The differing effects of a dual acting regulator on SIRT1
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-...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-08-01
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| Series: | Frontiers in Molecular Biosciences |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2023.1260489/full |
| _version_ | 1797730963784990720 |
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| author | 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 Ningkun Wang |
| author_facet | 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 Ningkun Wang |
| author_sort | Yujin Hur |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T11:51:44Z |
| format | Article |
| id | doaj.art-9a53748e6c074cca97e784324bd13789 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-03-12T11:51:44Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-9a53748e6c074cca97e784324bd137892023-08-31T06:46:38ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2023-08-011010.3389/fmolb.2023.12604891260489The differing effects of a dual acting regulator on SIRT1Yujin Hur0Johnson Huynh1Emily Leong2Reena Dosanjh3Annemarie F. Charvat4My H. Vu5Zain Alam6Yue Tong Lee7Christiane C. Cabreros8Emma C. Carroll9Greg L. Hura10Ningkun Wang11Department of Chemistry, San José State University, San José, CA, United StatesDepartment of Chemistry, San José State University, San José, CA, United StatesDepartment of Chemistry, San José State University, San José, CA, United StatesDepartment of Chemistry, San José State University, San José, CA, United StatesDepartment of Pharmaceutical Chemistry, University of California, San Francisco, CA, United StatesDepartment of Chemistry, San José State University, San José, CA, United StatesDepartment of Chemistry, San José State University, San José, CA, United StatesDepartment of Chemistry, San José State University, San José, CA, United StatesDepartment of Chemistry, San José State University, San José, CA, United StatesDepartment of Chemistry, San José State University, San José, CA, United StatesMolecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, United StatesDepartment of Chemistry, San José State University, San José, CA, United StatesSIRT1 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.https://www.frontiersin.org/articles/10.3389/fmolb.2023.1260489/fullallosteric regulationenzyme kineticsdeacetylaseconformational changeSIRT1 |
| spellingShingle | 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 Ningkun Wang The differing effects of a dual acting regulator on SIRT1 Frontiers in Molecular Biosciences allosteric regulation enzyme kinetics deacetylase conformational change SIRT1 |
| title | The differing effects of a dual acting regulator on SIRT1 |
| title_full | The differing effects of a dual acting regulator on SIRT1 |
| title_fullStr | The differing effects of a dual acting regulator on SIRT1 |
| title_full_unstemmed | The differing effects of a dual acting regulator on SIRT1 |
| title_short | The differing effects of a dual acting regulator on SIRT1 |
| title_sort | differing effects of a dual acting regulator on sirt1 |
| topic | allosteric regulation enzyme kinetics deacetylase conformational change SIRT1 |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2023.1260489/full |
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