Abstract
Trimethyllysine is an important post-translationally modified amino acid with functions in the carnitine biosynthesis and regulation of key epigenetic processes. Protein lysine methyltransferases and demethylases dynamically control protein lysine methylation, with each state of methylation changing the biophysical properties of lysine and the subsequent effect on protein function, in particular histone proteins and their central role in epigenetics. Epigenetic reader domain proteins can distinguish between different lysine methylation states and initiate downstream cellular processes upon recognition. Dysregulation of protein methylation is linked to various diseases, including cancer, inflammation, and genetic disorders. In this review, we cover biomolecular studies on the role of trimethyllysine in carnitine biosynthesis, different enzymatic reactions involved in the synthesis and removal of trimethyllysine, trimethyllysine recognition by reader proteins, and the role of trimethyllysine on the nucleosome assembly.
Highlights
In nature, over 300 amino acids exist, of which 22 function as building blocks for the formation of polypeptide chains called proteins [1]
Protein lysine methyltransferases and demethylases dynamically control protein lysine methylation, with each state of methylation changing the biophysical properties of lysine and the subsequent effect on protein function, in particular histone proteins and their central role in epigenetics
Epigenetic reader domain proteins can distinguish between different lysine methylation states and initiate downstream cellular processes upon recognition
Summary
Over 300 amino acids exist, of which 22 function as building blocks for the formation of polypeptide chains called proteins [1]. TTMMLLHH--CCaattaallyyzzeedd CC33 HHyyddrrooxxyyllaattiioonn ooff KKmmee aanndd Iittss RRoollee iinn tthhee CCaarrnniittiinnee BBiioossyynntthheessiiss PPaatthhwwaayy. The methyl group is not surrounded by any hydrophobic residues, but instead is coordinated by carbon–oxygen hydrogen bonds in a cage containing hydroxyl and carbonyl functionalities in close proximity In both cases, the distances between SAH and the substrates are appropriate for nucleophilic attack, as well as the angles between SAH and K and SAH (157◦) and Kme (166◦). Tyr245 plays a key role in SETD7 methyltransferase activity by undergoing hydrogen bonds with lysine, thereby stabilizing binding of the substrate, and at the same time positioning Kme in a favorable orientation that sterically excludes Kme and Kme3 [66]. Mutational studies on G9a, SETD8, MLL, and EZH2 confirmed that active site Tyr and Phe residues control methyltransferase product specificity [67]
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