NLN (gene)
Neurolysin, mitochondrial is a protein that in humans is encoded by the NLN gene.[5][6] It is a 78-kDa enzyme, widely distributed in mammalian tissues and found in various subcellular locations that vary with cell type.[7] Neurolysin exemplifies the ability of neuropeptidases to target various cleavage site sequences by hydrolyzing them in vitro,[8][9] and metabolism of neurotensin is the most important role of neurolysin in vivo.[10] Neurolysin has also been implicated in pain control,[11][12][13] blood pressure regulation,[14][15] sepsis,[16] reproduction,[17][18] cancer biology[19] pathogenesis of stroke,[20] and glucose metabolism.[21]
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Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
Aliases | NLN, AGTBP, EP24.16, MEP, MOP, neurolysin | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 611530 MGI: 1923055 HomoloGene: 69315 GeneCards: NLN | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Structure
Gene
The NLN gene lies on the chromosome location of 5q12.3 and consists of 14 exons.
Protein
Neurolysin, with 704 amino acid residues, is a zinc metalloendopeptidase with a conserved HEXXH motif. It has an overall prolate ellipsoid shape, with a deep narrow channel dividing it into two roughly equal domains.[22] The catalytic site is contained within a thermolysin-like region found in many metallopeptidases and located in the domain near the floor of the channel.[10][23]
Function
Neurolysin hydrolyzes only peptides containing 5-17 amino acids by cleaving at a limited set of sites.[22][24][25] The specificity of neurolysin for small bioactive peptides is due to the presence of large structural elements erected over its active site region that allow substrates access only through a deep narrow channel.[26] In vitro, neurolysin exemplifies the ability of some neuropeptidases to target diverse cleavage site sequences.[8][9] In vivo, their most established role is cleaving neurotensin between its 10th and 11th residues to produce inactive fragments and it has been recently identified as a non-AT1-non-AT2 angiotensin-binding site, with function pertaining to the rennin-angiotensin system.[10][27][28] Neurotensin is involved in many processes including mast cell degranulation and regulation of central nervous system dopaminergic and cholinergic circuits.[29][30][31] A lower level of neurotensin is associated with schizophrenia,[32] and it is implicated in cardiovascular disorders, addiction, Huntington disease and Parkinson disease.[30][33][34][35] Neurotensin is also one of the most potent blockers of pain perception.[36]
Clinical significance
Metabolism of neurotensin is the most important role of neurolysin in vivo and has been identified as a non-AT1-non-AT2 angiotensin-binding site.[10][27][28] Neurotensin is involved in many processes including mast cell degranullation and regulation of central nervous system dopaminergic and cholinergic circuits.[29][30][31] Neurolysin has also been implicated in pain control,[11][12][13] blood pressure regulation,[14][15] sepsis,[16] reproduction,[17][18] cancer biology,[19] pathogenesis of stroke,[20] and glucose metabolism.[21] Inhibition of neurolysin has been shown to produce neurotensin-induced analgesia in mice,[37] and control of neurotensin levels by neurolysin may serve as a potential target for antipsychotic therapies.
References
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- Barelli H, Fox-Threlkeld JE, Dive V, Daniel EE, Vincent JP, Checler F (May 1994). "Role of endopeptidase 3.4.24.16 in the catabolism of neurotensin, in vivo, in the vascularly perfused dog ileum". British Journal of Pharmacology. 112 (1): 127–32. doi:10.1111/j.1476-5381.1994.tb13041.x. PMC 1910296. PMID 8032633.
- Oliveira EB, Souza LL, Sivieri DO, Bispo-da-Silva LB, Pereira HJ, Costa-Neto CM, Sousa MV, Salgado MC (December 2007). "Carboxypeptidase B and other kininases of the rat coronary and mesenteric arterial bed perfusates". American Journal of Physiology. Heart and Circulatory Physiology. 293 (6): H3550-7. doi:10.1152/ajpheart.00784.2007. PMID 17906107. S2CID 23115730.
- Blais PA, Côté J, Morin J, Larouche A, Gendron G, Fortier A, Regoli D, Neugebauer W, Gobeil F (August 2005). "Hypotensive effects of hemopressin and bradykinin in rabbits, rats and mice. A comparative study". Peptides. 26 (8): 1317–22. doi:10.1016/j.peptides.2005.03.026. PMID 16042973. S2CID 36463460.
- Piliponsky AM, Chen CC, Nishimura T, Metz M, Rios EJ, Dobner PR, Wada E, Wada K, Zacharias S, Mohanasundaram UM, Faix JD, Abrink M, Pejler G, Pearl RG, Tsai M, Galli SJ (April 2008). "Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis". Nature Medicine. 14 (4): 392–8. doi:10.1038/nm1738. PMC 2873870. PMID 18376408.
- Dauch P, Masuo Y, Vincent JP, Checler F (November 1992). "Endopeptidase 24-16 in murines: tissue distribution, cerebral regionalization, and ontogeny". Journal of Neurochemistry. 59 (5): 1862–7. doi:10.1111/j.1471-4159.1992.tb11021.x. PMID 1402928. S2CID 41539518.
- Shrimpton CN, Smith AI, Lew RA (October 2002). "Soluble metalloendopeptidases and neuroendocrine signaling". Endocrine Reviews. 23 (5): 647–64. doi:10.1210/er.2001-0032. PMID 12372844.
- Paschoalin T, Carmona AK, Rodrigues EG, Oliveira V, Monteiro HP, Juliano MA, Juliano L, Travassos LR (9 July 2007). "Characterization of thimet oligopeptidase and neurolysin activities in B16F10-Nex2 tumor cells and their involvement in angiogenesis and tumor growth". Molecular Cancer. 6: 44. doi:10.1186/1476-4598-6-44. PMC 1965469. PMID 17620116.
- Rashid M, Wangler NJ, Yang L, Shah K, Arumugam TV, Abbruscato TJ, Karamyan VT (April 2014). "Functional up-regulation of endopeptidase neurolysin during post-acute and early recovery phases of experimental stroke in mouse brain". Journal of Neurochemistry. 129 (1): 179–89. doi:10.1111/jnc.12513. PMID 24164478. S2CID 206089871.
- Cavalcanti DM, Castro LM, Rosa Neto JC, Seelaender M, Neves RX, Oliveira V, Forti FL, Iwai LK, Gozzo FC, Todiras M, Schadock I, Barros CC, Bader M, Ferro ES (May 2014). "Neurolysin knockout mice generation and initial phenotype characterization". The Journal of Biological Chemistry. 289 (22): 15426–40. doi:10.1074/jbc.M113.539148. PMC 4140899. PMID 24719317.
- Brown CK, Madauss K, Lian W, Beck MR, Tolbert WD, Rodgers DW (March 2001). "Structure of neurolysin reveals a deep channel that limits substrate access". Proceedings of the National Academy of Sciences of the United States of America. 98 (6): 3127–32. Bibcode:2001PNAS...98.3127B. doi:10.1073/pnas.051633198. PMC 30618. PMID 11248043.
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- Ray K, Hines CS, Rodgers DW (September 2002). "Mapping sequence differences between thimet oligopeptidase and neurolysin implicates key residues in substrate recognition". Protein Science. 11 (9): 2237–46. doi:10.1110/ps.0216302. PMC 2373592. PMID 12192079.
- Yanagihara N, Toyohira Y, Yamamoto H, Ohta Y, Tsutsui M, Miyamoto E, Izumi F (September 1994). "Occurrence and activation of Ca2+/calmodulin-dependent protein kinase II and its endogenous substrates in bovine adrenal medullary cells". Molecular Pharmacology. 46 (3): 423–30. PMID 7935321.
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- Wangler NJ, Santos KL, Schadock I, Hagen FK, Escher E, Bader M, Speth RC, Karamyan VT (January 2012). "Identification of membrane-bound variant of metalloendopeptidase neurolysin (EC 3.4.24.16) as the non-angiotensin type 1 (non-AT1), non-AT2 angiotensin binding site". The Journal of Biological Chemistry. 287 (1): 114–22. doi:10.1074/jbc.M111.273052. PMC 3249063. PMID 22039052.
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- Rostène W, Brouard A, Dana C, Masuo Y, Agid F, Vial M, Lhiaubet AM, Pelaprat D (1992). "Interaction between neurotensin and dopamine in the brain. Morphofunctional and clinical evidence". Annals of the New York Academy of Sciences. 668: 217–31. doi:10.1111/j.1749-6632.1992.tb27352.x. PMID 1361114. S2CID 41673524.
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Further reading
- Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T (June 2002). "Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones". DNA Research. 9 (3): 99–106. doi:10.1093/dnares/9.3.99. PMID 12168954.
- Serizawa A, Dando PM, Barrett AJ (February 1995). "Characterization of a mitochondrial metallopeptidase reveals neurolysin as a homologue of thimet oligopeptidase". The Journal of Biological Chemistry. 270 (5): 2092–8. doi:10.1074/jbc.270.5.2092. PMID 7836437.
- Vincent B, Vincent JP, Checler F (February 1996). "Purification and characterization of human endopeptidase 3.4.24.16. Comparison with the porcine counterpart indicates a unique cleavage site on neurotensin". Brain Research. 709 (1): 51–8. doi:10.1016/0006-8993(95)01260-5. PMID 8869556. S2CID 24776559.
- Vincent B, Dauch P, Vincent JP, Checler F (February 1997). "Stably transfected human cells overexpressing rat brain endopeptidase 3.4.24.16: biochemical characterization of the activity and expression of soluble and membrane-associated counterparts". Journal of Neurochemistry. 68 (2): 837–45. doi:10.1046/j.1471-4159.1997.68020837.x. PMID 9003076. S2CID 20092972.
- Krause DR, Piva TJ, Brown SB, Ellem KA (September 1997). "Characterization and localization of mitochondrial oligopeptidase (MOP) (EC 3.4.24.16) activity in the human cervical adenocarcinoma cell line HeLa". Journal of Cellular Biochemistry. 66 (3): 297–308. doi:10.1002/(SICI)1097-4644(19970901)66:3<297::AID-JCB3>3.0.CO;2-K. PMID 9257187. S2CID 6428712.
- Rioli V, Kato A, Portaro FC, Cury GK, te Kaat K, Vincent B, Checler F, Camargo AC, Glucksman MJ, Roberts JL, Hirose S, Ferro ES (September 1998). "Neuropeptide specificity and inhibition of recombinant isoforms of the endopeptidase 3.4.24.16 family: comparison with the related recombinant endopeptidase 3.4.24.15". Biochemical and Biophysical Research Communications. 250 (1): 5–11. doi:10.1006/bbrc.1998.8941. PMID 9735321.
- Garrido PA, Vandenbulcke F, Ramjaun AR, Vincent B, Checler F, Ferro E, Beaudet A (April 1999). "Confocal microscopy reveals thimet oligopeptidase (EC 3.4.24.15) and neurolysin (EC 3.4.24.16) in the classical secretory pathway". DNA and Cell Biology. 18 (4): 323–31. doi:10.1089/104454999315385. PMID 10235115.
- Lew RA, Boulos E, Stewart KM, Perlmutter P, Harte MF, Bond S, Aguilar MI, Smith AI (September 2000). "Bradykinin analogues with beta-amino acid substitutions reveal subtle differences in substrate specificity between the endopeptidases EC 3.4.24.15 and EC 3.4.24.16". Journal of Peptide Science. 6 (9): 440–5. doi:10.1002/1099-1387(200009)6:9<440::AID-PSC280>3.0.CO;2-K. PMID 11016880. S2CID 21167268.
- Norman MU, Lew RA, Smith AI, Hickey MJ (June 2003). "Metalloendopeptidases EC 3.4.24.15/16 regulate bradykinin activity in the cerebral microvasculature". American Journal of Physiology. Heart and Circulatory Physiology. 284 (6): H1942-8. doi:10.1152/ajpheart.00948.2002. PMID 12586639. S2CID 27696550.
- Norman MU, Reeve SB, Dive V, Smith AI, Lew RA (June 2003). "Endopeptidases 3.4.24.15 and 24.16 in endothelial cells: potential role in vasoactive peptide metabolism". American Journal of Physiology. Heart and Circulatory Physiology. 284 (6): H1978-84. doi:10.1152/ajpheart.01116.2002. PMID 12609826.
- Lim EJ, Sampath S, Coll-Rodriguez J, Schmidt J, Ray K, Rodgers DW (March 2007). "Swapping the substrate specificities of the neuropeptidases neurolysin and thimet oligopeptidase". The Journal of Biological Chemistry. 282 (13): 9722–32. doi:10.1074/jbc.M609897200. PMID 17251185.