2.3.1.B43: protein-lysine desuccinylase (NAD+)
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For detailed information about protein-lysine desuccinylase (NAD+), go to the full flat file.
Word Map on EC 2.3.1.B43
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2.3.1.B43
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sirtuins
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sirt3
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deacetylation
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deacetylases
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desuccinylation
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malonylation
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nad-dependent
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sirt1-7
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glutarylation
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diagnostics
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medicine
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drug development
- 2.3.1.B43
- sirtuins
- sirt3
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deacetylation
- deacetylases
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desuccinylation
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malonylation
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nad-dependent
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sirt1-7
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glutarylation
- diagnostics
- medicine
- drug development
Reaction
Synonyms
CobB, CobB Sir2 protein, histone desuccinylase, hSIRT5, hSIRT6, lysine desuccinylase, mitochondrial NAD+-dependent lysine deacylase, NAD+ dependent deacetylase, NAD+-dependent protein deacetylase, NAD+-dependent protein deacylase, NAD+-dependent sirtuin deacetylase, nicotinamide adenine dinucleotide-dependent protein deacetylase, Sir2Af1, SIRT5, SIRT5iso1, SIRT5iso2, SIRT5iso3, SIRT5iso4, sirtuin 5, sirtuin 5 deacylase, sirtuin 5 lysine deacylase, sirtuin deacylase, sirtuin-5, zSIRT5
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General Information
General Information on EC 2.3.1.B43 - protein-lysine desuccinylase (NAD+)
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evolution
malfunction
metabolism
physiological function
additional information
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
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
evolution
mammals possess seven sirtuin family members (SIRT1-SIRT7), which display diverse subcellular localization patterns, catalytic activities, protein targets, and biological functions
evolution
SIRT5 gene encodes for four SIRT5 protein isoforms, namely SIRT5iso1, SIRT5iso2, SIRT5iso3, and SIRT5iso4
evolution
sirtuins (SIRTs) are proteins that possess nicotinxadamide-adenine dinucleotide-dependent deacetylase activity and belong to the histone deacetylase (HDAC) family, which consist of seven different subtypes in mammals (SIRT1-7)
evolution
sirtuins are a family of NAD+-dependent silent information regulator 2 (Sir2) enzymes that catalyze the removal of acyl groups from epsilon-N-amino groups of lysine residues in the proteome
evolution
sirtuins are a family of NAD+-dependent silent information regulator 2 (Sir2) enzymes that catalyze the removal of acyl groups from epsilon-N-amino groups of lysine residues in the proteome
evolution
sirtuins, which are class III histone deacetylases (HDACs), are an evolutionarily conserved family of NAD-dependent lysine deacetylases that play important roles in the regulation of aging, tumorigenesis, energy metabolism and stress resistance
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acetyl-coenzyme A synthetase overproduced by the cobB deletion mutant strain contains acetyllysine at residue Lys609
malfunction
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CobB knockout cells show slightly increased acetylation levels and succinylation levels relative to the wild type cells
malfunction
deletion of Sirt5 in mice increases the level of succinylation on carbamoyl phosphate synthase 1
malfunction
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RcsB protein isolated from a cobB deletion mutation strain is hyperacetylated
malfunction
SIRT5 knockdown in cardiomyocytes results in a marked reduction in cell viability, and a significant increase in the number of apoptotic cells
malfunction
SIRT5 knockdown represses lung cancer cell growth and transformation in vitro and in vivo. SIRT5 knockdown makes lung cancer cells more sensitive to drug (cis-diamminedichloroplatinum, 5-fluorouracil or bleomycin) treatment in vitro and in vivo. Nrf2, which is a core transcription factor for lung cancer growth and drug resistance, is a target of SIRT5
malfunction
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knockdown or knockout of the enzyme leads to high levels of cellular reactive oxygen species. SIRT5 inactivation leads to the inhibition of isocitrate dehydrogenase 2 and glucose-6-phosphate dehydrogenase, thereby decreasing NADPH production, lowering GSH, impairing the ability to scavenge ROS, and increasing cellular susceptibility to oxidative stress
malfunction
because these modifications by Sirt5 cover a broad range of pivotal protein substrates involved in cellular metabolism and metabolic energy homeostasis, aberrant activity of Sirt5 is considered to be a very critical factor for many human diseases, for example, cancer, Alzheimer's disease, and Parkinson's disease
malfunction
depletion of SIRT5, a lysine desuccinylase, leads to increased ubiquitination of glutaminase. SIRT5 knockdown acts as a marker for subsequent ubiquitination at residue K158
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
malfunction
SIRT5 deficiency decreases TLR-triggered inflammation in both acute and immunosuppressive phases of sepsis. Acetylation of p65 K310 is impaired in SIRT5-/- peritoneal macrophages upon TLR4 activation. The p65 overexpression-induced NF-kappaB reporter activity is significantly increased by SIRT5 overexpression, but impaired by SIRT1/2 overexpression in HEK-293T cells. Decreased expression of SIRT5 is found in cultured macrophages upon primary or second LPS stimulation
malfunction
SIRT5 knockout mice on the Sv129 background exhibit less browning capacity in subcutaneous white adipose tissue compared to controls and show apparent cold intolerance, suggesting that SIRT5 can modulate the browning process in vivo. Knockdown of SIRT5 impairs brown adipocyte differentiation of C3H10T1/2 multipotent mesenchymal cells and blocks adipogenic gene activation. Lipid accumulation and basal and uncoupled oxygen consumption rates are significantly reduced in SIRT5 knockdown cells. The expression levels of PPARgamma, PRDM16, and UCP1 are significantly augmented in the SIRT5 overexpression cells, which is consistent with the increased lipid accumulation. UCP1 expression is significantly increased in SIRT5 overexpression groups. Knockdown of SIRT5 reduces 2-oxoglutarate concentration and supplementation of 2-oxoglutarate partially rescues brown adipocyte differentiation in SIRT5 knockdown cells. Knockdown of SIRT5 results in increased H3K9me2 and H3K9me3 levels in the promoter regions of Ppargamma and Prdm16
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
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
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
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
malfunction
SIRT5-KO mice have reduced survival upon transverse aortic constriction (TAC) compared with wild-type mice but exhibit no mortality when undergoing a sham control operation. The increased mortality with TAC is associated with increased pathological hypertrophy and with key abnormalities in both cardiac performance and ventricular compliance. An accelerated development of cardiac dysfunction in SIRT5KO mice in response to TAC, explaining increased mortality upon cardiac stress. Protein succinylation is increased in SIRT5-KO hearts and abundant on enzymes in oxidative metabolism. SIRT5-KO mouse phenotype, detailed overview
malfunction
the SIRT5 deficiency mouse model shows that it is dispensable for metabolic homeostasis under normal conditions. The ob/ob-SIRT5 OE mice show decreased malonylation and succinylation, improved cellular glycolysis, suppressed gluconeogenesis, enhanced fatty acid oxidation, and attenuated hepatic steatosis. Hepatic overexpression of SIRT5 ameliorates the metabolic abnormalities of ob/obmice, probably through demalonylating and desuccinylating proteins in the main metabolic pathways. SIRT5 and related acylation might be potential targets for metabolic disorders
malfunction
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the SIRT5 deficiency mouse model shows that it is dispensable for metabolic homeostasis under normal conditions. The ob/ob-SIRT5 OE mice show decreased malonylation and succinylation, improved cellular glycolysis, suppressed gluconeogenesis, enhanced fatty acid oxidation, and attenuated hepatic steatosis. Hepatic overexpression of SIRT5 ameliorates the metabolic abnormalities of ob/obmice, probably through demalonylating and desuccinylating proteins in the main metabolic pathways. SIRT5 and related acylation might be potential targets for metabolic disorders
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because ammonia generated during fasting is toxic, SIRT5 might play a protective role by converting ammonia to non-toxic urea through deacetylation and activation of carbamoyl phosphate synthase 1
metabolism
human SIRT5 potentially controls various primate-specific functions via two isoforms with different intracellular localizations or stabilities
metabolism
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overexpression of CobB reduces the 6fold glucose-dependent induction to a more modest 3fold induction
metabolism
reversible Nepsilon-Lys acetylation of transcription factors is a mode of regulation of gene expression used by all cells
metabolism
SIRT5 deacetylates carbamoyl phosphate synthetase 1 (CPS1), an enzyme which is the first and rate-limiting step of urea cycle. Deacetylation of CPS1 by SIRT5 results in activation of CPS1 enzymatic activity
metabolism
SIRT5 has an emerging role in the metabolic adaptation to fasting, high protein diet and calorie restriction
metabolism
SIRT5 is a protein responsible for growth and drug resistance in human non-small cell lung cancer cells
metabolism
SIRT5 is involved in the regulation of oxidative stress induced apoptosis in cardiomyocytes
metabolism
SIRT5 plays a pivotal role in ammonia detoxification and disposal by activating carbamoyl phosphate synthetase 1 an enzyme, catalyzing the initial step of the urea cycle for ammonia detoxification and disposal
metabolism
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sirtuin deacetylase CobB deficiency leads to both site-specific and global changes in protein acetylation stoichiometry, affecting central metabolism
metabolism
the enzyme is involved in regulation of mitochondrial energy metabolism
metabolism
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the Gcn5-like acetyltransferase YfiQ and the sirtuin deacetylase CobB play crucial roles in the transcription regulation of the periplasmic stress-responsive promoter cpxP when cells of Escherichia coli grow in the presence of glucose, an environment that induces protein acetylation
metabolism
function of sirtuin family members in the inflammatory responses, overview. SIRT5 and SIRT1/2 have opposite expression patterns and functions in macrophages. Cytoplasmic SIRT5 counteracts the inhibitory effects of SIRT2 and enhances the innate inflammatory responses in macrophages and even in endotoxin-tolerant macrophages by promoting acetylation of p65 and activation of NF-kappaB pathway. Mechanistically, SIRT5 competes with SIRT2 to interact with NF-kappaB p65, in a deacetylase activity-independent way, to block the deacetylation of p65 by SIRT2, which consequently leads to increased acetylation of p65 and the activation of NF-kB pathway and its downstream cytokines
metabolism
protein malonylation and succinylation lysine sites are identified by immunoprecipitation coupled lipid chromatography-tandem mass spectrometry (LC-MS/MS) methods. A total of 955 malonylation sites on 434 proteins and 1377 succinylation sites on 429 proteins were identified and quantitated. Malonylation is the major SIRT5 target in the glycolysis/gluconeogenesis pathway, whereas succinylation is the preferred SIRT5 target in the oxidative phosphorylation pathway. Identification, quantification, and analysis of malonylome and succinylome
metabolism
SIRT5 regulates brown adipogenic gene activation at least partly through an indirect effect on histone modifications, linkage between epigenetics and cell differentiation. SIRT5 is implicated in the urea cycle by activating carbamoyl phosphate synthetase 1. SIRT5 modifies lysine succinylation, malonylation, and glutarylation both inside and outside of the mitochondria and impacts multiple enzymes involved in diverse mitochondrial metabolic pathways. SIRT5 has crucial effects on cellular metabolite flux
metabolism
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protein malonylation and succinylation lysine sites are identified by immunoprecipitation coupled lipid chromatography-tandem mass spectrometry (LC-MS/MS) methods. A total of 955 malonylation sites on 434 proteins and 1377 succinylation sites on 429 proteins were identified and quantitated. Malonylation is the major SIRT5 target in the glycolysis/gluconeogenesis pathway, whereas succinylation is the preferred SIRT5 target in the oxidative phosphorylation pathway. Identification, quantification, and analysis of malonylome and succinylome
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acetylation of the response regulator RcsB controls transcription from the small RNA promoter rprA
physiological function
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deacetylation by CobB activates the acetyl-coenzyme A synthetase
physiological function
protein lysine succinylation may represent a posttranslational modification that can be reversed by Sirt5
physiological function
SIRT5 is a central regulator of Lys succinylation in mammalian cells
physiological function
SIRT5 is involved in influencing oocyte quality and in-vitro-fertilisation outcomes
physiological function
SIRT5 overexpression increases ATP synthesis and oxygen consumption in HepG2 cells, but does not affect mitochondrial biogenesis
physiological function
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the enzyme regulates chemotaxis of Escherichia coli by deacetylating CheY
physiological function
the enzyme regulates protein function in diverse and often essential cellular processes, most notably translation. CobB is the predominate deacetylase in Escherichia coli loop or a helix that protrudes into the solution and thus in position to be an easily accessible target
physiological function
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the enzyme prevents cigarette smoke extract-induced apoptosis in lung epithelial cells via deacetylation of FOXO3
physiological function
adipose tissue plays a vital role in metabolic regulation. SIRT5 regulates brown adipocyte differentiation and browning of subcutaneous white adipose tissue. SIRT5 modifies lysine succinylation, malonylation, and glutarylation both inside and outside of the mitochondria. SIRT5 can desuccinylate and deglutarylate IDH2 and G6PD, respectively, thereby activating both enzymes to maintain cellular NADPH homeostasis and redox potential during oxidative stress. SIRT5 is essential for brown adipocyte differentiation in vitro and has an impact on browning of subcutaneous adipose tissue in vivo. SIRT5 may play an important role in adaptive thermogenesis of brown/beige adipocytes
physiological function
human sirtuin 5 (Sirt5) catalyzes the sequence-selective desuccinylation of numerous histone succinyl sites. Compared with Sirt1, 2, 3, and 6, enzyme Sirt5 exhibits relatively weak deacetylation activity but can more efficiently remove negatively charged modifications, such as malonylation, glutarylation, and especially succinylation, from lysine residues. Sirt5 is considered a desuccinylase
physiological function
in mitochondria, the sirtuin SIRT5 is an NAD+-dependent protein deacylase controls several metabolic pathways. A wide range of SIRT5 targets have been identified. SIRT5 functions in organismal metabolic homeostasis. SIRT5 plays a role in cardiac stress responses
physiological function
potential role of isozyme SIRT5iso2 in neuron system
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
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
physiological function
SIRT5 enhances acetylation (K310) of NF-kappaB p65 in response to innate stimuli. SIRT5 enhances acetylation of p65 by blocking p65 interaction of SIRT2. Endogenous SIRT5 interacts with p65 in the cytoplasm of macrophages. SIRT5 rescues hypo-inflammatory response in endotoxin-tolerant macrophages
physiological function
Sirt5 has only weak deacetylation, but has robust desuccinylation, demalonylation, and deglutarylation activities in vitro and in vivo. Modifications by Sirt5 cover a broad range of pivotal protein substrates involved in cellular metabolism and metabolic energy homeostasis
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
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
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
physiological function
SIRT5, a mitochondrial NAD+-dependent lysine deacylase, plays a key role in stabilizing glutaminase. In transformed cells, SIRT5 regulates glutamine metabolism by desuccinylating glutaminase and thereby protecting it from ubiquitin-mediated degradation. SIRT5 is upregulated during cellular transformation and supports proliferation and tumorigenesis. SIRT5 is upregulated during oncogenic transformation and stabilizes glutaminase, an enzyme with important functions in cancer-cell metabolic reprogramming. Elevated SIRT5 expression in human breast tumors correlates with poor patient prognosis. Role for SIRT5 in metabolic reprogramming and mammary tumorigenesis. SIRT5 supports proliferation and anchorage-independent growth
physiological function
Sirtuin 5 (SIRT5) is a NAD+-dependent lysine deacylase. SIRT5 deacylates metabolism-related proteins and attenuates hepatic steatosis in obese ob/ob mice
physiological function
sirtuin 5 (SIRT5) is upregulated in patients with type 2 diabetes. Elevated SIRT5 expression is positively associated with age and blood glucose levels, and negatively associated with pancreatic and duodenal homeobox 1 (PDX1) expression. SIRT5 regulates pancreatic beta cell proliferation and insulin secretion in type 2 diabetes. SIRT5 suppresses the proliferation of pancreatic beta cells in vitro. While SIRT5 possesses weak deacetylase activity, it catalyzes the modification of acidic lysine residues by glutaryxadlation, succinylation, and malonylation well. PDX1 is transcriptionally regulated by SIRT5 via H4K16 deacetylation. PDX1 is involved in SIRT5-mediated insulin secretion and pancreatic beta cell proliferation
physiological function
sirtuins are NAD+-dependent enzymes that regulate diverse cellular processes, thereby maintaining metabolic homeostasis and genomic integrity.Sirtuin-family deacylases promote health and longevity in mammals. The sirtuin SIRT5 localizes predominantly to the mitochondrial matrix. SIRT5 preferentially removes negatively charged modifications from its target lysines: succinylation, malonylation, and glutarylation. It regulates protein substrates involved in glucose oxidation, ketone body formation, ammonia detoxification, fatty acid oxidation, and ROS management
physiological function
sirtuins are protein deacylases that regulate metabolism and stress responses and are implicated in aging-related diseases
physiological function
Escherichia coli W3110 / ATCC 27325
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the enzyme regulates chemotaxis of Escherichia coli by deacetylating CheY
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physiological function
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Sirtuin 5 (SIRT5) is a NAD+-dependent lysine deacylase. SIRT5 deacylates metabolism-related proteins and attenuates hepatic steatosis in obese ob/ob mice
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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
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
additional information
molecular mechanism underlying the sequence-selective desuccinylase activity of Sirt5, overview. Human Sirt5 is a ubiquitous desuccinylase that catalyzes the desuccinylation of diverse histone succinyl sites with sequence selectivity. Among the 13 identified sites, H2BK116su is the most favorable Sirt5 substrate, with H4K12su showing the lowest catalytic efficiency and no activity observed in the presence of H4K31su
additional information
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molecular mechanism underlying the sequence-selective desuccinylase activity of Sirt5, overview. Human Sirt5 is a ubiquitous desuccinylase that catalyzes the desuccinylation of diverse histone succinyl sites with sequence selectivity. Among the 13 identified sites, H2BK116su is the most favorable Sirt5 substrate, with H4K12su showing the lowest catalytic efficiency and no activity observed in the presence of H4K31su
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)
additional information
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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)
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)
additional information
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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)