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

Abstract

The specificity of the lysine demalonylation substrates of the pharmaceutically attractive tumor promoter/suppressor SIRT5 is not comprehensively clarified. The present study re-analyses publicly available data and highlights potentially pharmaceutically interesting outcomes by the use of bioinformatics. The interaction networks of SIRT5 malonylome from the wild-type and ob/ob (obese pre-diabetic type) mice were subjected to the pathway enrichment and gene function prediction analysis using GeneMania (3.5.2) application run under Cytoscape (3.9.1) environment. The analysis in the wild-type mice revealed the involvement of SIRT5 malonylome in Eukaryotic translation elongation (ETE; the nodes EF1A1, EEF2, EEF1D, and EEF1G), Amino acid and derivative metabolism (AADM), and Selenoamino acid metabolism (SAM). The tumor promoter/suppressor activity of SIRT5 is mediated through the tumor promoter substrates included in AADM (GLUD1, SHMT1, ACAT1), and the tumor suppressor substrates involved in AADM and SAM (ALDH9A1, BHMT, GNMT). Selen stimulates the expression of SIRT5 and other sirtuins. SIRT5 in turn regulates the selenocysteine synthesis, which creates a regulatory loop. The analysis of SIRT5 malonylome in pre-diabetic ob/ob mice identifies the mTORC1 pathway as a mechanism, which facilitates SIRT5 functions. The comparison of the outcomes of SIRT5 malonylome, succinylome, and glutarylome analysis disclosed several differences. The analysis showed additional aspects of SIRT5 malonylome functions besides the control of glucose metabolism. It defined several unique substrates and pathways, and it showed differences compared to other enzymatic activities of SIRT5, which could be used for pharmaceutical benefits.