A new view on functions of the lysine demalonylase activity of SIRT5

Abstract

AbstractA substrate specificity of the pharmaceutically attractive tumor-promoter SIRT5 was already investigated multiple times by advanced proteomic tools. However, the present bioinformatic analysis brings new highlights to the knowledge about the lysine demalonylation activity of SIRT5, a member of the sirtuin family with multiple roles in aging and age-related diseases. It shows unreported functional aspects of the lysine demalonylated substrates in Eukaryotic translation elongation (ETE), Amino acid and derivative metabolism (AADM), and Selenoamino acid metabolism (SAM). The cluster of the elongation factors (EEF1A1, EEF2, EEF1D, and EEF1G) belonging to ETE participates in the peptide chain elongation and the export of the tRNA-s from the nucleus to the primary sites of the proteosynthesis. SIRT5 regulates the activity of the key enzymes with tumor-promoting functions involved in AADM (GLUD1, SHMT1, ACAT1). In contrast, SIRT5 also lysine demalonylates tumor suppressor substrates as a part of the AADM and SAM interaction networks (ALDH9A1, BHMT, GNMT). It indicates comparable functions like SIRT3, which has dual tumor promoter/oncogene functions. Similar to the roles of the sirtuins, the SAM pathway impacts longevity, protects against cardiovascular diseases, and is associated with hepatic steatosis. The selen supplementation mediates the calorie restriction effect, which increases the NAD+/NADH ratio in the cells and stimulates the expression of SIRT5 and other sirtuins. SIRT5 in turn regulates the selenocysteine synthesis through the lysine demalonylation of the participating ribosomal proteins, SECISBP2 and GNMT, which creates a regulatory loop.