Detection of active site conformation changes of gamma-secretase, a key enzyme associated with Alzheimer disease, with small molecules
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-secre...
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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 |
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my.upm.eprints.538742019-05-10T04:49:08Z http://psasir.upm.edu.my/id/eprint/53874/ Detection of active site conformation changes of gamma-secretase, a key enzyme associated with Alzheimer disease, with small molecules Gertsik, Natalya Li, Yue Ming Chau, De Ming 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. 2016 Conference or Workshop Item PeerReviewed text en 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 Gertsik, Natalya and Li, Yue Ming and Chau, De Ming (2016) Detection of active site conformation changes of gamma-secretase, a key enzyme associated with Alzheimer disease, with small molecules. In: 14th Meeting of the Asian-Pacific Society for Neurochemistry, 27-30 Aug. 2016, Kuala Lumpur, Malaysia. . 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 10.3389/conf.fncel.2016.36.00137 |
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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. |
format |
Conference or Workshop Item |
author |
Gertsik, Natalya Li, Yue Ming Chau, De Ming |
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Gertsik, Natalya Li, Yue Ming Chau, De Ming Detection of active site conformation changes of gamma-secretase, a key enzyme associated with Alzheimer disease, with small molecules |
author_facet |
Gertsik, Natalya Li, Yue Ming Chau, De Ming |
author_sort |
Gertsik, Natalya |
title |
Detection of active site conformation changes of gamma-secretase, a key enzyme associated with Alzheimer disease, with small molecules |
title_short |
Detection of active site conformation changes of gamma-secretase, a key enzyme associated with Alzheimer disease, with small molecules |
title_full |
Detection of active site conformation changes of gamma-secretase, a key enzyme associated with Alzheimer disease, with small molecules |
title_fullStr |
Detection of active site conformation changes of gamma-secretase, a key enzyme associated with Alzheimer disease, with small molecules |
title_full_unstemmed |
Detection of active site conformation changes of gamma-secretase, a key enzyme associated with Alzheimer disease, with small molecules |
title_sort |
detection of active site conformation changes of gamma-secretase, a key enzyme associated with alzheimer disease, with small molecules |
publishDate |
2016 |
url |
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 |
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1643835510951510016 |
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