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  3. Studying SIRT6 regulation using H3K56 based substrate and small molecules

Studying SIRT6 regulation using H3K56 based substrate and small molecules

  • Eur J Pharm Sci. 2014 Oct 15:63:71-6. doi: 10.1016/j.ejps.2014.06.015.
Piia Kokkonen 1,  Minna Rahnasto-Rilla 2,  Paolo Mellini 3,  Elina Jarho 1,  Maija Lahtela-Kakkonen 1,  Tarja Kokkola 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
  • 2 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland. Electronic address: Minna.Rahnasto@uef.fi.
  • 3 Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma "La Sapienza", P.le A. Moro 5, 00185 Rome, Italy. Electronic address: paolo.mellini@uniroma1.it.
  • 4 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland. Electronic address: Tarja.Kokkola@uef.fi.
PMID: 25004411 DOI: 10.1016/j.ejps.2014.06.015
Abstract

SIRT6 is a modulator of chromatin structure having an important role in healthy ageing, and there is a crucial need to find specific modulators for it. Therefore, the activity of SIRT6 should be studied using a variety of methods. We examined the capability of SIRT6 to deacetylate a set of five fluorogenic substrates based on p53 and histone H3 sequences. The substrate designed around H3K56 deacetylation site exhibited the best signal-to-background ratio and was chosen for further studies. Nicotinamide is a known inhibitor for sirtuins, and it was found to be less potent inhibitor for SIRT6 than it is for SIRT1. In addition, we studied 15 Other small molecule Sirtuin modulators using the H3K56 based substrate. EX-527, quercetin and three pseudopeptidic compounds were found to be the most potent SIRT6 inhibitors, exhibiting over 50% deacetylation inhibition. These findings describe the first modulators of SIRT6 activity at the physiologically important H3K56 deacetylation site.

Keywords

Fluorometric assay; Histone deacetylase; Nicotinamide; SIRT6; Sirtuins.

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