| Structural highlights
Function
SIR3_HUMAN NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels.[1] [2] [3] [4]
Publication Abstract from PubMed
Sirtuins (SIRTs) are nicotinamide adenine dinucleotide (NAD(+))-dependent lysine deacylases linked to key physiological and disease processes. Here, we report a new class of mechanism-based 1,2,3-triazole inhibitors that hijack SIRT catalysis by forming stalled triazolium- or triazole-ADP-ribose (ADPR) adducts derived from the cofactor NAD(+). These trapped adducts inhibit the enzyme without covalent protein modification, prompting us to term the compounds "Sirtuin Trapping Ligands" (SirTraps). X-ray crystallography and kinetics, together with mass spectrometry confirming adduct formation both in vitro and in cellulo, reveal that the triazole N3 of peptide- and small-molecule-based SirTraps triggers nucleophilic attack at C1' of the nicotinamide riboside moiety of NAD(+), mimicking the first deacylation step. Adduct formation critically depends on precise triazole positioning within the acyl-lysine channel and can be tuned through scaffold design, enabling potent and isoform-selective inhibition. Unlike thiocarbonyl-based NAD(+)-targeting SIRT inhibitors, which may suffer from instability and off-target effects, SirTraps combine high stability, synthetic accessibility, and structural tunability, while demonstrating nanomolar cellular target engagement confirmed by NanoBRET assays. Beyond SIRTs, this inhibition strategy may extend to other NAD(+)-dependent enzymes, including ADP-ribosyltransferases, opening new avenues for mechanism-driven drug discovery.
From Pharmacophore to Warhead: NAD(+)-Targeting Triazoles as Mechanism-Based Sirtuin Inhibitors.,Friedrich F, Meleshin M, Papenkordt N, Gaitzsch L, Prucker I, Borso M, Ruprecht J, Vorreiter C, Rast S, Zhang L, Schiedel M, Sippl W, Imhof A, Jessen HJ, Einsle O, Schutkowski M, Jung M Angew Chem Int Ed Engl. 2025 Oct 30:e16782. doi: 10.1002/anie.202516782. PMID:41165483[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Schwer B, Bunkenborg J, Verdin RO, Andersen JS, Verdin E. Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10224-9. Epub 2006 Jun 20. PMID:16788062 doi:10.1073/pnas.0603968103
- ↑ Schlicker C, Gertz M, Papatheodorou P, Kachholz B, Becker CF, Steegborn C. Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. J Mol Biol. 2008 Oct 10;382(3):790-801. doi: 10.1016/j.jmb.2008.07.048. Epub 2008, Jul 25. PMID:18680753 doi:10.1016/j.jmb.2008.07.048
- ↑ Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, Deng CX, Finkel T. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14447-52. doi:, 10.1073/pnas.0803790105. Epub 2008 Sep 15. PMID:18794531 doi:10.1073/pnas.0803790105
- ↑ Jin L, Wei W, Jiang Y, Peng H, Cai J, Mao C, Dai H, Choy W, Bemis JE, Jirousek MR, Milne JC, Westphal CH, Perni RB. Crystal structures of human SIRT3 displaying substrate-induced conformational changes. J Biol Chem. 2009 Sep 4;284(36):24394-405. Epub 2009 Jun 16. PMID:19535340 doi:10.1074/jbc.M109.014928
- ↑ Friedrich F, Meleshin M, Papenkordt N, Gaitzsch L, Prucker I, Borso M, Ruprecht J, Vorreiter C, Rast S, Zhang L, Schiedel M, Sippl W, Imhof A, Jessen HJ, Einsle O, Schutkowski M, Jung M. From Pharmacophore to Warhead: NAD(+)-Targeting Triazoles as Mechanism-Based Sirtuin Inhibitors. Angew Chem Int Ed Engl. 2025 Oct 30:e16782. PMID:41165483 doi:10.1002/anie.202516782
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