Update of the Methyltransferase Gene Family: Classification, Evolution and Biological Functions

Methylation is a crucial biochemical reaction involved in a wide range of processes including gene regulation, signal transduction, epigenetics, metabolism and detoxification. A number of methyltransferases (MTases) catalyze transfer of methyl groups from S-adenosyl-L-methionine (AdoMet or SAM) to nucleic acids, proteins, and small molecules, affecting chromatin structure, RNA function, and metabolic pathways. MTase dysregulation is associated with maladies such as cancer, neurodevelopmental disorders, and metabolic syndromes. Advancements in bioinformatics and high-throughput genomics have resulted in identification of ~ 200 human MTase genes, and most of the encoded proteins have now been characterized biochemically. Here, we have classified the human MTases into nine structural homology groups, including a distinct category of methyltransferases with unique structures. Major groups include the versatile seven-β-strand (7BS) MTases, the SET domain MTases which mainly mediate protein lysine methylation, and the SPOUT MTases involved in RNA modification. In addition, we categorized the MTases based on substrate specificity (e.g., nucleic acids, protein, and small-molecule MTases). This article provides a comprehensive classification and structural overview of human MTases, integrating recent nomenclature updates from the HUGO Gene Nomenclature Committee (HGNC). The evolutionary relationships and diversification of methyltransferases are also discussed in the context of structural classification and functional specialization. Emphasis is placed on biological functions, disease associations, and emerging therapeutic potential of the human MTases, particularly in oncology and neurodegenerative research. Despite significant progress, the biological function of many MTases remainselusive, necessitating further research to elucidate their enzymatic mechanisms and potential as drug targets. Understanding the MTase landscape is crucial for advancing biomedical research and developing targeted therapies for methylation-related disorders.