Potential Modulation of Sirtuins by Oxidative Stress

Leonardo Santos, Carlos Escande, Ana Denicola, Leonardo Santos, Carlos Escande, Ana Denicola

Abstract

Sirtuins are a conserved family of NAD-dependent protein deacylases. Initially proposed as histone deacetylases, it is now known that they act on a variety of proteins including transcription factors and metabolic enzymes, having a key role in the regulation of cellular homeostasis. Seven isoforms are identified in mammals (SIRT1-7), all of them sharing a conserved catalytic core and showing differential subcellular localization and activities. Oxidative stress can affect the activity of sirtuins at different levels: expression, posttranslational modifications, protein-protein interactions, and NAD levels. Mild oxidative stress induces the expression of sirtuins as a compensatory mechanism, while harsh or prolonged oxidant conditions result in dysfunctional modified sirtuins more prone to degradation by the proteasome. Oxidative posttranslational modifications have been identified in vitro and in vivo, in particular cysteine oxidation and tyrosine nitration. In addition, oxidative stress can alter the interaction with other proteins, like SIRT1 with its protein inhibitor DBC1 resulting in a net increase of deacetylase activity. In the same way, manipulation of cellular NAD levels by pharmacological inhibition of other NAD-consuming enzymes results in activation of SIRT1 and protection against obesity-related pathologies. Nevertheless, further research is needed to establish the molecular mechanisms of redox regulation of sirtuins to further design adequate pharmacological interventions.

Figures

Figure 1
Figure 1
Structure of sirtuins. (a) Crystal structure of a partial sequence of hSIRT1 (PDB 4KXQ) with bound substrates, acetylated peptide, and NAD. The catalytic core is depicted in yellow with the Zn2+ binding domain. (b) Zoom of catalytic site with the catalytic histidine colored in yellow.
Figure 2
Figure 2
Scheme of reactions catalyzed by sirtuins. Deacetylation is the most common reaction catalyzed by sirtuins, but some sirtuins catalyze deacylation of other posttranslational lysine modifications and mono ADP ribosylation. NAM = nicotinamide, OAADPR = O-acetyl-ADP-ribose.

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