Neprilysin
| Neprilysin | ||
|---|---|---|
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| Belt model according to PDB 1R1H | ||
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Existing structural data : 1DL9 , 1DMT , 1QVD , 1R1H , 1R1I , 1R1J , 1Y8J , 2QPJ , 2YB9 , 4CTH |
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| Properties of human protein | ||
| Mass / length primary structure | 749 amino acids | |
| Secondary to quaternary structure | single pass type 2 membrane protein | |
| Cofactor | Zn 2+ | |
| Identifier | ||
| Gene names | MME ; NEP; CALLA; CD10; DKFZp686O16152; MGC126681; MGC126707 | |
| External IDs | ||
| Enzyme classification | ||
| EC, category | 3.4.24.11 , metalloprotease | |
| MEROPS | M13.001 | |
| Response type | hydrolytic cleavage between hydrophobic amino acids, especially with phenylalanine or tyrosine | |
| Substrate | protein | |
| Occurrence | ||
| Homology family | Metallopeptidase | |
| Parent taxon | Creature | |
| Orthologue | ||
| human | House mouse | |
| Entrez | 4311 | 17380 |
| Ensemble | ENSG00000196549 | ENSMUSG00000027820 |
| UniProt | P08473 | Q61391 |
| Refseq (mRNA) | NM_000902 | NM_001289462 |
| Refseq (protein) | NP_000893 | NP_001276391 |
| Gene locus | Chr 3: 155.02 - 155.18 Mb | Chr 3: 63.24 - 63.39 Mb |
| PubMed search | 4311 |
17380
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Neprilysin is an enzyme that is widespread in the human body , especially in the kidneys and lungs . It is also known as neutral endopeptidase and membrane metallo-endopeptidase (MME) and is encoded by the MME gene. In addition, it plays a major role in oncology and immunohistochemistry , under the synonymous names CD 10 ( Cluster of Differentiation 10 ) and CALLA ( common acute lymphoblastic leukemia antigen ).
Mode of action
Neprilysin is a zinc (II) -dependent membrane-bound metalloprotease , whereby the part of the protein sitting on the cell membrane (the ectodomain) is then released into the extracellular space . There neprilysin breaks down numerous peptide hormones through enzymatic cleavage at the amino terminus of hydrophobic amino acids . These include hormones such as glucagon , but also numerous paracrine peptides such as bradykinin , oxytocin , substance P , endothelin and natriuretic peptides such as ANP and BNP , but also beta-amyloid .
Amyloid metabolism
In the human brain , neprilysin breaks down the protein beta-amyloid , the accumulation of which in the brain is associated with Alzheimer's disease . It is assumed that the neprilysin is the rate-limiting step. A therapeutic activation could thus accelerate the breakdown of the amyloid. In fact, the neprilysin knockout mouse shows an Alzheimer's-like behavior disorder and amyloid accumulation in the brain. A genetic defect in MME, which codes for neprilysin, is also suspected of increasing the risk of Alzheimer's disease in humans. The peptide hormone somatostatin, on the other hand, can increase the enzyme activity of neprilysin, but its production in the brain decreases with age. This could explain the age-related increase in amyloid deposits, but oxidative damage could also explain the decline in neprilysin activity with age.
oncology
While it is not clear whether neprilysin plays a role in tumor development , a typical expression pattern can be seen in individual types of cancer . In some types of cancer, especially metastatic tumors and especially in advanced malignant melanomas , neprilysin is strongly overexpressed, in others, such as lung cancer in particular , it is severely under-expressed. Then neprilysin can no longer inhibit the growth-promoting effect of autocrine tumor peptides, such as bombesin , through degradation.
In the field of hematology , hematopoietic precursor cells that express CD-10, i.e. neprilysin, are classified as "common lymphocyte precursor cells" ( common lymphoid progenitors ), since they can be divided into T lymphocytes as well as B lymphocytes and NK cells . Cells can differentiate . It also plays an important role in immunophenotyping as part of the classification of acute lymphoblastic leukemia , since CD-10 expression is particularly typical of "pre-B-ALL". Other hematological malignancies with CD-10 expression include. a. The Burkitt's lymphoma , angioimmunoblastic T-cell lymphoma , the chronic myelogenous leukemia in blast crisis, and occasionally diffuse large B-cell lymphoma , whereas a CD-10 expression in acute myeloid leukemia , the chronic lymphatic leukemia and mantle cell - and border zone lymphoma is rather negative.
Heart failure
Sacubitril , a neprilysin inhibitor, was combined with the AT1 antagonist valsartan in the active ingredient LCZ696 in the PARADIGM-HF study in 8442 patients for the treatment of heart failure . LCZ696 (brand name Entresto) showed better results in this study than the ACE inhibitor enalapril , which may be due to the inhibition of the breakdown of natriuretic proteins. Drugs in this group are called angiotensin receptor neprilysin inhibitors (ARNIs) .
Other neprilysin inhibitors are Omapatrilat , RB-101, and UK-414,495 . In a larger study, omapatrilat, unlike sacubitril, did not show significantly better results than enalapril in the treatment of heart failure, but it may have been underdosed with once daily dosing.
Some plant extracts also showed an inhibition of the enzymatic activity of neprilysin, such as methanol extracts from Ceropegia rupicola , Kniphofia sumarae , Plectranthus cf. barbatus and aqueous extracts from Pavetta longiflora .
Individual evidence
- ↑ E. Malito, RE Hulse, WJ Tang: Amyloid beta-degrading cryptidases: insulin degrading enzyme, presequence peptidase, and neprilysin. In: Cellular and molecular life sciences: CMLS. Volume 65, Number 16, August 2008, pp. 2574-2585, ISSN 1420-682X . doi: 10.1007 / s00018-008-8112-4 . PMID 18470479 . PMC 2756532 (free full text).
- ^ J. Pacheco-Quinto, A. Herdt, CB Eckman, EA Eckman: Endothelin-converting enzymes and related metalloproteases in Alzheimer's disease. In: Journal of Alzheimer's disease: JAD. Volume 33 Suppl 1, 2013, pp. S101-S110, ISSN 1875-8908 . doi: 10.3233 / JAD-2012-129043 . PMID 22903130 . PMC 3677825 (free full text).
- ↑ John JV McMurray, Milton Packer, Akshay S. Desai, Jianjian Gong, Martin P. Lefkowitz, Adel R. Rizkala, Jean L. Rouleau, Victor C. Shi, Scott D. Solomon, Karl Swedberg, Michael R. Zile, for the PARADIGM-HF Investigators and Committees: Angiotensin – Neprilysin Inhibition versus Enalapril in Heart Failure New England Journal of Medicine , 2014, Volume 371, Issue 11, September 11, 2014, pages 993-1004; doi: 10.1056 / NEJMoa1409077 .
- ↑ Mariell Jessup: Neprilysin inhibition - a novel therapy for heart frailure New England Journal of Medicine 2014, Volume 371, Issue 11 of September 11, 2014, pages 1062-1064, doi: 10.1056 / NEJMe1409898 .
- ↑ M. Packer, RM Califf, MA Konstam et al .: Comparison of omapatrilat and enalapril in patients with chronic heart failure: the omapatrilat versus enalapril randomized trial of utility in reducing events (OVERTURE) Circulation 2002, Volume 106, pages 920-926 .
- ↑ R. Alasbahi, MF Melzig: Screening of some Yemeni medicinal plants for inhibitory activity against peptidases. In: The Pharmacy. Volume 63, Number 1, January 2008, pp. 86-88, PMID 18271311 .