The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
Ex-527 inhibits Sirtuins by exploiting their unique NAD + -dependent deacetylation mechanism
Open accessAbstract
Significance: Sirtuin enzymes regulate metabolism and stress responses through deacetylation of specific protein lysine residues. Sirtuins are considered attractive drug targets, but selective inhibitors are rare, and their mechanisms mostly unknown. We report the mechanism of Sirtuin inhibition by Ex-527, a potent Sirt1 inhibitor widely used in physiological studies. A set of Sirtuin/ligand crystal structures, together with activity and binding data, reveals that the compound inhibits by forming a trimeric Sirtuin complex with a NAD + -derived coproduct. Our results yield insights in the unique Sirtuin catalytic mechanism and how it is exploited by Ex-527, and they provide essential information for rational drug development.
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Cites
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Phaser crystallographic software
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Sirt5 Is a NAD-Dependent Protein Lysine Demalonylase and Desuccinylase
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Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5
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Cited by
Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target
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Sirtuin activators and inhibitors: Promises, achievements, and challenges
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“N-alkylated thiobabiturates are assumed to exploit, with a certain specificity, SIRT5’s acylLys pocket (Maurer et al., 2012).”
BackgroundInfluentialSelf-citationSirtuin functions and modulation: from chemistry to the clinic
Carafa, V., Rotili, D., Forgione, M., Cuomo, F., Serretiello, E., Hailu, G. S., Jarho, E., Lahtela-Kakkonen, M., Mai, A., & Altucci, L. (2016) · Clinical Epigenetics · doi:10.1186/s13148-016-0224-3 · Cited by 387
Lysine Acetylation Goes Global: From Epigenetics to Metabolism and Therapeutics
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Metadata
- Authors
- Gertz, M., Fischer, F., Nguyen, G. T. T., Lakshminarasimhan, M., Schutkowski, M., Weyand, M., & Steegborn, C.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2013-07-09
- Volume
- 110
- Issue
- 30
- Pages
- E2772-81
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W1968098522
- Cited by
- 317
- References
- 6
- FWCI
- 10.61
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Gertz, M., Fischer, F., Nguyen, G. T. T., Lakshminarasimhan, M., Schutkowski, M., Weyand, M., & Steegborn, C. (2013). Ex-527 inhibits Sirtuins by exploiting their unique NAD + -dependent deacetylation mechanism. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1303628110
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
