Finding
The requirement of NAD as a cofactor for enzymatic activity, along with the ability to deacetylate both histones and a variety of non-histone proteins, suggests that the sirtuins play a crucial role in metabolism and energy-dependent transcription.
Paper
Identification of Tri‐ and Tetracyclic Pyrimidinediones as Sirtuin Inhibitors
Abstract
Sirtuins (SIRT1–7) are a family of NAD-dependent deacetylases and/or ADP-ribosyltransferases that modify a broad range of distinct protein substrates with various subcellular localizations. SIRT1 and SIRT2 are mainly localized in the nucleus (SIRT1) or the cytoplasm (SIRT2), SIRT3–5 are typically mitochondrial enzymes, and SIRT6 and SIRT7 are localized in the cell nucleus and nucleolus, respectively. The requirement of NAD as a cofactor for enzymatic activity, along with the ability to deacetylate both histones and a variety of non-histone proteins, suggests that the sirtuins play a crucial role in metabolism and energy-dependent transcription. SIRT1 has been shown to deacetylate more than 30 different acetylated substrates such as H4K16, H3K9, p53, forkhead box class O (FoxO), p300, the DNA repair factor Ku70, peroxisome proliferator-activated receptor g co-activator 1a (PGC-1a), nuclear factor-kB (NF-kB), and many others. Therefore, not surprisingly, SIRT1 is implicated in carcinogenesis, in metabolic and cardiovascular diseases, and in neurodegeneration. In addition to a protective role described for SIRT1 in DNA damage, accumulation of mutations, and genomic instability, SIRT1 has been found to be up-regulated in human lung cancer, prostate cancer, colon carcinoma, and leukemia. Moreover, a deleted-in-breast-cancer (DBC) protein has recently been described as an endogenous inhibitor of SIRT1 to promote p53 acetylation and activation. Cambinol (1; Figure 1), a well-known SIRT inhibitor, is able to inactivate the transcriptional repressor BCL6 in Burkitt’s lymphoma cells through ace-
Authors
D. Rotili, D. Tarantino, V. Carafa
Journal
ChemMedChem