Sirtuin 1 and sirtuin 3: physiological modulators of metabolism

Abstract

The sirtuins are a family of highly conserved NAD(+)-dependent deacetylases that act as cellular sensors to detect energy availability and modulate metabolic processes. Two sirtuins that are central to the control of metabolic processes are mammalian sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), which are localized to the nucleus and mitochondria, respectively. Both are activated by high NAD(+) levels, a condition caused by low cellular energy status. By deacetylating a variety of proteins that induce catabolic processes while inhibiting anabolic processes, SIRT1 and SIRT3 coordinately increase cellular energy stores and ultimately maintain cellular energy homeostasis. Defects in the pathways controlled by SIRT1 and SIRT3 are known to result in various metabolic disorders. Consequently, activation of sirtuins by genetic or pharmacological means can elicit multiple metabolic benefits that protect mice from diet-induced obesity, type 2 diabetes, and nonalcoholic fatty liver disease.

FIGURE 1

Structure of yeast Sir2 in complex with an acetyl-ribosyl-ADP intermediate. Yeast Sir2 is depicted in the cartoon representation with the zinc binding site highlighted in cyan, the helical module highlighted in magenta, and the Rossmann foldlike NAD⁺ binding site highlighted in orange. The acetyl-ADP intermediate is depicted as a stick representation with carbon atoms in gray, oxygen atoms in red, nitrogen atoms in blue, sulfur atoms in yellow, and phosphate atoms in orange. The structure was assembled from Protein Data Bank code 2HJH (Protein Data Bank: Hall BE, Buchberger JR, Gerber SA, Ambrosio ALB, Gygi SP, Filman D, Moazed D, Ellenberger T.).

FIGURE 2

Structure of apo SIRT3. SIRT3 is depicted in the cartoon representation with the zinc binding site highlighted in cyan, the helical module highlighted in magenta, the Rossmann foldlike NAD⁺ binding site highlighted in orange, and the domain interface loops highlighted in white. The structure was assembled from Protein Data Bank code 3GLS (Jin et al., Ref. 160).

FIGURE 3

Structure of SIRT3 in complex with AceCS2-Ks-acetyl-ADPR. SIRT3 is depicted in the cartoon representation with the zinc binding site highlighted in cyan, the helical module highlighted in magenta, and the Rossmann foldlike NAD⁺ binding site highlighted in orange. The acetyl-lysine substrate, which here is the trapped reaction intermediate AceCS2-Ks-acetyl-ADPR peptidal compound, inserts into the domain interface populated by loops that are highlighted in white where catalysis of the deacetylation occurs. The AceCS2-Ks-acetyl-ADPR is depicted as a stick representation with carbon atoms in gray, oxygen atoms in red, nitrogen atoms in blue, sulfur atoms in yellow, and phosphate atoms in orange. The structure was assembled from PDB code 3GLT (Jin et al., Ref. 160).

FIGURE 4

Schematic overview of the endogenous regulators and molecular targets of SIRT1.

FIGURE 5

Schematic overview of the endogenous regulators and molecular targets of SIRT3.

FIGURE 6

Metabolic roles of SIRT1 in peripheral tissues and the central nervous system.

FIGURE 7

Metabolic roles of SIRT3 in peripheral tissues and the central nervous system.