Sirtuin catalysis and regulation

Abstract

Sirtuins are a family of NAD(+)-dependent protein deacetylases/deacylases that dynamically regulate transcription, metabolism, and cellular stress response. Their general positive link with improved health span in mammals, potential regulation of pathways mediated by caloric restriction, and growing links to human disease have spurred interest in therapeutics that target their functions. Here, we review the current understanding of the chemistry of catalysis, biological targets, and endogenous regulation of sirtuin activity. We discuss recent efforts to generate small-molecule regulators of sirtuin activity.

FIGURE 1.

Representative structure of a human sirtuin (Protein Data Bank code 3GLR) bound to acetylated peptide and NAD⁺. Key locations for sirtuin modulation are highlighted. Positive regulators of sirtuin activity are indicated in green, negative regulators are indicated in red, and regulators that can activate or inhibit depending on the sirtuin are in yellow. Proposed activators include NAD⁺ synthesis, Sirtris compound 11 (90) and other reported activators, and phosphorylation of SIRT1. Inhibitors include cysteine nitrosylation, DBC1 binding SIRT1, pseudopeptidic inhibitors (95) and other small molecules, nicotinamide, and sumoylation of SIRT1.

FIGURE 2.

Substrates and products of the sirtuin-catalyzed reaction and potential fate of the product OAADPr. The unique use of NAD⁺ as a co-substrate distinguishes sirtuins from other deacetylase classes and provides a direct link to energy metabolism.

FIGURE 3.

Subcellular localization of mammalian sirtuins and reported enzymatic activities, substrates/targets, and cellular functions. PPARγ, peroxisome proliferator-activated receptor-γ; PCAF, p300/CBP-associated factor; OTC, ornithine transcarbamylase; LCAD, long chain acyl-CoA dehydrogenase; GDH, glutamate dehydrogenase; SDH, succinate dehydrogenase; pol, polymerase; CtIP, CTBP-interacting protein; DNA-PK, DNA-dependent protein kinase.

FIGURE 4.

Structures of known acyl modifications found on lysine residues.