title: Potential Modulation of Sirtuins by Oxidative Stress.
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.
authors.affiliation: Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Santos
authors.affiliation: Laboratorio de Patologías del Metabolismo y Envejecimiento, Institut Pasteur de Montevideo, Mataojo 2020, 11400 Montevideo, Uruguay.
authors.forename: Carlos
authors.initials: C
authors.lastname: Escande
authors.affiliation: Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay.
authors.forename: Ana
authors.initials: A
authors.lastname: Denicola
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D004194:Disease; D006801:Humans; D058990:Molecular Targeted Therapy; D018384:Oxidative Stress; D011485:Protein Binding; D037761:Sirtuins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D037761:Sirtuins