Abstract
Superoxide is a precursor of many free radicals and reactive oxygen species (ROS) in biological systems. It has been shown that superoxide regulates major epigenetic processes of DNA methylation, histone methylation, and histone acetylation. We suggested that superoxide, being a radical anion and a strong nucleophile, could participate in DNA methylation and histone methylation and acetylation through mechanism of nucleophilic substitution and free radical abstraction. In nucleophilic reactions superoxide is able to neutralize positive charges of methyl donors S-adenosyl-L-methionine (SAM) and acetyl-coenzyme A (AcCoA) enhancing their nucleophilic capacity or to deprotonate cytosine. In the reversed free radical reactions of demethylation and deacetylation superoxide is formed catalytically by the (Tet) family of dioxygenates and converted into the iron form of hydroxyl radical with subsequent oxidation and final eradication of methyl substituents. Double role of superoxide in these epigenetic processes might be of importance for understanding of ROS effects under physiological and pathological conditions including cancer and aging.
Highlights
Superoxide is a precursor of many free radicals and reactive oxygen species (ROS) in biological systems
In vitro experiments confirmed a high efficiency of the superoxide-dependent Fenton reaction, but later on it was found that the in vitro experiments were erroneous because an effective artificial chelator EDTA was presented in reaction mixtures, which was absent in real biological systems
It has been shown that superoxide signaling is an important characteristic of epigenetic processes under physiologic conditions, but it is of a more importance for many pathologic disorders which as a rule are characterized by ROS overproduction
Summary
In vitro experiments confirmed a high efficiency of the superoxide-dependent Fenton reaction, but later on it was found that the in vitro experiments were erroneous because an effective artificial chelator EDTA was presented in reaction mixtures, which was absent in real biological systems. It has been found that superoxide is able to participate in the other important biological reactions, namely in the reactions of nucleophilic substitution. Numerous chemical studies demonstrated the ability of superoxide to ta k e p art in the nucleophilic reactions of hydrolysis and esterification [1]. In 1978 Niehaus proposed that superoxide might be involved in enzymatic nucleophilic reactions such as phosphorylation, acetylation, etc. I am certain that this proposal was a really important and promising idea (see, for example [7]). Hydrogen atom by the methyl group at the cytosine C5 position during DNA methylation does not correspond to the original definition of nucleophilic process because the methyl group is transferred from the positively (and not negatively) charged (-S-(+)) center of SAM (Figure 1A)
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