Biophysical characterization of hit compounds for mechanism-based enzyme activation.
Across all families of enzymes, only a dozen or so distinct classes of non-natural small molecule activators have been characterized, with only four known modes of activation among them. All of these modes of activation rely on naturally evolved binding sites that trigger global conformational chang...
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doaj-046f5bca8f0a4815ad347ba5281620842020-11-25T02:24:39ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01133e019417510.1371/journal.pone.0194175Biophysical characterization of hit compounds for mechanism-based enzyme activation.Xiangying GuanAlok UpadhyaySudipto MunshiRaj ChakrabartiAcross all families of enzymes, only a dozen or so distinct classes of non-natural small molecule activators have been characterized, with only four known modes of activation among them. All of these modes of activation rely on naturally evolved binding sites that trigger global conformational changes. Among the enzymes that are of greatest interest for small molecule activation are the seven sirtuin enzymes, nicotinamide adenine dinucleotide (NAD+)-dependent protein deacylases that play a central role in the regulation of healthspan and lifespan in organisms ranging from yeast to mammals. However, there is currently no understanding of how to design sirtuin-activating compounds beyond allosteric activators of SIRT1-catalyzed reactions that are limited to particular substrates. Here, we introduce a general mode of sirtuin activation that is distinct from the known modes of enzyme activation. Based on the conserved mechanism of sirtuin-catalyzed deacylation reactions, we establish biophysical properties of small molecule modulators that can in principle result in enzyme activation for diverse sirtuins and substrates. Building upon this framework, we propose strategies for the identification, characterization and evolution of hits for mechanism-based enzyme activating compounds.http://europepmc.org/articles/PMC5856274?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xiangying Guan Alok Upadhyay Sudipto Munshi Raj Chakrabarti |
spellingShingle |
Xiangying Guan Alok Upadhyay Sudipto Munshi Raj Chakrabarti Biophysical characterization of hit compounds for mechanism-based enzyme activation. PLoS ONE |
author_facet |
Xiangying Guan Alok Upadhyay Sudipto Munshi Raj Chakrabarti |
author_sort |
Xiangying Guan |
title |
Biophysical characterization of hit compounds for mechanism-based enzyme activation. |
title_short |
Biophysical characterization of hit compounds for mechanism-based enzyme activation. |
title_full |
Biophysical characterization of hit compounds for mechanism-based enzyme activation. |
title_fullStr |
Biophysical characterization of hit compounds for mechanism-based enzyme activation. |
title_full_unstemmed |
Biophysical characterization of hit compounds for mechanism-based enzyme activation. |
title_sort |
biophysical characterization of hit compounds for mechanism-based enzyme activation. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2018-01-01 |
description |
Across all families of enzymes, only a dozen or so distinct classes of non-natural small molecule activators have been characterized, with only four known modes of activation among them. All of these modes of activation rely on naturally evolved binding sites that trigger global conformational changes. Among the enzymes that are of greatest interest for small molecule activation are the seven sirtuin enzymes, nicotinamide adenine dinucleotide (NAD+)-dependent protein deacylases that play a central role in the regulation of healthspan and lifespan in organisms ranging from yeast to mammals. However, there is currently no understanding of how to design sirtuin-activating compounds beyond allosteric activators of SIRT1-catalyzed reactions that are limited to particular substrates. Here, we introduce a general mode of sirtuin activation that is distinct from the known modes of enzyme activation. Based on the conserved mechanism of sirtuin-catalyzed deacylation reactions, we establish biophysical properties of small molecule modulators that can in principle result in enzyme activation for diverse sirtuins and substrates. Building upon this framework, we propose strategies for the identification, characterization and evolution of hits for mechanism-based enzyme activating compounds. |
url |
http://europepmc.org/articles/PMC5856274?pdf=render |
work_keys_str_mv |
AT xiangyingguan biophysicalcharacterizationofhitcompoundsformechanismbasedenzymeactivation AT alokupadhyay biophysicalcharacterizationofhitcompoundsformechanismbasedenzymeactivation AT sudiptomunshi biophysicalcharacterizationofhitcompoundsformechanismbasedenzymeactivation AT rajchakrabarti biophysicalcharacterizationofhitcompoundsformechanismbasedenzymeactivation |
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1724854299375173632 |