Abstract
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.
Highlights
The silent information regulator proteins have emerged as critical regulators of many cellular pathways
In order to extend mammalian healthspan and lifespan, intense interest has developed in the activation of the seven mammalian sirtuin enzymes (SIRT1-7)
We present a general framework for activation of sirtuin enzymes that is distinct from any of the known modes of enzyme activation
Summary
The silent information regulator proteins (sirtuins) have emerged as critical regulators of many cellular pathways. These enzymes protect against age-related diseases and serve as key mediators of longevity in evolutionarily distant organismic models [1]. A thorough understanding of sirtuin chemistry is of fundamental importance, and of considerable medicinal importance, since there is enormous interest in the development of new mechanism-based sirtuin modulators [2, 3]. The mechanism of sirtuincatalyzed deacylation is depicted in S1 Fig [4,5,6,7,8,9]. In order to extend mammalian healthspan and lifespan, intense interest has developed in the activation of the seven mammalian sirtuin enzymes (SIRT1-7).
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