title: Characterizing Sirtuin 3 Deacetylase Affinity for Aldehyde Dehydrogenase 2.
abstract: Mitochondrial aldehyde dehydrogenase (ALDH2) plays a central role in the detoxification of reactive aldehydes generated through endogenous and exogenous sources. The biochemical regulation of enzyme activity through post-translational modification provides an intricate response system regulating mitochondrial detoxification pathways. ALDH2 is a known target of lysine acetylation, which arises as a consequence of mitochondrial bioenergetic flux and sirtuin deacetylase activity. The mitochondrial deacetylase Sirtuin 3 (SIRT3) has been reported to alter ALDH2 lysine acetylation status, yet the mechanism and consequence of this interaction remain unknown. The in vitro results presented here provide a novel biochemical approach using stable-isotope dilution mass spectrometry to elucidate which lysine residues are targeted by SIRT3 for deacetylation. Furthermore, HPLC-MS/MS and computational modeling elucidate a potential role for acetyl-Lys369 on ALDH2 in perturbing normal β-nicotinamide adenine dinucleotide (NAD+) cofactor binding.
authors.affiliation: Graduate Program in Toxicology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus , Aurora, Colorado 80045, United States.
authors.forename: Peter S
authors.identifier: 0000-0003-0324-0862
authors.initials: PS
authors.lastname: Harris
authors.affiliation: Graduate Program in Toxicology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus , Aurora, Colorado 80045, United States.
authors.forename: Joe D
authors.initials: JD
authors.lastname: Gomez
authors.affiliation: Graduate Program in Toxicology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus , Aurora, Colorado 80045, United States.
authors.forename: Donald S
authors.identifier: 0000-0001-6735-6210
authors.initials: DS
authors.lastname: Backos
authors.affiliation: Graduate Program in Toxicology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus , Aurora, Colorado 80045, United States.
authors.forename: Kristofer S
authors.identifier: 0000-0002-1499-6174
authors.initials: KS
authors.lastname: Fritz
mesh_terms: D000107:Acetylation; D000444:Aldehyde Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D006801:Humans; D008239:Lysine / Q000737:chemistry; D013058:Mass Spectrometry; D056566:Sirtuin 3 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000444:Aldehyde Dehydrogenase; D056566:Sirtuin 3; D008239:Lysine