Sirtuins

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Sirtuins

Description

Sirtuins are NAD+-dependent deacetylases which play a prominent role as metabolic regulators. Their dependence on intracellular levels of NAD+ (NAD+ activates sirtuin activity, whereas NADH inhibits it) makes them suitable as sensors that can detect cellular energy status. » MiPNet article

Abbreviation: Sirt

Reference: Houtkooper_2012_Nat Rev Mol Cell BiolLin_2004_Genes DevFerrara_2008_Rejuvenation Res



MitoPedia topics: Enzyme 

Sirtuin family

Publications in the MiPMap
Pesta D (2012) Sirtuin family. Mitochondr Physiol Network 2012-06-29.

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Pesta D (2012) MiPNet

Abstract: A brief accout of the sirtuin family.


O2k-Network Lab: AT Innsbruck Gnaiger E


Labels:



Enzyme: Marker enzyme 


HRR: Theory 


Characterization

Seven sirtuin orthologs (SIRT1–SIRT7) make up the ubiquitously expressed sirtuin family of enzymes as known to date. Although all sirtuins have a conserved catalytic core comprising 275 amino acids, they differ in their subcellular localization. The best characterized sirtuin, SIRT1, is mostly found in the nucleus but can shuttle to the cytosol. SIRT2 by contrast is found mainly in the cytoplasm. SIRT3, SIRT4, and SIRT5 are mainly located within the mitochondrion and SIRT6 and SIRT7 are nuclear proteins.

Activity

Sirtuins also differ according to their enzymatic activities. SIRT1 and SIRT5 exhibit deacetylase activity, SIRT4 probably acts as a mono-ADP-ribosyl transferase; SIRT2, SIRT3, and SIRT6 show both activities and the activity of SIRT7 remains still unclear although it is hypothesized that it acts as a deacetylase.

Metabolic stressors such as increased oxidative stress, intense endurance training or caloric restriction have an impact on SIRT activities, especially on SIRT1. It has been shown that activation of SIRT2 via decreased NADH levels in response to caloric restriction increases life-span in yeast.

Mechanism

Essentially, sirtuins catalyse the deacetylation of an acetylated substrate where NAD+ functions as a cosubstrate, yielding the deacetylated substrate, nicotinamide, and 2’-O-acetyl-ADP-ribose. A relatively high Km' for NAD+ and the NAD+ dependency puts the class of enzymes at the forefront of metabolic control in the cell by linking NAD+/NADH ratios with protein deacetylation.