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Characterizing Sirtuin 3 Deacetylase Affinity for Aldehyde Dehydrogenase 2

2017; American Chemical Society; Volume: 30; Issue: 3 Linguagem: Inglês

10.1021/acs.chemrestox.6b00315

1520-5010

Peter S. Harris, Joe Gomez, Donald S. Backos, Kristofer S. Fritz,

Autophagy in Disease and Therapy

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.