Mechanism-based sirtuin enzyme activation

BioRxiv : the Preprint Server for Biology
Xiangying GuanRaj Chakrabarti

Abstract

Sirtuin enzymes are NAD+-dependent protein deacylases that play a central role in the regulation of healthspan and lifespan in organisms ranging from yeast to mammals. There is intense interest in the activation of the seven mammalian sirtuins (SIRT1-7) in order to extend mammalian healthspan and lifespan. 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. Moreover, 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. None of these modes of activation are based on the unique catalytic reaction mechanisms of the target enzymes. Here, we report 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 ...Continue Reading

Related Concepts

SIRT1 protein, human
SIRT1
Enzymes, antithrombotic
Regulation of Biological Process
SIRT1 gene
Yeasts
SIRT7
Biophysics
Protein Deacylation
Enzyme Activity

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