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N-terminal domain of Bothrops asper Myotoxin II Enhances the Activity of Endothelin Converting Enzyme-1 and Neprilysin


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)

DOI: doi:10.1038/srep22413


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 ÁM 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
Author:Small, DH (Professor David Small)
ID Code:107923
Year Published:2016
Web of Science® Times Cited:5
Deposited By:Menzies Institute for Medical Research
Deposited On:2016-03-31
Last Modified:2017-11-06
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