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14-September-2008 18:02:49 - Neprilysin Membrane metallo-endopeptidase The structure of the neprilysin ectodomain in complex with a zinc-chelating inhibitor. The zinc atom is shown as a gray sphere and the inhibitor is shown in green. Rendering based on 1r1h. Available structures: 1dmt, 1r1h, 1r1i, 1r1j, 1y8j Identifiers Symbols MME; NEP; CALLA; CD10; DKFZp686O16152; MGC126681; MGC126707 External IDs OMIM: 120520 MGI: 97004 HomoloGene: 5275 EC number 3.4.24.11 Gene ontology Molecular function: neprilysin activity metallopeptidase activity zinc ion binding metal ion binding Cellular component: plasma membrane integral to plasma membrane Biological process: proteolysis cell-cell signaling RNA expression pattern More reference expression data Orthologs Human Mouse Entrez 4311 17380 Ensembl ENSG00000196549 ENSMUSG00000027820 Uniprot P08473 Q8BNU9 Refseq NM_000902 mRNA NP_000893 protein NM_008604 mRNA NP_032630 protein Location Chr 3: 156.28 - 156.38 Mb Chr 3: 63.38 - 63.47 Mb Pubmed search 1 2 Neprilysin, also known as neutral endopeptidase NEP, CD10, and common acute lymphoblastic leukemia antigen CALLA, is a zinc-dependent metalloprotease enzyme that degrades a number of small secreted peptides, most notably the amyloid beta peptide whose abnormal misfolding and aggregation in neural tissue has been implicated as a cause of Alzheimer's disease. Synthesized as a membrane-bound protein, the neprilysin ectodomain is released into the extracellular domain after it has been transported from the Golgi apparatus to the cell surface. In neurons, neprilysin is regulated by the protein nicastrin, a component of the gamma secretase complex that performs a necessary step in processing amyloid precursor protein to amyloid beta.1 Contents 1 Amyloid beta regulation 2 Signaling peptides 3 References 4 External links Amyloid beta regulation Mutations in the neprilysin gene have been associated with familial forms of Alzheimer's disease,2 and neprilysin-deficient knockout mice show both Alzheimer's-like behavioral impairment and amyloid-beta deposition in the brain,3 providing strong evidence for the protein's association with the Alzheimer's disease process. Because neprilysin is thought to be the rate-limiting step in amyloid beta degradation,4 it has been considered a potential therapeutic target; compounds such as the peptide hormone somatostatin have been identified that increase the enzyme's activity level.5 One hypothesis for the strong dependence of Alzheimer's incidence on age focuses on the declining production of somatostatin the brains of elderly people, which thus depresses the activity of neprilysin and promotes aggregation of unprocessed amyloid beta.6 Declining neprilysin activity with increasing age may also be explained by oxidative damage, known to be a causative factor in Alzheimer's disease; higher levels of inappropriately oxidized neprilysin have been found in Alzheimer's patients compared to cognitively normal elderly people.7 Signaling peptides Neprilysin is also associated with other biochemical processes, and is particularly highly expressed in kidney and lung tissues. Inhibitors have been designed with the aim of developing analgesic and antihypertensive agents that act by preventing neprilysin's activity against signaling peptides such as enkephalins, substance P, endothelin, and atrial natriuretic factor.89 Associations have been observed between neprilysin expression and various types of cancer; however, the relationship between neprilysin expression and carcinogenesis remains obscure. In cancer biomarker studies, the neprilysin gene is often referred to as CD10 or CALLA. In some types of cancer, such as metastatic carcinoma and some advanced melanomas, neprilysin is overexpressed;10 in other types, most notably lung cancers, neprilysin is downregulated, and thus unable to modulate the pro-growth autocrine signaling of cancer cells via secreted peptides such as mammalian homologs related to bombesin.11 References ^ Pardossi-Piquard, R.; Dunys J., Yu G., St George-Hyslop P., Alves da Costa C. and Checler F. May 2006. Neprilysin activity and expression are controlled by nicastrin. Journal of Neurochemistry 97 4: 1052-6. doi:10.1111/j.1471-4159.2006.03822.x. PMID 16606360. ^ Helisalmi, S coauthors= M. Hiltunen, S. Vepsäläinen, S. Iivonen, A. Mannermaa, M. Lehtovirta, A. M. Koivisto, I. Alafuzoff and H. Soininen 2004. Polymorphisms in neprilysin gene affect the risk of Alzheimer's disease in Finnish patients. Journal of Neurology Neurosurgery and Psychiatry 75 12: 1746-8. doi:10.1136/jnnp.2004.036574. PMID 15548496. Retrieved on 2007-03-11. ^ Madan, Rime; Raphael Poirier, David P. Wolfer, Hans Welzl, Peter Groscurth, Hans-Peter Lipp, Bao Lu, Mohammed El Mouedden, Marc Mercken, Roger M. Nitsch and M. Hasan Mohajeri December 2006. Lack of neprilysin suffices to generate murine amyloid-like deposits in the brain and behavioral deficit in vivo. Journal of Neuroscience Research 84 8: 1871-8. doi:10.1002/jnr.21074. PMID 16998901. ^ Iwata, Nobuhisa; Satoshi Tsubuki, Yoshie Takaki, Kaori Watanabe, Misaki Sekiguchi, Emi Hosoki, Maho Kawashima-Morishima, Hahn-Jun Lee, Emi Hama, Yoko Sekine-Aizawa and Takaomi C. Saido February 2000. Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nature Medicine 6 2: 143-50. doi:10.1038/72237. PMID 10655101. ^ Iwata, Nobuhisa; Makoto Higuchi and Takaomi C. Saido November 2005. Metabolism of amyloid-beta peptide and Alzheimer's disease. Pharmacology Therapeutics 108 2: 129-48. doi:10.1016/j.pharmthera.2005.03.010. PMID 16112736. ^ Hama, Emi; Takaomi C. Saido 2005. Etiology of sporadic Alzheimer's disease: somatostatin, neprilysin, and amyloid beta peptide. Medical Hypotheses 65 3: 498-500. doi:10.1016/j.mehy.2005.02.045. PMID 15921860. ^ Wang, Deng-Shun; Nobuhisa Iwata, Emi Hama, Takaomi C. Saido and Dennis W. Dickson October 2003. Oxidized neprilysin in aging and Alzheimer's disease brains. Biochemical and Biophysical Research Communications 310 1: 236-41. doi:10.1016/j.bbrc.2003.09.003. PMID 14511676. ^ Sahli, Stefan; Bernhard Stump, Tobias Welti, W. Bernd Schweizer, François Diederich, Denise Blum-Kaelin, Johannes D. Aebi and Hans-Joachim Böhm April 2005. A New Class of Inhibitors for the Metalloprotease Neprilysin Based on a Central Imidazole Scaffold. Helvetica Chimica Acta 88 4: 707-730. doi:10.1002/hlca.200590050. ^ Oefner, C.; B. P. Roques, M.-C. Fournie-Zaluski and G. E. Dale February 2004. Structural analysis of neprilysin with various specific and potent inhibitors. Acta Crystallographica Section D Biological Crystallography 60, prt 2: 392-396. doi:10.1107/S0907444903027410. PMID 14747736. ^ Velasquez, Elsa F.; Molly Yancovitz, Anna Pavlick, Russell Berman, Richard Shapiro, Dusan Bogunovic, David O'Neill, Yi-Lo Yu, Joanna Spira, Paul J Christos, Xi Kathy Zhou, Madhu Mazumdar4, David M Nanus, Leonard Liebes, Nina Bhardwaj, David Polsky and Iman Osman January 2007. Clinical relevance of Neutral Endopeptidase NEP/CD10 in melanoma. Journal of Translational Medicine 5 2: 2. doi:10.1186/1479-5876-5-2. PMID 17207277. ^ Cohen, Andrea J.; Paul A. Bunn, Wilbur Franklin, Catherine Magill-Solc, Christa Hartmann, Barbara Heifrich, Laura Gilman, Joy Folkvord, Karen Helm, and York E. Miller February 1996. Neutral endopeptidase: variable expression in human lung, inactivation in lung cancer, and modulation of peptide-induced calcium flux. Cancer Research 56 4: 831-9. PMID 8631021. Retrieved on 2006-03-11. External links MeSH Neprilysin v d e Proteins: clusters of differentiation see also list of human clusters of differentiation 1-50 CD1 a-c, 1A, 1D, 1E - CD2 - CD3 γ, δ, ε - CD4 - CD5 - CD6 - CD7 - CD8 a - CD9 - CD10 - CD11 a, b, c - CD13 - CD14 - CD15 - CD16 A, B - CD18 - CD19 - CD20 - CD21 - CD22 - CD23 - CD24 - CD25 - CD26 - CD27 - CD28 - CD29 - CD30 - CD31 - CD32 A, B - CD33 - CD34 - CD35 - CD36 - CD37 - CD38 - CD39 - CD40 - CD41- CD42 a, b, c, d - CD43 - CD44 - CD45 - CD46 - CD47 - CD48 - CD49 a, b, c, d, e, f - CD50 51-100 CD51 - CD52 - CD53 - CD54 - CD55 - CD56 - CD57- CD58 - CD59 - CD61 - CD62 E, L, P - CD63 - CD64 - CD66 a, b, c, d, e, f - CD68 - CD69 - CD70 - CD71 - CD72 - CD73 - CD74 - CD79 a, b - CD80 - CD81 - CD82 - CD83 - CD84 - CD85 a, d, e, h, j, k - CD86 - CD87 - CD88 - CD89 - CD90 - CD91- CD92 - CD93 - CD94 - CD95 - CD97 - CD98 - CD99 - CD100 101-150 CD101 - CD102 - CD103 - CD104 - CD105 - CD106 - CD107 a, b - CD108 - CD109 - CD110 - CD111 - CD112 - CD113 - CD114 - CD115 - CD116 - CD117 - CD118 - CD119 - CD120 a, b - CD121 a, b - CD122 - CD123 - CD124 - CD125 - CD126 - CD127 - CD129 - CD130 - CD131 - CD132 - CD133 - CD134 - CD135 - CD136 - CD137 - CD138 - CD140b - CD141 - CD142 - CD143 - CD144 - CD146 - CD147 - CD148 - CD150 151-200 CD151 - CD152 - CD153 - CD154 - CD155 - CD156 a, b, c - CD157 - CD158 a, d, e, i, k - CD159 a, c - CD160 - CD161 - CD162 - CD163 - CD164 - CD166 - CD167 a, b - CD168 - CD169 - CD170 - CD171 - CD172 a, b, g - CD174 - CD177 - CD178 - CD179 a, b - CD181 - CD182 - CD183 - CD184 - CD185 - CD186 - CD191 - CD192 - CD193 - CD194 - CD195 - CD196 - CD197 - CDw198 - CDw199 - CD200 201-250 CD201 - CD202b - CD204 - CD205 - CD206 - CD207 - CD208 - CD209 - CDw210 a, b - CD212 - CD213a 1, 2 - CD217 - CD218 a, b - CD220 - CD221 - CD222 - CD223 - CD224 - CD225 - CD226 - CD227 - CD228 - CD229 - CD230 - CD233 - CD234 - CD235 a, b - CD236 - CD238 - CD239 - CD240CE - CD241 - CD243 - CD244 - CD246 - CD247- CD248 - CD249 251-300 CD252 - CD253 - CD254 - CD256 - CD257 - CD258 - CD261 - CD262 - CD264 - CD265 - CD266 - CD267 - CD268 - CD269 - CD271 - CD272 - CD273 - CD274 - CD275 - CD276 - CD278 - CD279 - CD280 - CD281 - CD282 - CD283 - CD284 - CD286 - CD288 - CD289 - CD290 - CD292 - CDw293 - CD294 - CD295 - CD297 - CD298 - CD299 301-350 CD300A - CD304 - CD305 - CD307 - CD309 - CD312 - CD314 - CD315 - CD316 - CD317 - CD318 - CD320 - CD321 - CD322 - CD324 - CD325 - CD326 - CD328 - CD329 - CD331 - CD332 - CD333 - CD334 - CD335 - CD336 - CD337 - CD338 - CD339 - CD340 - CD344 - CD349 - CD350 v d e Proteases: metalloendopeptidases EC 3.4.24 ADAM proteins Alpha secretases ADAM9 · ADAM10 · ADAM17 · ADAM19 · ADAM2 · ADAM7 · ADAM8 · ADAM11 · ADAM12 · ADAM15 · ADAM18 · ADAM22 · ADAM23 · ADAM28 · ADAM33 · ADAMTS1 · ADAMTS2 · ADAMTS3 · ADAMTS4 · ADAMTS5 · ADAMTS8 · ADAMTS9 · ADAMTS10 · ADAMTS12 · ADAMTS13 Matrix metalloproteinase Collagenase · Gelatinase Other Neprilysin · Procollagen peptidase · Thermolysin · Pregnancy-associated plasma protein A · Bone morphogenetic protein 1 · Insulysin · Lysostaphin · Insulin degrading enzyme v d e Tumor markers Reproductive ovarian cancer: CA-125 - CD30 testicular cancer: βHCG - Alpha-fetoprotein/AFP-L3 - CD30 prostate cancer: Prostatic acid phosphatase - Prostate specific antigen - Glutamate carboxypeptidase II - erbB-3 receptor - Early prostate cancer antigen-2 - SPINK1 - GOLPH2 - PCA3 germ cell tumor: NANOG Digestive colorectal cancer: CA 19-9 hepatocellular carcinoma: Alpha-fetoprotein/AFP-L3 pancreatic cancer: CA 19-9 - Carcinoembryonic antigen Endocrine medullary thyroid cancer: Calcitonin pheochromocytoma: Normetanephrine - Enolase 2 Other breast cancer: CA 15-3 - erbB-2 receptor - erbB-3 receptor lung cancer: Carcinoembryonic antigen - Enolase 2 - Autocrine motility factor neuroendocrine tumors: Synaptophysin brain tumor: PCNA lymphoma: Neprilysin bladder cancer: erbB-3 receptor note: all are peptide except normetanephrine Retrieved from http://en..org/wiki/Neprilysin Categories: Genes on chromosome 3 | Human proteins | Alzheimer's disease | EC 3.4.24 Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Deutsch Italiano Polski This page was last modified on 8 July 2008, at 04:17
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