Acts as NAD-dependent protein lipoamidase, biotinylase, deacetylase and ADP-ribosyl transferase (PubMed:16959573, PubMed:17715127, PubMed:24052263, PubMed:25525879). Catalyzes more efficiently removal of lipoyl- and biotinyl- than acetyl-lysine modifications (PubMed:24052263, PubMed:25525879). Inhibits the pyruvate dehydrogenase complex (PDH) activity via the enzymatic hydrolysis of the lipoamide cofactor from the E2 component, DLAT, in a phosphorylation-independent manner (PubMed:25525879). Catalyzes the transfer of ADP-ribosyl groups onto target proteins, including mitochondrial GLUD1, inhibiting GLUD1 enzyme activity (PubMed:16959573, PubMed:17715127). Acts as a negative regulator of mitochondrial glutamine metabolism by mediating mono ADP-ribosylation of GLUD1: expressed in response to DNA damage and negatively regulates anaplerosis by inhibiting GLUD1, leading to block metabolism of glutamine into tricarboxylic acid cycle and promoting cell cycle arrest (PubMed:16959573, PubMed:17715127). In response to mTORC1 signal, SIRT4 expression is repressed, promoting anaplerosis and cell proliferation (PubMed:23663782). Acts as a tumor suppressor (PubMed:23562301, PubMed:23663782). Also acts as a NAD-dependent protein deacetylase: mediates deacetylation of 'Lys-471' of MLYCD, inhibiting its activity, thereby acting as a regulator of lipid homeostasis (By similarity). Does not seem to deacetylate PC (PubMed:23438705). Controls fatty acid oxidation by inhibiting PPARA transcriptional activation (PubMed:24043310). Impairs SIRT1-PPARA interaction probably through the regulation of NAD(+) levels (PubMed:24043310). Down-regulates insulin secretion (PubMed:17715127). (R)-N(6)-lipoyl-L-lysyl-[protein] + H2O + NAD(+) = 2''-O-lipoyl-ADP-D-ribose + L-lysyl-[protein] + nicotinamide H2O + N(6)-biotinyl-L-lysyl-[protein] + NAD(+) = 2''-O-biotinyl-ADP-D-ribose + L-lysyl-[protein] + nicotinamide H2O + N(6)-acetyl-L-lysyl-[protein] + NAD(+) = 2''-O-acetyl-ADP-D-ribose + L-lysyl-[protein] + nicotinamide L-cysteinyl-[protein] + NAD(+) = H(+) + nicotinamide + S-(ADP-D-ribosyl)-L-cysteinyl-[protein] Binds 1 zinc ion per subunit. kcat is 0.0019 sec(-1) for the delipoylation of H3 'Lys-9'. kcat is 0.0005 sec(-1) for the debiotinylation of H3 'Lys-9'. kcat is 0.0018 sec(-1) for the delipoylation of DLAT 'Lys-259'. Interacts with GLUD1, IDE and SLC25A5 (PubMed:16959573, PubMed:17715127). Interacts with DLAT and PDHX (PubMed:25525879). Interacts with MCCC1 (via the biotin carboxylation domain) (PubMed:23438705). Interacts with PCCA and PC (PubMed:23438705). Detected in vascular smooth muscle and striated muscle. Detected in insulin-producing beta-cells in pancreas islets of Langerhans (at protein level). Widely expressed. Weakly expressed in leukocytes and fetal thymus. Induced by glutamine (at protein level). Expression is down-regulated in a number of cancers, while overexpression reduces cell proliferation, transformation, and tumor development (PubMed:23562301, PubMed:23663782). According to some authors, ADP-ribosyltransferase activity of sirtuins may be an inefficient side reaction of the deacetylase activity and may not be physiologically relevant. Belongs to the sirtuin family. Class II subfamily.