Lysine malonylation (Kmal)

Lysine malonylation (Kmal) is a reversible post-translational modification (PTM) where a malonyl group is covalently added to the ε-amino group of a lysine residue in a protein, typically using malonyl-CoA as the donor substrate [4, 7]. This modification is evolutionarily conserved across prokaryotes and eukaryotes and is particularly abundant on mitochondrial and metabolic enzymes, where it regulates protein function by reversing the charge of the lysine side chain from positive to negative [1, 5]. The enzymatic regulation of lysine malonylation is primarily mediated by sirtuin 5 (SIRT5), which serves as the principal nicotinamide adenine dinucleotide (NAD+)-dependent demalonylase [1, 10]. Malonylation plays a critical role in metabolic homeostasis, influencing key pathways such as glycolysis, the tricarboxylic acid cycle, and fatty acid oxidation [1, 4]. Dysregulation of this modification is strongly associated with metabolic diseases like type 2 diabetes and obesity, as well as inflammatory conditions and certain cancers [3, 5]. For example, elevated malonylation of glycolytic enzymes in the liver is a hallmark of insulin resistance in diabetic models [1, 5]. While the modification itself is not a direct therapeutic target, the enzymes that govern it, specifically SIRT5, are significant targets for drug development [10, 12]. Currently, various SIRT5 modulators, including experimental inhibitors like Sirtinol and repurposed drugs like Probucol, are being explored for their potential to restore metabolic balance by influencing malonylation dynamics [6, 9, 10].

Other names

KmalmaKProtein malonylationLysine malonyl modification

Modulation of sirtuin 5 (SIRT5) demalonylase activity to regulate protein acylation status; regulation of malonyl-CoA donor levels via malonyl-CoA decarboxylase (MCD) or acetyl-CoA carboxylase (ACC) inhibition.