A Molecular Perspective on Sirtuin Activity

Abstract

The protein acetylation of either the α-amino groups of amino-terminal residues or of internal lysine or cysteine residues is one of the major posttranslational protein modifications that occur in the cell with repercussions at the protein as well as at the metabolome level. The lysine acetylation status is determined by the opposing activities of lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), which add and remove acetyl groups from proteins, respectively. A special group of KDACs, named sirtuins, that require NAD⁺ as a substrate have received particular attention in recent years. They play critical roles in metabolism, and their abnormal activity has been implicated in several diseases. Conversely, the modulation of their activity has been associated with protection from age-related cardiovascular and metabolic diseases and with increased longevity. The benefits of either activating or inhibiting these enzymes have turned sirtuins into attractive therapeutic targets, and considerable effort has been directed toward developing specific sirtuin modulators. This review summarizes the protein acylation/deacylation processes with a special focus on the current developments in the sirtuin research field.

Keywords: lysine deacetylases; posttranslational modifications; protein acylation; sirtuins.

Figure 1

General overview of the cellular events related with the protein acylation process.

Figure 2

Classification of different lysine deacylases (KDACs) based on their phylogenetic conservation and/or sequence similarities.

Figure 3

(a) VMD representation of the crystallographic structure of a ternary complex from a wild-type Sir2Tm enzyme from Thermatoga maritima (PDB ID: 2H4F [97]) (new cartoon representation) with 9 residues from the acetylated p53 peptide (licorice representation), one NAD⁺ molecule (CPK representation) and one Zn²⁺ molecule (VDW representation). The peptide-binding domain (orange) was obtained from the PDB ID structure 2H59 [97] through structural alignment. (b) VMD representation of the acylated peptide-binding cleft and (c) VMD representation of the C pocket with NAD⁺ inside it.

Figure 4

Sirtuins’ catalytic mechanism proposal [122]. The red arrows represent the movement of electrons.