Non-enzymatic N-acetylation of Lysine Residues by AcetylCoA Often Occurs via a Proximal S-acetylated Thiol Intermediate Sensitive to Glyoxalase II.

TitleNon-enzymatic N-acetylation of Lysine Residues by AcetylCoA Often Occurs via a Proximal S-acetylated Thiol Intermediate Sensitive to Glyoxalase II.
Publication TypeJournal Article
Year of Publication2017
AuthorsJames, AM, Hoogewijs, K, Logan, A, Hall, AR, Ding, S, Fearnley, IM, Murphy, MP
JournalCell Rep
Volume18
Issue9
Pagination2105-2112
Date Published2017 Feb 28
ISSN2211-1247
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.

DOI10.1016/j.celrep.2017.02.018
Alternate JournalCell Rep
Citation Key10.1016/j.celrep.2017.02.018
PubMed ID28249157
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom