Publication Date
1-1-2023
Document Type
Article
Publication Title
Frontiers in Molecular Biosciences
Volume
10
DOI
10.3389/fmolb.2023.1260489
Abstract
SIRT1 is an NAD+-dependent protein deacetylase that has been shown to play a significant role in many biological pathways, such as insulin secretion, tumor formation, lipid metabolism, and neurodegeneration. There is great interest in understanding the regulation of SIRT1 to better understand SIRT1-related diseases and to better design therapeutic approaches that target SIRT1. There are many known protein and small molecule activators and inhibitors of SIRT1. One well-studied SIRT1 regulator, resveratrol, has historically been regarded as a SIRT1 activator, however, recent studies have shown that it can also act as an inhibitor depending on the identity of the peptide substrate. The inhibitory nature of resveratrol has yet to be studied in detail. Understanding the mechanism behind this dual behavior is crucial for assessing the potential side effects of STAC-based therapeutics. Here, we investigate the detailed mechanism of substrate-dependent SIRT1 regulation by resveratrol. We demonstrate that resveratrol alters the substrate recognition of SIRT1 by affecting the KM values without significantly impacting the catalytic rate (kcat). Furthermore, resveratrol destabilizes SIRT1 and extends its conformation, but the conformational changes differ between the activation and inhibition scenarios. We propose that resveratrol renders SIRT1 more flexible in the activation scenario, leading to increased activity, while in the inhibition scenario, it unravels the SIRT1 structure, compromising substrate recognition. Our findings highlight the importance of substrate identity in resveratrol-mediated SIRT1 regulation and provide insights into the allosteric control of SIRT1. This knowledge can guide the development of targeted therapeutics for diseases associated with dysregulated SIRT1 activity.
Funding Number
1R16GM149377
Funding Sponsor
National Institutes of Health
Keywords
allosteric regulation, conformational change, deacetylase, enzyme kinetics, SIRT1
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Department
Chemistry
Recommended Citation
Yujin Hur, Johnson Huynh, Emily Leong, Reena Dosanjh, Annemarie F. Charvat, My H. Vu, Zain Alam, Yue Tong Lee, Christiane C. Cabreros, Emma C. Carroll, Greg L. Hura, and Ningkun Wang. "The differing effects of a dual acting regulator on SIRT1" Frontiers in Molecular Biosciences (2023). https://doi.org/10.3389/fmolb.2023.1260489
