Activating Compound | Comment | Organism | Structure |
---|---|---|---|
cardiolipin | SIRT5 electrostatically binds to cardiolipin, an N-terminal amphipathic helix mediates SIRT5 binding to cardiolipin, cardiolipin activates desuccinylation of membrane proteins | Homo sapiens | |
cardiolipin | SIRT5 electrostatically binds to cardiolipin, an N-terminal amphipathic helix mediates SIRT5 binding to cardiolipin, cardiolipin activates desuccinylation of membrane proteins | Mus musculus |
Protein Variants | Comment | Organism |
---|---|---|
additional information | CRISPR (clustered regularly interspaced short palindromic repeats) is used to delete SIRT5 in human cell line HEK-293 | Homo sapiens |
additional information | generation of SIRT5 deletion mutant mice, homogenates prepared from whole SIRT5-/- liver show reduced Complex II-driven respiration. The enzymatic activities of Complex II and ATP synthase are also significantly reduced | Mus musculus |
Localization | Comment | Organism | GeneOntology No. | Textmining |
---|---|---|---|---|
mitochondrial inner membrane | SIRT5 is targeted to protein complexes on the inner mitochondrial membrane via affinity for cardiolipin | Homo sapiens | 5743 | - |
mitochondrial inner membrane | SIRT5 is targeted to protein complexes on the inner mitochondrial membrane via affinity for cardiolipin | Mus musculus | 5743 | - |
mitochondrion | - |
Homo sapiens | 5739 | - |
mitochondrion | - |
Mus musculus | 5739 | - |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
additional information | Homo sapiens | SIRT5 electrostatically binds to cardiolipin and desuccinylates mitochondrial inner membrane proteins including multiple subunits of all four electron transport chain (ETC) complexes and ATP synthase. SIRT5 targets lysines at the protein-lipid interface of Complex II. Mass spectrometry identifies 14 SIRT5 target sites on the SDHA subunit of Complex II and another eight on SDHB. Molecular modeling reveals that six of the eight SIRT5 target sites on SDHB orient toward the predicted membrane interface where SDHB interacts with SDHC/SDHD | ? | - |
- |
|
additional information | Mus musculus | three-dimensional modeling of Complex II suggests that several SIRT5-targeted lysine residues lie at the protein-lipid interface of succinate dehydrogenase subunit B. Succinylation at these sites may disrupt Complex II subunit-subunit interactions and electron transfer. SIRT5 electrostatically binds to cardiolipin and desuccinylates mitochondrial inner membrane proteins including multiple subunits of all four electron transport chain (ETC) complexes and ATP synthase. SIRT5 targets lysines at the protein-lipid interface of Complex II | ? | - |
- |
|
NAD+ + [ATP synthase]-N6-succinyl-L-lysine | Homo sapiens | - |
nicotinamide + [ATP synthase]-L-lysine + 2'-O-succinyl-ADP-ribose | - |
? | |
NAD+ + [ATP synthase]-N6-succinyl-L-lysine | Mus musculus | - |
nicotinamide + [ATP synthase]-L-lysine + 2'-O-succinyl-ADP-ribose | - |
? |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | Q9NXA8 | - |
- |
Mus musculus | A0A1Y7VM56 | - |
- |
Source Tissue | Comment | Organism | Textmining |
---|---|---|---|
HEK-293 cell | - |
Homo sapiens | - |
liver | SIRT5 expression is observed to localize strictly to the periportal hepatocytes | Mus musculus | - |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
additional information | SIRT5 electrostatically binds to cardiolipin and desuccinylates mitochondrial inner membrane proteins including multiple subunits of all four electron transport chain (ETC) complexes and ATP synthase. SIRT5 targets lysines at the protein-lipid interface of Complex II. Mass spectrometry identifies 14 SIRT5 target sites on the SDHA subunit of Complex II and another eight on SDHB. Molecular modeling reveals that six of the eight SIRT5 target sites on SDHB orient toward the predicted membrane interface where SDHB interacts with SDHC/SDHD | Homo sapiens | ? | - |
- |
|
additional information | three-dimensional modeling of Complex II suggests that several SIRT5-targeted lysine residues lie at the protein-lipid interface of succinate dehydrogenase subunit B. Succinylation at these sites may disrupt Complex II subunit-subunit interactions and electron transfer. SIRT5 electrostatically binds to cardiolipin and desuccinylates mitochondrial inner membrane proteins including multiple subunits of all four electron transport chain (ETC) complexes and ATP synthase. SIRT5 targets lysines at the protein-lipid interface of Complex II | Mus musculus | ? | - |
- |
|
NAD+ + [ATP synthase]-N6-succinyl-L-lysine | - |
Homo sapiens | nicotinamide + [ATP synthase]-L-lysine + 2'-O-succinyl-ADP-ribose | - |
? | |
NAD+ + [ATP synthase]-N6-succinyl-L-lysine | - |
Mus musculus | nicotinamide + [ATP synthase]-L-lysine + 2'-O-succinyl-ADP-ribose | - |
? |
Synonyms | Comment | Organism |
---|---|---|
lysine desuccinylase | - |
Homo sapiens |
lysine desuccinylase | - |
Mus musculus |
SIRT5 | - |
Homo sapiens |
SIRT5 | - |
Mus musculus |
Cofactor | Comment | Organism | Structure |
---|---|---|---|
NAD+ | - |
Homo sapiens | |
NAD+ | - |
Mus musculus |
General Information | Comment | Organism |
---|---|---|
malfunction | SIRT5-/- mice have mild lactic acidosis. SIRT5 deficiency does not affect the abundance of the respiratory chain complexes in liver mitochondria. Complex II and ATP synthase activities are reduced in SIRT5-/- liver | Mus musculus |
malfunction | SIRT5-deficient HEK-293 cells show defects in both Complex I- and Complex II-driven respiration. Humans with Complex II deficiency have mild lactic acidosis | Homo sapiens |
additional information | the mitochondrial processing peptidase cleavage site of SIRT5 leaves an amphipathic helix on the mature protein at the extreme N terminus. This N-terminal amphipathic helix has three positively charged residues that orient into the solvent as seen in the SIRT5 crystal structure These positively charged residues might confer cardiolipin binding to SIRT5, similar to the amphipathic helix previously identified in very-long-chain acyl-CoA dehydrogenase (VLCAD) | Mus musculus |
additional information | the mitochondrial processing peptidase cleavage site of SIRT5 leaves an amphipathic helix on the mature protein at the extreme N-terminus. This N-terminal amphipathic helix has three positively charged residues that orient into the solvent as seen in the SIRT5 crystal structure These positively charged residues might confer cardiolipin binding to SIRT5, similar to the amphipathic helix previously identified in very-long-chain acyl-CoA dehydrogenase (VLCAD) | Homo sapiens |
physiological function | SIRT5 is a lysine desuccinylase known to regulate mitochondrial fatty acid oxidation and the urea cycle. SIRT5 binds to cardiolipin and regulates the electron transport chain. SIRT5 is targeted to protein complexes on the inner mitochondrial membrane via affinity for cardiolipin to promote respiratory chain function. SIRT5 restores membrane binding of very-long-chain acyl-CoA dehydrogenase (VLCAD). SIRT5 electrostatically binds to cardiolipin and desuccinylates mitochondrial inner membrane proteins including multiple subunits of all four electron transport chain (ETC) complexes and ATP synthase. SIRT5 counteracts succinylation of mitochondrial membrane proteins, overview | Homo sapiens |
physiological function | SIRT5 is a lysine desuccinylase known to regulate mitochondrial fatty acid oxidation and the urea cycle. SIRT5 binds to cardiolipin and regulates the electron transport chain. SIRT5 is targeted to protein complexes on the inner mitochondrial membrane via affinity for cardiolipin to promote respiratory chain function. Three-dimensional modeling of Complex II suggests that several SIRT5-targeted lysine residues lie at the protein-lipid interface of succinate dehydrogenase subunit B. Succinylation at these sites may disrupt Complex II subunit-subunit interactions and electron transfer. SIRT5 restores membrane binding of very-long-chain acyl-CoA dehydrogenase (VLCAD). SIRT5 electrostatically binds to cardiolipin and desuccinylates mitochondrial inner membrane proteins including multiple subunits of all four electron transport chain (ETC) complexes and ATP synthase. SIRT5 counteracts succinylation of mitochondrial membrane proteins, overview | Mus musculus |