Literature summary for 2.3.1.B43 extracted from

Zhang, Y.; Bharathi, S.S.; Rardin, M.J.; Lu, J.; Maringer, K.V.; Sims-Lucas, S.; Prochownik, E.V.; Gibson, B.W.; Goetzman, E.S.
Lysine desuccinylase SIRT5 binds to cardiolipin and regulates the electron transport chain (2017), J. Biol. Chem., 292, 10239-10249 .

Search for more literature for 2.3.1.B43

Activating Compound

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

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

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/ Products (Substrates)

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

Organism	UniProt	Comment	Textmining
Homo sapiens	Q9NXA8	-	-
Mus musculus	A0A1Y7VM56	-	-

Source Tissue

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 and Products (Substrate)

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

Synonyms	Comment	Organism
lysine desuccinylase	-	Homo sapiens
lysine desuccinylase	-	Mus musculus
SIRT5	-	Homo sapiens
SIRT5	-	Mus musculus

Cofactor

Cofactor	Comment	Organism	Structure
NAD+	-	Homo sapiens
NAD+	-	Mus musculus

General Information

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

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Release 2023.1 (January 2023)