title: Non-enzymatic N-acetylation of Lysine Residues by AcetylCoA Often Occurs via a Proximal S-acetylated Thiol Intermediate Sensitive to Glyoxalase II.
abstract: Acetyl coenzyme A (AcCoA), a key intermediate in mitochondrial metabolism, N-acetylates lysine residues, disrupting and, in some cases, regulating protein function. The mitochondrial lysine deacetylase Sirtuin 3 (Sirt3) reverses this modification with benefits reported in diabetes, obesity, and aging. We show that non-enzymatic lysine N-acetylation by AcCoA is greatly enhanced by initial acetylation of a cysteine residue, followed by SN-transfer of the acetyl moiety to a nearby lysine on mitochondrial proteins and synthetic peptides. The frequent occurrence of an S-acetyl intermediate before lysine N-acetylation suggests that proximity to a thioester is a key determinant of lysine susceptibility to acetylation. The thioesterase glyoxalase II (Glo2) can limit protein S-acetylation, thereby preventing subsequent lysine N-acetylation. This suggests that the hitherto obscure role of Glo2 in mitochondria is to act upstream of Sirt3 in minimizing protein N-acetylation, thus limiting protein dysfunction when AcCoA accumulates.
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, UK. Electronic address: aj@mrc-mbu.cam.ac.uk.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: James
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, UK; Laboratory of Molecular Biology, Medical Research Council, Cambridge CB2 0QH, UK; The Wellcome Trust Centre for Mitochondrial Research, Institute for Cell and Molecular Biosciences, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Kurt
authors.initials: K
authors.lastname: Hoogewijs
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Logan
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Hall
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, UK.
authors.forename: Shujing
authors.initials: S
authors.lastname: Ding
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, UK.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Fearnley
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, Cambridge CB2 0XY, UK. Electronic address: mpm@mrc-mbu.cam.ac.uk.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000107:Acetylation; D003545:Cysteine / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D056566:Sirtuin 3 / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013869:Thiolester Hydrolases / Q000378:metabolism*; D000099301:Hydroxyacylglutathione Hydrolase
chemical_list: D000105:Acetyl Coenzyme A; D003545:Cysteine; D064429:Fatty Acid Synthases; D008239:Lysine; D024101:Mitochondrial Proteins; D011994:Recombinant Proteins; D056566:Sirtuin 3; D013438:Sulfhydryl Compounds; D013869:Thiolester Hydrolases; D000099301:Hydroxyacylglutathione Hydrolase; C022738:thioesterase II
keywords: AcetylCoA; glyoxalase; lysine acetylation