Therapeutic Potential and Activity Modulation of the Protein Lysine Deacylase Sirtuin 5

Abstract

Sirtiun 5 (SIRT5) is a NAD + -dependent protein lysine deacylase primarily located in mitochondria. SIRT5 displays an affinity for negatively charged acyl groups and mainly catalyzes lysine deglutarylation, desuccinylation, and demalonylation while possessing weak deacetylase activity. SIRT5 substrates play crucial roles in metabolism and reactive oxygen species (ROS) detoxification, and SIRT5 activity is protective in neuronal and cardiac physiology. Moreover, SIRT5 exhibits a dichotomous role in cancer, acting as context-dependent tumor promoter or suppressor. Given its multifaceted activity, SIRT5 is a promising target in the design of activators or inhibitors that might act as therapeutics in many pathologies, including cancer, cardiovascular disorders, and neurodegeneration. To date, few cellular-active peptide-based SIRT5 inhibitors (SIRT5i) have been described, and potent and selective small-molecule SIRT5i have yet to be discovered. In this perspective, we provide an outline of SIRT5’s roles in different biological settings and describe SIRT5 modulators in terms of their mode of action, pharmacological activity, and structure–activity relationships.

Emerging Roles of SIRT5 in Metabolism, Cancer, and SARS-CoV-2 Infection

“…Like other SIRTs, the role of SIRT5 in cancer is rather controversial [ 16 , 38 , 47 , 109 , 110 ]. In humans, the SIRT5 gene is present in the highly unstable cytogenetic band on chromosome 6p23 [ 49 , 111 ].…”

“…Considering the key role of SIRT5 in a wide range of pathways, increasing research is being conducted over the possibility of targeting SIRT5 through either activators or inhibitors [ 47 ]. While the majority of studies have focused on SIRT5 inhibitors, recent reports have identified the first-in-class SIRT5 activators.…”

“…The roles played by SIRT5 in different pathways imply that its dysregulation is associated with the development of different diseases, including metabolic disorders, cardiovascular and neurodegenerative pathologies, infectious diseases, and cancer. Consequently, SIRT5 has gained interest as a possible drug target in the treatment of these diseases [ 47 ].…”

Structure–Activity Relationship Studies of 2,4,5-Trisubstituted Pyrimidine Derivatives Leading to the Identification of a Novel and Potent Sirtuin 5 Inhibitor against Sepsis-Associated Acute Kidney Injury

“…Sirtuin 5 (SIRT5), a member of the sirtuin family, predominantly localizes to mitochondria, − modulating the activity of protein succinylation. − Due to its crucial role in regulating ATP production and metabolism, oxidative stress, fatty acid metabolism, and mitochondrial biology, ,,− SIRT5 participates in a variety of metabolic disorder-associated diseases, such as cancers, cardiometabolic diseases, kidney diseases, etc. − As reported, gene knockout of SIRT5 protected renal tubular epithelium from ischemic/reperfusion- or cisplatin-induced AKI by maintaining the balance between mitochondrial and peroxisomal FAO . However, no study has investigated the medicinal use of the SIRT5 inhibitor for septic AKI.…”

The Mechanistic Roles of Sirtuins in Breast and Prostate Cancer

“…In mammals, seven sirtuins (SIRT1–7) have been identified, which primarily function as NAD-dependent deacetylases (SIRT1–3 and SIRT5–7) [ 8 ] and ADP-ribosyl transferases (SIRT4 and 6) [ 9 , 10 ]. Additionally, sirtuins have been reported to function as demyristoylases (SIRT1–3 and 6) [ 11 , 12 ], lipoamidases (SIRT4) [ 13 ], and desuccinylases/demalonylases/deglutarylases (SIRT5) [ 14 , 15 ]. However, despite these functional differences, sirtuins are classified and distinguished by their subcellular location ( Figure 2 ).…”