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Review
. 2024 Jul 19;14(7):862.
doi: 10.3390/biom14070862.

Roles of Lysine Methylation in Glucose and Lipid Metabolism: Functions, Regulatory Mechanisms, and Therapeutic Implications

Zhen Wang  1 , Huadong Liu  1
Affiliations
Review

Roles of Lysine Methylation in Glucose and Lipid Metabolism: Functions, Regulatory Mechanisms, and Therapeutic Implications

Zhen Wang et al. Biomolecules. .

Abstract

Glucose and lipid metabolism are essential energy sources for the body. Dysregulation in these metabolic pathways is a significant risk factor for numerous acute and chronic diseases, including type 2 diabetes (T2DM), Alzheimer's disease (AD), obesity, and cancer. Post-translational modifications (PTMs), which regulate protein structure, localization, function, and activity, play a crucial role in managing cellular glucose and lipid metabolism. Among these PTMs, lysine methylation stands out as a key dynamic modification vital for the epigenetic regulation of gene transcription. Emerging evidence indicates that lysine methylation significantly impacts glucose and lipid metabolism by modifying key enzymes and proteins. This review summarizes the current understanding of lysine methylation's role and regulatory mechanisms in glucose and lipid metabolism. We highlight the involvement of methyltransferases (KMTs) and demethylases (KDMs) in generating abnormal methylation signals affecting these metabolic pathways. Additionally, we discuss the chemical biology and pharmacology of KMT and KDM inhibitors and targeted protein degraders, emphasizing their clinical implications for diseases such as diabetes, obesity, neurodegenerative disorders, and cancers. This review suggests that targeting lysine methylation in glucose and lipid metabolism could be an ideal therapeutic strategy for treating these diseases.

Keywords: glucose metabolism; lipid metabolism; lysine methylation.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Schematic diagram of the methyltransferase catalytic reaction. (A) In each lysine methylation reaction, the methyl donor cofactor SAM is converted into SAH. Sites where key chemical changes occur during this catalytic reaction are circled in red. (B) Methyltransferases catalyze the methylation of the ε-amino group of the target lysine residue on the protein, subsequent methylation of target lysine residue results in mono-, di-, and trimethylated lysine.
Figure 2
Figure 2
Schematic representation of the domains of selected methyltransferases. Different domains are represented in different colors.
Figure 3
Figure 3
Schematic representation of the domains of demethylases. Different domains are represented in different colors.
Figure 4
Figure 4
Schematic depiction of a nucleosome showing principal lysine methylation sites on histones H3 and H4. The figure presents the known writers (methyltransferases) and erasers (demethylases) associated with each lysine methylation site.
Figure 5
Figure 5
Alterations of lysine methylation and targeted genes affecting glucose metabolism. The figure highlights the involvement of lysine methyltransferases (KMTs), lysine demethylases (KDMs), and their respective histone methylation marks in processes such as glucose uptake, glycolysis, the tricarboxylic acid cycle, and gluconeogenesis.
Figure 6
Figure 6
Alterations of lysine methylation and targeted genes affecting lipid metabolism. The figure depicts the involvement of lysine methyltransferases (KMTs), lysine demethylases (KDMs), and their respective histone methylation marks in processes such as lipid energy metabolism, fatty acid transport, insulin sensitization, and cholesterol metabolism.
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