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.
Highlights
Sirtuins are a conserved family of enzymes, originally defined as histone deacetylases [1]
Proposed as histone deacetylases, it is 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
Oxidative stress can alter the interaction with other proteins, like SIRT1 with its protein inhibitor DBC1 resulting in a net increase of deacetylase activity
Summary
Sirtuins are a conserved family of enzymes, originally defined as histone deacetylases (class III HDAC) [1]. SREBP-1c: sterol regulatory element binding protein c, PGC1α: peroxisome proliferator-activated receptor gamma coactivator 1 alpha, FOXO1: Forkhead box protein O1, PPARα: peroxisome proliferator-activated receptor alpha, NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells, AKT: protein kinase B, UCP-2: uncoupling protein 2, HIF-1α: hypoxia-inducible factor 1 alpha, PPARγ: peroxisome proliferatoractivated receptor gamma, TFAM: transcription factor A, mitochondrial, APE1: apurinic/apyrimidinic endonuclease 1, PARP-1: poly(ADP-ribose) polymerase 1, PEPCK: phosphoenolpyruvate carboxykinase, LCAD: long-chain acyl-CoA dehydrogenase, HMGCS2: 3-hydroxy-3-methylglutaryl-CoA synthase 2, SOD2: superoxide dismutase, IDH2: isocitrate dehydrogenase 2, PDC: pyruvate dehydrogenase complex, GDH: glutamate dehydrogenase, CPS1: carbamoyl-phosphate synthase 1, TNFα: tumor necrotic factor alpha, PAF53: RNA polymerase associated factor, and AceCS: acetyl-CoA synthetase. Understanding the role and mechanism of action of sirtuins in the context of a pathophysiological inflammatory condition will help to identify novel interventions to manage important chronic diseases
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