Inhibition of Silencing and Accelerated Aging by Nicotinamide, a Putative Negative Regulator of Yeast Sir2 and Human SIRT1*
By Kevin J. Bitterman, Rozalyn M. Anderson, H. Cohen, Magda Latorre-Esteves, D. Sinclair. Journal of Biological Chemistry, 2002
1,040 citations recorded by the source corpus.
The Saccharomyces cerevisiae Sir2 protein is an NAD+-dependent histone deacetylase that plays a critical role in transcriptional silencing, genome stability, and longevity. A human homologue of Sir2, SIRT1, regulates the activity of the p53 tumor suppressor and inhibits apoptosis. The Sir2 deacetylation reaction generates two products:O-acetyl-ADP-ribose and nicotinamide, a precursor of nicotinic acid and a form of niacin/vitamin B3. We show here that nicotinamide strongly inhibits yeast silencing, increases rDNA recombination, and shortens replicative life span to that of asir2 mutant. Nicotinamide abolishes silencing and leads to an eventual delocalization of Sir2 even in G1-arrested cells, demonstrating that silent heterochromatin requires continual Sir2 activity. We show that physiological concentrations of nicotinamide noncompetitively inhibit both Sir2 and SIRT1 in vitro. The degree of inhibition by nicotinamide (IC50< 50 μm) is equal to or better than the most effective known synthetic inhibitors of this class of proteins. We propose a model whereby nicotinamide inhibits deacetylation by binding to a conserved pocket adjacent to NAD+, thereby blocking NAD+ hydrolysis. We discuss the possibility that nicotinamide is a physiologically relevant regulator of Sir2 enzymes.
Subfields: Geriatrics and Gerontology, Oncology, Physiology
View Paper: https://www.semanticscholar.org/paper/a900c08686eb55b9dc077ddfc3e311e68e11d5ec
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Citations in the corpus
- Sirt1 Regulates Insulin Secretion by Repressing UCP2 in Pancreatic β Cells (2005, positive): “INS-1 or MIN6 cells were treated with 10 mM nicotinamide, an inhibitor of Sirt1 [41], for 48 h, and the levels of insulin secreted into the media were measured without and with induction by glucose (Figure 3B and 3F, respectively).”
- Class I histone deacetylases (HDAC1–3) are histone lysine delactylases (2021, background): “S2 for structures) by HEK293T whole-cell lysates, and inhibition with an HDAC inhibitor (trichostatin A, TSA) or a pan-sirtuin inhibitor (nicotinamide, NAM).”
- Therapeutic potential of NAD-boosting molecules: the in vivo evidence (2018, neutral): “NR and NMN are more promising because they do not cause flushing nor do they inhibit PARPs and sirtuins as does NAM (Bitterman et al., 2002).”
- Cancer epigenetics reaches mainstream oncology (2011, background): “Immediately before nicotinamide was reported to be a physiological inhibitor of sirtuins, sirtinol and splitomicin were described as SIRT inhibitor”
- SIRTUIN 1 AND SIRTUIN 3: PHYSIOLOGICAL MODULATORS OF METABOLISM (2012, background): “A caveat of this efficient reaction is its inhibition by the reaction product nicotinamide (42).”
- Circadian Clock NAD+ Cycle Drives Mitochondrial Oxidative Metabolism in Mice (2013, background): “Because nicotinamide is also able to inhibit sirtuin function (34), we measured amounts of nicotinamide in wild-type and Bmal1 liver tissue to determine whether altered nicotinamide concentrations contribute to decreased SIRT3 function in circadian mutants.”
- NAD+ intermediates: The biology and therapeutic potential of NMN and NR (2017, positive): “It is conceivable that age-associated decline in NAD+ availability (Braidy et al., 2011; Camacho-Pereira et al., 2016; Frederick et al., 2016; Gomes et al., 2013; Massudi et al., 2012; Stein and Imai, 2014; Yoshino et al., 2011) could sensitize aged mice to NAD+ replenishment by NMN administration.”