Detection of active site conformation changes of gamma-secretase, a key enzyme associated with Alzheimer disease, with small molecules

• Main Authors: Gertsik, Natalya, Li, Yue Ming, Chau, De Ming
• Format: Conference or Workshop Item
• Language: English
• Published: 2016
• Online Access: http://psasir.upm.edu.my/id/eprint/53874/1/Detection%20of%20active%20site%20conformation%20changes%20of%20gamma-secretase%2C%20a%20key%20enzyme%20associated%20with%20Alzheimer%20disease%2C%20with%20small%20molecules.pdf; http://psasir.upm.edu.my/id/eprint/53874/; https://www.frontiersin.org/10.3389/conf.fncel.2016.36.00137/3912/14%3Csup%3Eth%3C_sup%3E_Meeting_of_the_Asian-Pacific_Society_for_Neurochemistry/all_events/event_abstract

Gamma-secretase is a membrane-bound aspartyl-protease that cleaves many membrane substrates including Amyloid Precursor Protein (APP), Notch, E-cadherin, Her4 and CD44. APP is a particularly notable substrate because of its association with Alzheimer disease. Together, gamma-secretase and beta-secretase cleave APP to produce amyloid beta peptides that aggregate in the brain as cytotoxic beta-amlyoid plaques, which is one of the hallmarks of Alzheimer disease. Many small molecules are being developed to target gamma-secretase as a therapeutic strategy for Alzheimer disease. However, studying the effects of these molecules on the active site conformation of gamma-secretase is challenging due to the complexity of this enzyme. In our study, we have developed new biochemical techniques to probe the active site structure of gamma-secretase. We are able to show that different gamma-secretase inhibitors and modulators, when bind to gamma-secretase, affect the active site structure of gamma-secretase differently. More importantly, we discovered that these small molecules, which were developed to target gamma-secretase, also affect the active site structure of Signal Peptide Peptidase, a similar membrane-bound aspartyl-protease. This discovery has major implication on the development of gamma-secretase inhibitors as therapeutic drugs for Alzheimer disease due to potential off-target effects.