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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Main Authors: Xiangying Guan, Alok Upadhyay, Sudipto Munshi, Raj Chakrabarti
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2018-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC5856274?pdf=render
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spelling 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
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AT alokupadhyay biophysicalcharacterizationofhitcompoundsformechanismbasedenzymeactivation
AT sudiptomunshi biophysicalcharacterizationofhitcompoundsformechanismbasedenzymeactivation
AT rajchakrabarti biophysicalcharacterizationofhitcompoundsformechanismbasedenzymeactivation
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