Deciphering the Allosteric Activation Mechanism of SIRT6 Using Molecular Dynamics Simulations

by Selleckchem | Nov 13 2023

As a member of the histone deacetylase protein family, the NAD+-dependent SIRT6 plays an important role in maintaining genomic stability and regulating cell metabolism. Interestingly, SIRT6 has been found to have a preference for hydrolyzing long-chain fatty acyls relative to deacetylation, and it can be activated by fatty acids. However, the mechanisms by which SIRT6 recognizes different substrates and can be activated by small molecular activators are still not well understood. In this study, we carried out extensive molecular dynamic simulations to shed light on these mechanisms. Our results revealed that the binding of the myristoylated substrate stabilizes the catalytically favorable conformation of NAD+, while the binding of the acetyl-lysine substrate leads to a loose binding of NAD+ in SIRT6. Based on these observations, we proposed a reasonable allosteric binding mode for myristic acid, which can enhance the catalytic activity of SIRT6 by stabilizing the binding of NAD+ with His131 as well as the acetylated substrate. Furthermore, our molecular dynamics simulations demonstrated that synthetic SIRT6 activators, such as UBCS039, MDL-801, and 12q, block the flipping of ribose in NAD+ and therefore can stabilize substrate-NAD+-His131 interactions in a manner similar to fatty acids. In summary, our newly proposed activation mechanism of SIRT6 highlights the importance of protein-substrate interactions, which would facilitate the rational design of new SIRT6 activators.

Comments:

Your summary provides an overview of a hypothetical study focused on understanding the mechanisms by which the NAD+-dependent protein SIRT6 recognizes different substrates and can be activated by small molecular activators. Here's a breakdown of the key findings and implications of the study:

1. **SIRT6's Substrate Preference:** SIRT6, a member of the histone deacetylase protein family, is known to preferentially hydrolyze long-chain fatty acyls over deacetylation. This substrate preference is significant for its cellular functions, which include maintaining genomic stability and regulating cell metabolism.

2. **Role of Substrates in NAD+ Binding:** The study suggests that the binding of different substrates influences the conformation of NAD+ within the SIRT6 protein. Specifically, when myristoylated substrates are bound, they stabilize a catalytically favorable conformation of NAD+. In contrast, when acetyl-lysine substrates are bound, the binding of NAD+ becomes less stable within SIRT6.

3. **Proposed Allosteric Binding Mode for Myristic Acid:** The study proposes an allosteric binding mode for myristic acid, a long-chain fatty acid. This binding mode enhances the catalytic activity of SIRT6 by stabilizing the binding of NAD+ with a specific amino acid residue, His131, as well as the acetylated substrate. This suggests that myristic acid can enhance the deacetylation activity of SIRT6.

4. **SIRT6 Activators:** The study also investigates synthetic SIRT6 activators, such as UBCS039, MDL-801, and 12q. It is found that these activators block the flipping of ribose in NAD+, leading to the stabilization of substrate-NAD+-His131 interactions. This mechanism of action is similar to that of fatty acids, suggesting that these synthetic activators mimic the effect of fatty acids in enhancing SIRT6 activity.

5. **Implications for Drug Design:** The findings of this study have important implications for drug design. Understanding the mechanisms of SIRT6 activation and substrate recognition could aid in the rational design of new SIRT6 activators. Such activators could potentially be used as therapeutic agents in conditions where SIRT6 plays a critical role in cellular processes, such as genomic stability and metabolism.

Overall, this study provides valuable insights into the molecular mechanisms underlying SIRT6 function and activation, opening up possibilities for the development of novel drugs that modulate SIRT6 activity for therapeutic purposes.