13 1 General Introduction IMMUNOMETABOLISM AND LYSINE ACETYLATION The concept of immunometabolism involves the interaction between immune and metabolic processes (57). Recent research suggests that chronic inflammation is connected to changes in energy metabolism through lysine acetylation, a posttranslational modification of proteins. Lysine acetylation alters the behavior of acetylated proteins, affecting their interactions with other molecules, catalytic activity, subcellular localization, and stability (58). Lysine acetyltransferases (KATs) and lysine deacetylases (KDACs) regulate the precise stoichiometry of site-specific lysine acetylation (59). KDACs are classified into four groups, while KATs are divided into three. Lysine acetylation can also occur non-enzymatically, especially in alkaline environments like the mitochondrial matrix (58). Fluctuations in acetyl-CoA concentration, which vary in different cellular compartments, can influence the catalytic activity and selectivity of KATs (60). Reversible protein acetylation plays a role in gene expression, affecting histones, transcription factors, and enzymes involved in cellular energy metabolism (61). Changes in glycolysis, the tricarboxylic acid cycle (TCA), and fatty acid oxidation impact cellular acetyl-CoA levels, establishing a connection between energy metabolism, protein acetylation, and gene expression. Histone acetylation Chromatin is a complex of DNA and proteins called histones. The nucleosome is the fundamental subunit of chromatin, which is formed of an octamer of histones, an H3/H4 tetramer, and two H2A/H2B dimers, around which 146 bp of DNA is wrapped (62). The conformation of the chromatin changes to allow gene transcription due to changes in the histone acetylation stoichiometry and dynamics (63) Histone acetylation is a key component in the regulation of gene expression: during activation of gene transcription, chromatin conformation changes from tightly compacted to relaxed, allowing DNA binding proteins to interact with the DNA. The interaction of positively-charged epsilon amino groups in histones belonging to lysine residues with the negatively charged phosphate groups of DNA will decrease due to the removal of the positive charges on the histones upon acetylation. The fact that acetylation is a key component in the regulation of gene expression and that elevated levels of histone deacetylation are evident in several chronic human diseases has motivated the study of KDACs in relation to the often observed aberrant gene expression. The KDAC family consists of different classes of enzymes involved in the regulation of protein acetylation. Class I KDACs, including KDAC1, 2, 3, and 8, are primarily
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