Cloned (Comment) | Organism |
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gene SIRT5, recombinant expression of tagged SIRT5 in HEK-293T cells, coexpression of wild-type and mutant protein kinase M2s, i.e. wild-type and mutants K62R/E, K135R/E, K311R/E, K498R/E, K311R/K498R, and K311E/K498E. Interactions between endogenous PKM2 and ectopically expressed FLAG-tagged PKM2, including the wild-type PKM2, the K311R mutant, and the succinylation-mimic K311E mutant, overview | Mus musculus |
Protein Variants | Comment | Organism |
---|---|---|
additional information | generation of Sirt5-KO mice | Mus musculus |
Localization | Comment | Organism | GeneOntology No. | Textmining |
---|---|---|---|---|
mitochondrion | - |
Mus musculus | 5739 | - |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
NAD+ + [pyruvate kinase M2]-N6-succinyl-L-lysine311 | Mus musculus | SIRT5 desuccinylates and activates PKM2 | nicotinamide + [pyruvate kinase M2]-L-lysine311 + 2'-O-succinyl-ADP-ribose | - |
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Organism | UniProt | Comment | Textmining |
---|---|---|---|
Mus musculus | A0A1Y7VM56 | - |
- |
Source Tissue | Comment | Organism | Textmining |
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Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
NAD+ + [pyruvate kinase M2]-N6-succinyl-L-lysine311 | SIRT5 desuccinylates and activates PKM2 | Mus musculus | nicotinamide + [pyruvate kinase M2]-L-lysine311 + 2'-O-succinyl-ADP-ribose | - |
? | |
NAD+ + [pyruvate kinase M2]-N6-succinyl-L-lysine311 | SIRT5 also desuccinylates recombinant Flag-tagged PKM2 substrate, but does not but affect its malonylation and glutarylation. The K311E mutation and K311E/K498E double mutation of PKM2 both increase the succinylation level of PKM2 by about 25%, while mutations K62R/E, K135R/E, and K498R/E have no significant effect | Mus musculus | nicotinamide + [pyruvate kinase M2]-L-lysine311 + 2'-O-succinyl-ADP-ribose | - |
? |
Synonyms | Comment | Organism |
---|---|---|
SIRT5 | - |
Mus musculus |
Cofactor | Comment | Organism | Structure |
---|---|---|---|
NAD+ | - |
Mus musculus |
General Information | Comment | Organism |
---|---|---|
malfunction | Sirt5-deficiency-mediated IL-1beta upregulation in LPS-stimulated macrophages, which can be attenuated by activation of PKM2 using TEPP-46. Sirt5-deficient mice are more susceptible to dextran sodium sulfate (DSS)-induced colitis, which is associated with Sirt5 deficiency prompted PKM2 hypersuccinylation and boosted IL-1beta production. Both activation of PKM2 and neutralization of IL-1beta in vivo confer protection against dextran sodium sulfate (DSS)-induced colitis in Sirt5-deficiency mice | Mus musculus |
physiological function | SIRT5 plays an important role in inhibiting inflammation. SIRT5 suppresses the pro-inflammatory response in macrophages at least in part by regulating PKM2 succinylation, activity, and function. SIRT5 desuccinylates and activates pyruvate kinase M2 (PKM2) to block macrophage IL-1beta production and to prevent DSS-induced colitis in mice. Lys311 is a key succinylated site in the regulation of PKM2 activity. SIRT5-regulated hypersuccinylation inhibits the pyruvate kinase activity of PKM2 by promoting its tetramer-to-dimer transition. A succinylation-mimetic PKM2 K311E mutation promotes nuclear accumulation and increases protein kinase activity. SIRT5-dependent succinylation promotes PKM2 entry into nucleus, where a complex of PKM2-HIF1alpha is formed at the promoter of interleukin-1beta gene in LPS-stimulated macrophages. SIRT5-dependent succinylation promotes PKM2 dimerization and increases its protein kinase activity | Mus musculus |