Literature summary for 2.3.1.B43 extracted from

Kumar, S.; Lombard, D.B.
Functions of the sirtuin deacylase SIRT5 in normal physiology and pathobiology (2018), Crit. Rev. Biochem. Mol. Biol., 53, 311-334 .

Search for more literature for 2.3.1.B43

Activating Compound

Activating Compound	Comment	Organism	Structure
additional information	SIRT can be targeted by small molecules	Mus musculus
additional information	SIRT can be targetted via small molecules	Homo sapiens

Application

Application	Comment	Organism
drug development	SIRT5 is a drug target	Homo sapiens

Cloned(Commentary)

Cloned (Comment)	Organism
the human SIRT5 gene encodes two main SIRT5 isoforms, SIRT5iso1 and SIRT5iso2 comprising 310 amino acids and 299 amino acids respectively, which differ slightly from one other at their C-termini, two other human SIRT5 isoforms (SIRT5iso3 and SIRT5iso4) have been reported. SIRT5iso3 is identical to SIRT5iso1 except that it lacks an internal sequence of 18 amino acids, while in SIRT5iso4 the initial 108 amino acids of SIRT5iso1 are missing, including the mitochondrial localization sequence	Homo sapiens

Cloned (Comment)

Organism

the human SIRT5 gene encodes two main SIRT5 isoforms, SIRT5iso1 and SIRT5iso2 comprising 310 amino acids and 299 amino acids respectively, which differ slightly from one other at their C-termini, two other human SIRT5 isoforms (SIRT5iso3 and SIRT5iso4) have been reported. SIRT5iso3 is identical to SIRT5iso1 except that it lacks an internal sequence of 18 amino acids, while in SIRT5iso4 the initial 108 amino acids of SIRT5iso1 are missing, including the mitochondrial localization sequence

Homo sapiens

Inhibitors

Inhibitors	Comment	Organism
additional information	SIRT can be targeted by small molecules, structure-activity relationship study leading to identification of SIRT5 selective inhibitors that exhibit sub-micromolar potency via a slow, tight-binding mechanism	Homo sapiens
additional information	SIRT can be targeted by small molecules, structure-activity relationship study leading to identification of SIRT5 selective inhibitors that exhibited sub-micromolar potency via a slow, tight-binding mechanism	Mus musculus
nicotinamide	NAM, feedback inhibitor. NAM is a pan sirtuin inhibitor	Homo sapiens
nicotinamide	NAM, feedback inhibitor. NAM is a pan sirtuin inhibitor	Mus musculus

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
cytoplasm	-	Homo sapiens	5737	-
cytoplasm	-	Mus musculus	5737	-
mitochondrial matrix	predominantly	Homo sapiens	5759	-
mitochondrial matrix	predominantly	Mus musculus	5759	-
additional information	SIRT5 is predominantly a mitochondrial matrix protein, but a significant portion of SIRT5 localizes to the cytosol, peroxisomes, and nucleus as well. SIRT5 activity is non-redundant with other sirtuins in mitochondria, and likely elsewhere in the cell as well	Homo sapiens	-	-
additional information	SIRT5 is predominantly a mitochondrial matrix protein, but a significant portion of SIRT5 localizes to the cytosol, peroxisomes, and nucleus as well. SIRT5 activity is non-redundant with other sirtuins in mitochondria, and likely elsewhere in the cell as well	Mus musculus	-	-
nucleus	-	Homo sapiens	5634	-
nucleus	-	Mus musculus	5634	-
peroxisome	-	Homo sapiens	5777	-
peroxisome	-	Mus musculus	5777	-

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
additional information	Homo sapiens	SIRT5 catalyzes the removal of negatively charged lysine acyl modifications: succinyl, malonyl, and glutaryl groups. SIRT5 is selective only for 3-5 carbon chains acidic acyl modifications, and displays no detectable activity against either an acetyl modification, a neutral 2 carbon group, or an adipoyl, a 6-carbon acidic modification	?	-	-
additional information	Mus musculus	SIRT5 catalyzes the removal of negatively charged lysine acyl modifications: succinyl, malonyl, and glutaryl groups. SIRT5 is selective only for 3-5 carbon chains acidic acyl modifications, and displays no detectable activity against either an acetyl modification, a neutral 2 carbon group, or an adipoyl, a 6-carbon acidic modification	?	-	-

Organism

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

Source Tissue

Source Tissue	Comment	Organism	Textmining
brain	-	Homo sapiens	-
brain	-	Mus musculus	-
embryonic fibroblast	-	Mus musculus	-
heart	-	Homo sapiens	-
heart	-	Mus musculus	-
hepatocyte	-	Mus musculus	-
kidney	-	Homo sapiens	-
kidney	-	Mus musculus	-
additional information	SIRT5 displays broad tissue distribution, with highest levels in brain, heart, liver, kidney, muscle, and testis	Homo sapiens	-
additional information	SIRT5 displays broad tissue distribution, with highest levels in brain, heart, liver, kidney, muscle, and testis	Mus musculus	-
muscle	-	Homo sapiens	-
muscle	-	Mus musculus	-
testis	-	Homo sapiens	-
testis	-	Mus musculus	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
additional information	SIRT5 catalyzes the removal of negatively charged lysine acyl modifications: succinyl, malonyl, and glutaryl groups. SIRT5 is selective only for 3-5 carbon chains acidic acyl modifications, and displays no detectable activity against either an acetyl modification, a neutral 2 carbon group, or an adipoyl, a 6-carbon acidic modification	Homo sapiens	?	-	-
additional information	SIRT5 catalyzes the removal of negatively charged lysine acyl modifications: succinyl, malonyl, and glutaryl groups. SIRT5 is selective only for 3-5 carbon chains acidic acyl modifications, and displays no detectable activity against either an acetyl modification, a neutral 2 carbon group, or an adipoyl, a 6-carbon acidic modification	Mus musculus	?	-	-

Synonyms

Synonyms	Comment	Organism
SIRT5	-	Homo sapiens
SIRT5	-	Mus musculus
sirtuin deacylase	-	Homo sapiens
sirtuin deacylase	-	Mus musculus

Cofactor

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

Expression

Organism	Comment	Expression
Mus musculus	overexpression or metformin-mediated activation of AMPK inhibited SIRT5 expression	down
Homo sapiens	SIRT5 expression is reported to be regulated by two major cellular regulators of metabolism, peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha), and AMP-activated protein kinase (AMPK)	additional information
Mus musculus	SIRT5 expression is reported to be regulated by two major cellular regulators of metabolism, peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha), and AMP-activated protein kinase (AMPK). PGC-1alpha overexpression or food withdrawal increases SIRT5 mRNA and protein levels in mouse primary hepatocytes, whereas overexpression or metformin-mediated activation of AMPK inhibits SIRT5 expression	additional information
Mus musculus	PGC-1alpha overexpression or food withdrawal increases SIRT5 mRNA and protein levels in mouse primary hepatocytes	up

General Information

General Information	Comment	Organism
evolution	in mammals, the sirtuin family comprises seven members (SIRT1-7), which possess conserved NAD+-binding and catalytic domains, while their flanking N- and C-termini are distinct from one another, and contribute to differences in subcellular localization, enzymatic activity, and substrate specificity among sirtuin proteins. Phylogenetically, SIRT5 is distinct from other mammalian sirtuins, and belongs to the so-called class III sirtuin family, a family that includes mostly prokaryotic sirtuins. Mouse Sirt5 gene encodes a single protein of 310 amino acids, corresponding to human SIRT5 isoform 1	Mus musculus
evolution	in mammals, the sirtuin family comprises seven members (SIRT1-7), which possess conserved NAD+-binding and catalytic domains, while their flanking N- and C-termini are distinct from one another, and contribute to differences in subcellular localization, enzymatic activity, and substrate specificity among sirtuin proteins. Phylogenetically, SIRT5 is distinct from other mammalian sirtuins, and belongs to the so-called class III sirtuin family, a family that includes mostly prokaryotic sirtuins. The human SIRT5 gene encodes two main SIRT5 isoforms, SIRT5iso1 and SIRT5iso2 comprising 310 amino acids and 299 amino acids respectively, which differ slightly from one other at their C-termini, two other human SIRT5 isoforms (SIRT5iso3 and SIRT5iso4) have been reported. SIRT5iso3 is identical to SIRT5iso1 except that it lacks an internal sequence of 18 amino acids, while in SIRT5iso4 the initial 108 amino acids of SIRT5iso1 are missing, including the mitochondrial localization sequence. SIRT5iso4 completely aligns with amino acids 109-310 of SIRT5iso1. SIRT5 polymorphisms may impact human lifespan. Presence of a single-nucleotide polymorphism (SNP) (rs9382222) in a conserved region of the SIRT5 promoter correlates with reduced SIRT5 mRNA expression levels in the anterior cingulate cortex (ACC) region of the brain in individuals with the CC genotype relative to individuals with the CT genotype. SNP rs2841505 is associated with slightly reduced lifespan in cohort members with a GG genotype compared to those with other genotypes. Another SIRT5 SNP, rs4712047, displays gender-specific impact on the lifespan, females with a GG genotype exhibited an increased lifespan compared to those with a GA or a AA genotype, whereas males with a GG genotype display decreased lifespan compared to males with the other genotypes. Association of SIRT5 SNP rs2253217 with human lifespan, cohort members with TT genotype live longer than those with TC or CC genotype	Homo sapiens
malfunction	in addition to mitochondrial proteins, a large number of cytosolic and nuclear proteins exhibit increased succinylation, malonylation, and glutarylation upon SIRT5 deletion. Despite the broad expression and unique activity profile of SIRT5, which is non-redundant with other mitochondrial sirtuins, Sirt5 knockout (KO) mice display no strong phenotypes or major metabolic abnormalities, and germline ablation of Sirt5 is well tolerated in mice under basal, unstressed conditions. Sirt5 KO mice on the C57BL/6 background are born at a sub-Mendelian ratio, an effect not observed in Sirt5 KO 129/J background animals. Sirt5 ablation in mice causes a dramatic increase of Ksucc, Kmal, and Kglu levels, globally across multiple tissues and embryonic fibroblasts, while it has very little impact on Kac levels	Mus musculus
malfunction	SIRT5 polymorphisms may impact human lifespan. Presence of a single-nucleotide polymorphism (SNP) (rs9382222) in a conserved region of the SIRT5 promoter correlates with reduced SIRT5 mRNA expression levels in the anterior cingulate cortex (ACC) region of the brain in individuals with the CC genotype relative to individuals with the CT genotype. SNP rs2841505 is associated with slightly reduced lifespan in cohort members with a GG genotype compared to those with other genotypes. Another SIRT5 SNP, rs4712047, displays gender-specific impact on the lifespan, females with a GG genotype exhibited an increased lifespan compared to those with a GA or a AA genotype, whereas males with a GG genotype display decreased lifespan compared to males with the other genotypes. Association of SIRT5 SNP rs2253217 with human lifespan, cohort members with TT genotype live longer than those with TC or CC genotype. In addition to mitochondrial proteins, a large number of cytosolic and nuclear proteins exhibit increased succinylation, malonylation, and glutarylation upon SIRT5 deletion	Homo sapiens
additional information	lysine succinylation (Ksucc), malonylation (Kmal), and glutarylation (Kglu), derived from succinyl-CoA, malonyl-CoA, and glutaryl-CoA respectively, have emerged as functionally important modifications, but most likely have distinct functions from Kac in regulating metabolism and other cellular processes. The presence of succinyl, malonyl, or glutaryl moiety confers upon a modified lysine residue a negative charge at physiological pH. SIRT5 preferentially catalyzes the removal of these negatively charged acidic modifications, thereby functioning as the dominant cellular desuccinylase, demalonylase, and deglutarylase. Compared to other sirtuins, SIRT5 possess a larger acyl binding pocket, able to accommodate these acyl modifications, which are bulkier than an acetyl group. The presence of alanine (Ala86), arginine (Arg105), and tyrosine (Tyr102) residues in the catalytic pocket of SIRT5 appears to be responsible for its specificity for negatively charged acyl groups	Homo sapiens
additional information	lysine succinylation (Ksucc), malonylation (Kmal), and glutarylation (Kglu), derived from succinyl-CoA, malonyl-CoA, and glutaryl-CoA respectively, have emerged as functionally important modifications, but most likely have distinct functions from Kac in regulating metabolism and other cellular processes. The presence of succinyl, malonyl, or glutaryl moiety confers upon a modified lysine residue a negative charge at physiological pH. SIRT5 preferentially catalyzes the removal of these negatively charged acidic modifications, thereby functioning as the dominant cellular desuccinylase, demalonylase, and deglutarylase. Compared to other sirtuins, SIRT5 possess a larger acyl binding pocket, able to accommodate these acyl modifications, which are bulkier than an acetyl group. The presence of alanine (Ala86), arginine (Arg105), and tyrosine (Tyr102) residues in the catalytic pocket of SIRT5 appears to be responsible for its specificity for negatively charged acyl groups	Mus musculus
physiological function	role of SIRT5 as a significant regulator of cellular homeostasis in a context- and cell-type specific manner. SIRT5 regulates protein substrates involved in glycolysis, TCA cycle, fatty acid oxidation, electron transport chain, ketone body formation, nitrogenous waste management, and ROS detoxification, among other processes. SIRT5 plays pivotal roles in cardiac physiology and stress responses, and is involved in the regulation of numerous aspects of myocardial energy metabolism. SIRT5 is implicated in neoplasia, as both a tumor promoter and suppressor in a context-specific manner, and may serve a protective function in the setting of neurodegenerative disorders. SIRT5 displays a unique affinity for negatively charged acyl lysine modifications, and performs protein desuccinylation, demalonylation, and deglutarylation reactions. SIRT5 is selective only for 3-5 carbon chains acidic acyl modifications, and displays no detectable activity against either an acetyl modification, a neutral 2 carbon group, or an adipoyl, a 6-carbon acidic modification. SIRT5 regulates glycolysis, the TCA cycle and the electron transport chain. It plays a role in fatty acid beta-oxidation and promotes reactive oxygen species (ROS) detoxification. SIRT5 contributes to nitrogenous waste management and maintains cardiac homeostasis under stress. SIRT5 plays Janus-faced roles in cancer, it acts as a tumor promoter and s tumor suppressor. Role of SIRT5 in the pathogenesis of neurodegenerative disorders. Physiological function of SIRT5 , detailed overview	Homo sapiens
physiological function	role of SIRT5 as a significant regulator of cellular homeostasis in a context- and cell-type specific manner. SIRT5 regulates protein substrates involved in glycolysis, TCA cycle, fatty acid oxidation, electron transport chain, ketone body formation, nitrogenous waste management, and ROS detoxification, among other processes. SIRT5 plays pivotal roles in cardiac physiology and stress responses, and is involved in the regulation of numerous aspects of myocardial energy metabolism. SIRT5 is implicated in neoplasia, as both a tumor promoter and suppressor in a context-specific manner, and may serve a protective function in the setting of neurodegenerative disorders. SIRT5 displays a unique affinity for negatively charged acyl lysine modifications, and performs protein desuccinylation, demalonylation, and deglutarylation reactions. SIRT5 is selective only for 3-5 carbon chains acidic acyl modifications, and displays no detectable activity against either an acetyl modification, a neutral 2 carbon group, or an adipoyl, a 6-carbon acidic modification. SIRT5 regulates glycolysis, the TCA cycle and the electron transport chain. It plays a role in fatty acid beta-oxidation and promotes reactive oxygen species (ROS) detoxification. SIRT5 contributes to nitrogenous waste management and maintains cardiac homeostasis under stress. SIRT5 plays Janus-faced roles in cancer, it acts as a tumor promoter and s tumor suppressor. Role of SIRT5 in the pathogenesis of neurodegenerative disorders. Physiological function of SIRT5, detailed overview	Mus musculus