Acts as NAD-dependent protein lipoamidase, biotinylase, deacetylase and ADP-ribosyl transferase (PubMed:19220062). Catalyzes more efficiently removal of lipoyl- and biotinyl- than acetyl-lysine modifications. 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. 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). 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 (PubMed:23746352). Does not seem to deacetylate PC (PubMed:23438705). Controls fatty acid oxidation by inhibiting PPARA transcriptional activation. Impairs SIRT1-PPARA interaction probably through the regulation of NAD(+) levels (PubMed:24043310, PubMed:20685656). Down-regulates insulin secretion (By similarity). (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. Interacts with IDE and SLC25A5 (By similarity). Interacts with GLUD1 (PubMed:16959573). Interacts with DLAT and PDHX (By similarity). Interacts with MCCC1 (via the biotin carboxylation domain) (PubMed:23438705). Interacts with PCCA and PC (PubMed:23438705). Detected in kidney, heart, brain, liver and pancreatic islets (at protein level). Expression is directly activated by ATF4/CREB2. In response to mTORC1 signal, expression is down-regulated due to degradation of ATF4/CREB2 (PubMed:23663782). Induced following DNA damage (PubMed:23562301). The expression is strongly inhibited by fasting (PubMed:24043310). No visible phenotype. Decreased mitochondrial protein ADP-ribosylation. Increased plasma insulin levels. Mice develop lung tumors more frequently. Defects in lipid metabolism, leading to increased protection against diet-induced obesity. Animals show higher levels of NAD(+) in liver (PubMed:24043310). In the hepatic periportal zone, decreased number of mitochondria with an increase in their length (PubMed:24043310). 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. Extended N-terminus.