2. Non-enzymatic acetylation
Acetyl-CoA is synthesized by different reactions: oxidative
decarboxylation of pyruvate during glycolysis; catabolism of some amino
acids (isoleucine, leucine, and threonine); and β-oxidation of fatty
acids. Several lysine acetyltransferases use this molecule to acetylate
proteins (previously mentioned) and can modify the amino group of lysine
side chains non-enzymatically. The chemical acetylation was first
mentioned in histone proteins by Phillips in 1963. A few years later, it
was demonstrated that purified histones, albumin, and synthetic lysine
homopolymer are acetylated in vitro at a pH ~9
and in the presence of acetyl-CoA without additional enzymes (Paik et
al., 1970). In eukaryotic cells, specifically in the mitochondria, the
absence of acetyltransferases and the unique conditions, such as the
high concentration of acetyl-CoA (1.5 mM steady-state) and alkaline pH
(7.9–8.0), suggests that lysine acetylation occurs chemically. For
example, many mitochondrial proteins are acetylated under conditions
mimicking those of the mitochondria matrix in a mechanism that is
generally pH- and acyl-CoA concentration-dependent (Wagner & Payne,
2013). The proposed mechanism for mitochondrial non-enzymatic
acetylation appears to occur by a nucleophilic attack on the acetyl
carbonyl by the side-chain amine of a lysine residue (Wagner & Payne,
2013). However, under the physiological characteristic of the
mitochondrial matrix, the reaction would be slow, so it has been
proposed that protein acetylation occurs via S-acetylation cysteine
thiol with the subsequent transfer of the acetyl group to a nearby
deprotonated lysine residue (Christensen et al., 2019; James et al.,
2017).
Direct acetylation has also been observed in bacteria, where at elevated
concentrations, acetyl phosphate (AcP) can non-enzymatically acetylate
lysine residues on many proteins. AcP is a highly reactive molecule
susceptible to hydrolyzing or acetylating without enzymes. It undergoes
rapid hydrolysis under basic or acid conditions and in the presence of
some ions (Mg2+ or
Ca2+). However, in the presence of
nucleophilic reagents such as thiols, hydroxyl groups, ε-amino or
α-amino groups of lysine side chains or proteins, the chemical
acetylation of these groups is favored (Kuhn et al., 2014).