Journal
CELL REPORTS
Volume 18, Issue 9, Pages 2105-2112Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.02.018
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Funding
- Medical Research Council [MC_U105663142]
- Wellcome Trust investigator award [110159/Z/15/Z]
- Medical Research Council [MC_U105663142] Funding Source: researchfish
- MRC [MC_U105663142] Funding Source: UKRI
- Wellcome Trust [110159/Z/15/Z] Funding Source: Wellcome Trust
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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.
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