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N-terminal domain of Bothrops asper Myotoxin II Enhances the Activity of Endothelin Converting Enzyme-1 and Neprilysin
Citation
Smith, AI and Rajapakse, NW and Kleifeld, O and Lomonte, B and Sikanyika, NL and Spicer, AJ and Hodgson, WC and Conroy, PJ and Small, DH and Kaye, DM and Parkington, HC and Whisstock, JC and Kuruppu, S, N-terminal domain of Bothrops asper Myotoxin II Enhances the Activity of Endothelin Converting Enzyme-1 and Neprilysin, Scientific Reports, 6 Article 22413. ISSN 2045-2322 (2016) [Refereed Article]
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Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/
Abstract
Neprilysin (NEP) and endothelin converting enzyme-1 (ECE-1) are two enzymes that degrade amyloid beta in the brain. Currently there are no molecules to stimulate the activity of these enzymes. Here we report, the discovery and characterisation of a peptide referred to as K49-P1-20, from the venom of Bothrops asper which directly enhances the activity of both ECE-1 and NEP. This is evidenced by a 2- and 5-fold increase in the Vmax of ECE-1 and NEP respectively. The K49-P1-20 concentration required to achieve 50% of maximal stimulation (AC50) of ECE-1 and NEP was 1.92 ± 0.07 and 1.33 ± 0.12 µM respectively. Using BLITZ biolayer interferometry we have shown that K49-P1-20 interacts directly with each enzyme. Intrinsic fluorescence of the enzymes change in the presence of K49-P1-20 suggesting a change in conformation. ECE-1 mediated reduction in the level of endogenous soluble amyloid beta 42 in cerebrospinal fluid is significantly higher in the presence of K49-P1-20 (31 ± 4% of initial) compared with enzyme alone (11 ± 5% of initial; N = 8, P = 0.005, unpaired t-test). K49-P1-20 could be an excellent research tool to study mechanism(s) of enzyme stimulation, and a potential novel drug lead in the fight against Alzheimer's disease.
Item Details
| Item Type: | Refereed Article |
|---|---|
| Research Division: | Medical and Health Sciences |
| Research Group: | Neurosciences |
| Research Field: | Neurosciences not elsewhere classified |
| Objective Division: | Health |
| Objective Group: | Clinical Health (Organs, Diseases and Abnormal Conditions) |
| Objective Field: | Neurodegenerative Disorders Related to Ageing |
| UTAS Author: | Small, DH (Professor David Small) |
| ID Code: | 107923 |
| Year Published: | 2016 |
| Web of Science® Times Cited: | 8 |
| Deposited By: | Menzies Institute for Medical Research |
| Deposited On: | 2016-03-31 |
| Last Modified: | 2017-11-06 |
| Downloads: | 112 View Download Statistics |
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