP generate renoprotective angiotensin (1-7) from angiotensin II and angiotensin I, respectively, and therefore could have a major role in chronic kidney disease (CKD). Recent data demonstrated increased urinary ACE2 in patients with diabetes with CKD and kidney transplants. We tested the hypothesis that urinary ACE2, NEP, and a disintegrin and metalloproteinase 17 (ADAM17) are increased and could be risk predictors of CKD in patients with diabetes. ACE2, NEP, and ADAM17 were investigated in 20 nondiabetics (ND) and 40 patients with diabetes with normoalbuminuria (Dnormo), microalbuminuria (Dmicro), and macroalbuminuria (Dmacro) using ELISA, Western blot, and fluorogenic and mass spectrometric-based enzyme assays. Logistic regression model was applied to predict the risk prediction. Receiver operating characteristic curves were drawn, and prediction accuracies were calculated to explore the effectiveness of ACE2 and NEP in predicting diabetes and CKD. Results demonstrated that there is no evidence of urinary ACE2 and ADAM17 in ND subjects, but both enzymes were increased in patients with diabetes, including Dnormo. Although there was no detectable plasma ACE2 activity, there was evidence of urinary and plasma NEP in all the subjects, and urinary NEP was significantly increased in Dmicro patients. NEP and ACE2 showed significant correlations with metabolic and renal characteristics. In summary, urinary ACE2, NEP, and ADAM17 are increased in patients with diabetes and could be used as early biomarkers to predict the incidence or progression of CKD at early stages among individuals with type 2 diabetes.
5. Our detailed analyses, with a substantial number of brain samples, provide the first convincing evidence that DNA methylation of the NEP promoter is not involved in Alzheimer disease development and progression.
6. Tumorous CD10 is more strongly related to progression of urothelial carcinoma than stromal CD10 and is an independent factor for UC prognosis
7. showed CD10 positivity in fibroblast-like stromal cells and fibrous material
8. these data indicated under cigarette smoke condensate treatment; losing of membrane p120ctn could upregulate surface NEP protein level and thus facilitate BEAS-2B cell migration.
9. High expression of CD10 is associated with lymph node invasion in colorectal cancer.
10. We observed an increase of VCAM-1 urine levels in diabetic nephropathy-basal patients compared to diabetic controls and an increase of urinary neprilysin in DN-treated patients with persistent albuminuria

 Tietoja  Neprilysiiniproteiinista

 https://www.ncbi.nlm.nih.gov/protein/NP_000893.2

Tässä on isoformi a (1..750 amiohappoa) TM kohta merkattutummalla (29..51) ,

Aktiivikohta merkattu isoilla kirjaimilla. 543N, 544A, 581V, 584H, 585E, 588H, 647E, 690F, 691A 712H, 718R.

Zinkkiä sitova kohta m, kolme aminohappoa osuu aktiiviin kohtaan, tummalla merkatut. 

Näkyy olevan yksi  motiivi llxxl  (674-680) (lie tumareseptori?) 

peptidista koko mitalta  79-748  on M12 peptidaasiperheen M12 endoteliinia konvertoiva entsyymi I (ECE-1) .

N-terminaalinen sytoplasminen osa:

1 mgksesqmdi tdintpkpkk kqrwtple

ORIGIN      
        1 mgksesqmdi tdintpkpkk kqrwtpleis lsvlvlllti iavtmialya tyddgickss
       61 dciksaarli qnmdattepc tdffkyacgg wlkrnvipet ssrygnfdil rdelevvlkd
      121 vlqepktedi vavqkakaly rscinesaid srggepllkl lpdiygwpva tenweqkyga
      181 swtaekaiaq lnskygkkvl inlfvgtddk nsvnhvihid qprlglpsrd yyectgiyke
      241 actayvdfmi svarlirqee rlpidenqla lemnkvmele keianatakp edrndpmlly
      301 nkmtlaqiqn nfsleingkp fswlnftnei mstvnisitn eedvvvyape yltklkpilt
      361 kysardlqnl mswrfimdlv sslsrtykes rnafrkalyg ttsetatwrr canyvngnme
      421 navgrlyvea afageskhvv edliaqirev fiqtlddltw mdaetkkrae ekalaikeri
      481 gypddivsnd nklnneylel nykedeyfen iiqnlkfsqs kqlkklrekv dkdewisgaa
      541 vvNAfyssgr nqivfpagil qppffsaqqs nslnyggigm VigHEitHgf ddngrnfnkd
      601 gdlvdwwtqq sasnfkeqsq cmvyqygnfs wdlaggqhln gintlgEnia dngglgqayr
      661 ayqnyikkng eekllpgldl nhkqlfflnF Aqvwcgtyrp eyavnsiktd vHspgnfRii
      721 gtlqnsaefs eafhcrknsy mnpekkcrvw
//

Tietoja Neprilysiinin  perheestä "M13".

Metallopeptidase family M13 includes neprilysin (NEP) and other members: 

M13 family of metallopeptidases includes
 neprilysin (neutral endopeptidase, NEP, enkephalinase, CD10, CALLA, EC 3.4.24.11),
endothelin-converting enzyme I (ECE-1, EC 3.4.24.71),
 erythrocyte surface antigen KELL (ECE-3),
phosphate-regulating gene on the X chromosome (PHEX),
 soluble secreted endopeptidase (SEP), and
 damage-induced neuronal endopeptidase (DINE)/X-converting enzyme (XCE).

 These proteins consist of a short N-terminal cytoplasmic domain,
 a single transmembrane helix,
and a larger C-terminal extracellular domain containing the active site.
Proteins in this family fulfill a broad range of physiological roles due to the greater variation in the S2' subsite allowing substrate specificity.

NEP is expressed in a variety of tissues including kidney and brain, and is involved in many physiological and pathological processes, including blood pressure and inflammatory response. It degrades a wide array of substrates such as substance P (SP), enkephalins, cholecystokinin (CCK), neurotensin and somatostatin. It is an important enzyme in the regulation of amyloid-beta (Abeta) protein that forms amyloid plaques that are associated with Alzeimers disease (AD).

 ECE-1 catalyzes the final rate-limiting step in the biosynthesis of endothelins via post-translational conversion of the biologically inactive big endothelins. Like NEP, it also hydrolyses bradykinin, substance P, neurotensin and Abeta.  

Endothelin-1 overproduction has been implicated in various diseases, including stroke, asthma, hypertension, and cardiac and renal failure.

 Kell is a homolog of NEP and constitutes a major antigen on human erythrocytes; it preferentially cleaves big endothelin-3 to produce bioactive endothelin-3, but is also known to cleave substance P and neurokinin A.

PHEX forms a complex interaction with fibroblast growth factor 23 (FGF23) and matrix extracellular phosphoglycoprotein, causing bone mineralization. A loss-of-function mutation in PHEX disrupts this interaction leading to hypophosphatemic rickets; X-linked hypophosphatemic (XLH) rickets is the most common form of metabolic rickets.

 ECEL1 is a brain metalloprotease involved in the critical role in the nervous regulation of the respiratory system, while

DINE (damage induced neuronal endopeptidase) is abundantly expressed in the hypothalamus and its expression responds to nerve injury as well.

 Thus, majority of these M13 proteases are prime therapeutic targets for selective inhibition.

 https://www.ncbi.nlm.nih.gov/pubmed

Liekö yhteyttä  ylläolevilla tekijöillä respiraation kerebraaliseen säätelyyn? Katsotaan,mitä tiede löytää lähi tulevaisuudesa.

Neurosci Biobehav Rev. 2020 Feb 3;112:95-106. doi: 10.1016/j.neubiorev.2020.02.001. [Epub ahead of print]

Respiratory regulation & interactions with neuro-cognitive circuitry.

Maric V¹, Ramanathan D², Mishra J³.

Abstract

It is increasingly being recognized that active control of breathing - a key aspect of ancient Vedic meditative practices, can relieve stress and anxiety and improve cognition. However, the underlying mechanisms of respiratory modulation of neurophysiology are just beginning to be elucidated. Research shows that brainstem circuits involved in the motor control of respiration receive input from and can directly modulate activity in subcortical circuits, affecting emotion and arousal. Meanwhile, brain regions involved in the sensory aspects of respiration, such as the olfactory bulb, are like-wise linked with wide-spread brain oscillations; and perturbing olfactory bulb activity can significantly affect both mood and cognition. Thus, via both motor and sensory pathways, there are clear mechanisms by which brain activity is entrained to the respiratory cycle. Here, we review evidence gathered across multiple species demonstrating the links between respiration, entrainment of brain activity and functional relevance for affecting mood and cognition. We also discuss further linkages with cardiac rhythms, and the potential translational implications for biorhythm monitoring and regulation in neuropsychiatric disorders.

Copyright © 2020 Elsevier Ltd. All rights reserved.

 ----------------Päivitys 26.2. 2020