| Structural highlights
Function
[NEP_HUMAN] Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids. Biologically important in the destruction of opioid peptides such as Met- and Leu-enkephalins by cleavage of a Gly-Phe bond. Able to cleave angiotensin-1, angiotensin-2 and angiotensin 1-9. Involved in the degradation of atrial natriuretic factor (ANF). Displays UV-inducible elastase activity toward skin preelastic and elastic fibers.[1] [2] [3]
Publication Abstract from PubMed
Neprilysin is a transmembrane zinc metallopeptidase that degrades a wide range of peptide substrates. It has received attention as a potential therapy for Alzheimer's disease due to its ability to degrade the peptide amyloid beta. However, its broad range of peptide substrates has the potential to limit its therapeutic use due to degradation of additional peptides substrates that tightly regulate many physiological processes. We sought to generate a soluble version of the ectodomain of neprilysin with improved activity and specificity towards amyloid beta as a potential therapeutic for Alzheimer's disease. Extensive amino acid substitutions were performed at positions surrounding the active site and inner surface of the enzyme and variants screened for activity on amyloid beta 1-40, 1-42 and a variety of other physiologically relevant peptides. We identified several mutations that modulated and improved both enzyme selectivity and intrinsic activity. Neprilysin variant G399V/G714K displayed an approximately 20-fold improved activity on amyloid beta 1-40 and up to a 3,200-fold reduction in activity on other peptides. Along with the altered peptide substrate specificity, the mutant enzyme produced a markedly altered series of amyloid beta cleavage products compared to the wild-type enzyme. Crystallisation of the mutant enzyme revealed that the amino acid substitutions result in alteration of the shape and size of the pocket containing the active site compared to the wild-type enzyme. The mutant enzyme offers the potential for the more efficient degradation of amyloid beta in vivo as a therapeutic for the treatment of Alzheimer's disease.
Engineering neprilysin activity and specificity to create a novel therapeutic for Alzheimer's disease.,Webster CI, Burrell M, Olsson LL, Fowler SB, Digby S, Sandercock A, Snijder A, Tebbe J, Haupts U, Grudzinska J, Jermutus L, Andersson C PLoS One. 2014 Aug 4;9(8):e104001. doi: 10.1371/journal.pone.0104001. eCollection, 2014. PMID:25089527[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Yandle TG, Brennan SO, Espiner EA, Nicholls MG, Richards AM. Endopeptidase-24.11 in human plasma degrades atrial natriuretic factor (ANF) to ANF(99-105/106-126). Peptides. 1989 Jul-Aug;10(4):891-4. PMID:2531377
- ↑ Rice GI, Thomas DA, Grant PJ, Turner AJ, Hooper NM. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J. 2004 Oct 1;383(Pt 1):45-51. PMID:15283675 doi:http://dx.doi.org/10.1042/BJ20040634
- ↑ Morisaki N, Moriwaki S, Sugiyama-Nakagiri Y, Haketa K, Takema Y, Imokawa G. Neprilysin is identical to skin fibroblast elastase: its role in skin aging and UV responses. J Biol Chem. 2010 Dec 17;285(51):39819-27. doi: 10.1074/jbc.M110.161547. Epub, 2010 Sep 28. PMID:20876573 doi:http://dx.doi.org/10.1074/jbc.M110.161547
- ↑ Webster CI, Burrell M, Olsson LL, Fowler SB, Digby S, Sandercock A, Snijder A, Tebbe J, Haupts U, Grudzinska J, Jermutus L, Andersson C. Engineering neprilysin activity and specificity to create a novel therapeutic for Alzheimer's disease. PLoS One. 2014 Aug 4;9(8):e104001. doi: 10.1371/journal.pone.0104001. eCollection, 2014. PMID:25089527 doi:http://dx.doi.org/10.1371/journal.pone.0104001
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