2.3.1.B41	evolution	SIRT6 belongs to the mammalian homologues of Sir2 histone NAD+-dependent deacylase family	756407	
2.3.1.B41	evolution	sirtuin 6 (SIRT6) is a member of the sirtuin family of nicotinamide adenine dinucleotide?dependent protein deacetylases	757294	
2.3.1.B41	evolution	sirtuin6 belongs to the Sirtuin family	757644	
2.3.1.B41	evolution	sirtuin6 is a member of the sirtuin family which function as NAD+-dependent deacetylases	757530	
2.3.1.B41	evolution	sirtuins are an evolutionarily conserved family of proteins originally defined as the class III histone deacetylases (HDACs). The sirtuin family of proteins share a conserved central catalytic domain and the ability to couple the cleavage of NAD+ to the removal of an acyl group from the epsilon-amino group of lysines. Each family member (SIRT1-7) contains variable N-terminal and C-terminal domains and has diverse subcellular localization and function	757236	
2.3.1.B41	evolution	sirtuins, silent mating-type information regulation 2 (SIRTs), are a family of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases with important roles in regulating energy metabolism and senescence. SIRT6 reduces the upregulation of genes involved in inflammation, vascular remodeling, oxidative stress, and angiogenesis, including interleukin 1-beta	755918	
2.3.1.B41	evolution	there are seven evolutionarily conserved mammalian sirtuins (SIRT1-7) distributed to different compartments of the cell. They possess different deacylation activities to post-translationally modulate functions of their targets influencing major cellular pathways. SIRT6 is associated with chromatin and possesses histone deacetylase as well as mono-ADP-ribosylase activities, for both of which it needs NAD+ as a co-substrate	758395	
2.3.1.B41	malfunction	an inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality. The homozygous inactivating mutation D63H in the histone deacetylase SIRT6 results in severe congenital anomalies and perinatal lethality in four affected fetuses. Human induced pluripotent stem cells (iPSCs) derived from D63H homozygous fetuses fail to differentiate into embryoid bodies (EBs), functional cardiomyocytes, and neural progenitor cells due to a failure to repress pluripotent genes. SIRT6 knockout ESCs cultured to form EBs are significantly smaller than their wild-type counterparts. SIRT6 D63H mutant mESCs fail to differentiate into functional cardiomyocyte foci. SIRT6 D63H mutant cardiomyocytes fail to suppress HAND1 expression while exhibiting significantly reduced FBN1 levels when compared with SIRT6 knockout cells	756879	
2.3.1.B41	malfunction	analysis of effects of inhibition of SIRT6 on differentiation and lipid synthesis, and related molecular mechanisms, overview. Overexpression of SIRT6 significantly inhibits the mRNA expression of key adipogenesis genes such as CCAAT enhancer binding protein alpha (CEBPalpha), FABP4, FASN, peroxisome proliferator-activated receptor gamma (PPARgamma), and stearoyl-CoA desaturase (SCD), and promotes the expression of lipolysis genes including lipoprotein lipase (LPL), while interference of SIRT6 obtains the opposite results. The lipolysis drug Cl316,243 interfering with SIRT6 significantly promotes the expression of CEBPalpha, FABP4, FASN, PPARgamma, and SCD, and inhibited the expression of LPL, while overexpression of SIRT6 results in the opposite results	755904	
2.3.1.B41	malfunction	diabetic mice exhibit reduced Sirt6 expression and AMP kinase (AMPK) dephosphorylation accompanied by mitochondrial morphological abnormalities. Hyperglycemia-induced Sirt6 levels are decreased in vivo. Hyperglycemia promotes podocyte mitochondrial dysfunction in mice with diabetic nephropathy (DN)	-, 756973	
2.3.1.B41	malfunction	downregulation of SIRT6 enables forkhead box O3 (FOXO3) upregulation, translocation into the nucleus, and increased expression of its target genes p27 and Bim, which further induce apoptosis. Overexpression of SIRT6, but not enzyme-inactivated mutants, prevents FOXO3 translocation into the nucleus and doxorubicin-induced cell death	757883	
2.3.1.B41	malfunction	E-cadherin degradation and invasion, migration induced by SIRT6 overexpression can be rescued by dual mutation of Beclin-1 (inhibition of acetylation), CQ (autophagy inhibitor), and knockdown of Atg7	757530	
2.3.1.B41	malfunction	enzyme inactivation in cells leads to histone H3-Lys18 hyperacetylation and aberrant accumulation of pericentric transcripts	739158	
2.3.1.B41	malfunction	enzyme knockout is associated with derepression of Oct4, Sox2 and Nanog, which in turn causes an upregulation of Tet enzymes and elevated production of 5-hydroxymethylcytosine	739132	
2.3.1.B41	malfunction	functionally, SIRT6 D63H mouse embryonic stem cells (mESCs) fail to repress pluripotent gene expression, direct targets of SIRT6, and exhibit an even more severe phenotype than Sirt6-deficient ESCs when differentiated into embryoid bodies (EBs). When terminally differentiated toward cardiomyocyte lineage, D63H mutant mESCs maintain expression of pluripotent genes and fail to form functional cardiomyocyte foci	756879	
2.3.1.B41	malfunction	in SIRT6-overexpressing cells, NAD(H) levels are upregulated, as a consequence of NAMPT activation	756689	
2.3.1.B41	malfunction	in vitro, podocytes exposed to high-glucose present with mitochondrial morphological alterations and podocyte apoptosis accompanied by Sirt6 and p-AMPK downregulation. The mitochondrial defects induced by high-glucose are significantly alleviated by Sirt6 plasmid transfection. Sirt6 overexpression simultaneously alleviates high-glucose-induced podocyte apoptosis and oxidative stress, as well as increased AMPK phosphorylation. Increased levels of H3K9ac and H3K56ac induced by high-glucose are attenuated in podocytes transfected with Sirt6 plasmids. Cell apoptosis is significantly ameliorated after the transfection of the Sirt6 plasmid in high-glucose-stimulated podocytes	756973	
2.3.1.B41	malfunction	inhibiting SIRT6 activity enhances anti-multiple myeloma activity of doxorubicin in vivo	737930	
2.3.1.B41	malfunction	knock-down of SIRT6 does not sensitize bladder cancer cell lines to DNA damaging drugs	729849	
2.3.1.B41	malfunction	Loss of Sirt6 jeopardizes circadian phase. Reduction of Per2 protein level in Sirt6 null cells	755978	
2.3.1.B41	malfunction	minute cholesterol crystals (CCs) significantly suppress SIRT6 expression in endothelial cells. The overexpression of SIRT6 can mitigate minute CC-induced endothelial dysfunction. Expression of Nuclear factor erythroid2-related factor2 (Nrf2) is suppressed after minute CC treatment, whereas SIRT6 overexpression reverses this decrease in Nrf2 expression. Nrf2 activation also notably attenuates minute CC-induced endothelial dysfunction. SIRT6 depletion impairs vascular endothelial function and suppresses Nrf2 expression in hyperlipidemic mice	756672	
2.3.1.B41	malfunction	minute cholesterol crystals (CCs) significantly suppress SIRT6 expression in endothelial cells. The overexpression of SIRT6 can mitigate minute CC-induced endothelial dysfunction. Expression of Nuclear factor erythroid2-related factor2 (Nrf2) is suppressed after minute CC treatment, whereas SIRT6 overexpression reverses this decrease in Nrf2 expression. Nrf2 activation also notably attenuates minute CC-induced endothelial dysfunction. SIRT6 depletion impairs vascular endothelial function and suppresses Nrf2 expression in hyperlipidemic mice. Hearts, livers, spleens, lungs, kidneys and aortas from ecSIRT6-/- mice fed a normal diet do not show obvious pathological differences compared with ecSIRT6+/+ mice. Endothelium-specific SIRT6 knockout further impairs NO synthesis, significantly decreases eNOS activity and suppresses eNOS expression in hyperlipidemic mice. Endothelium-specific SIRT6 knockout further exacerbates endothelial dysfunction in hyperlipidemic mice	756672	
2.3.1.B41	malfunction	overexpression of SIRT6 in astrocytes by itself abrogates the neurotoxic phenotype of amyotrophic lateral sclerosis (ALS) astrocytes. Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex	756691	
2.3.1.B41	malfunction	overexpression of SIRT6 significantly suppresses TGF-beta1-induced myofibroblast differentiation in HFL1 cells. Mutant SIRT6 (H133Y) without histone deacetylase activity fails to inhibit phosphorylation and nuclear translocation of Smad2. Overexpression of wild-type SIRT6 but not the H133Y mutant inhibits the expression of NF-kappaB-dependent genes including interleukin (IL)-1beta, IL-6 and matrix metalloproteinase-9 (MMP-9) induced by TGF-beta1, all of which have been demonstrated to promote myofibroblast differentiation. SIRT6 overexpression suppresses TGF-beta1-induced Smad2 activation	757294	
2.3.1.B41	malfunction	SIRT6 activity declines with age, with a concomitant accumulation of DNA damage. SIRT6 and its downstream signaling can be targeted in Alzheimer's disease and age related neurodegeneration. Patients with Alzheimer's disease show a remarkable reduction in SIRT6 at both protein and mRNA levels, with further reduction with increased severity of Braak stages. SIRT6KO cells are more sensitive to apoptosis, prevented by GSK3 or ATM inhibition	756392	
2.3.1.B41	malfunction	SIRT6 activity declines with age, with a concomitant accumulation of DNA damage. SIRT6 knockout mice exhibit an accelerated aging phenotype and die prematurely. Brain-specific SIRT6-deficient mice survive, but present behavioral defects with major learning impairments by 4 months of age. Moreover, the brains of these mice show increased signs of DNA damage, cell death and hyperphosphorylated Tau, a critical mark in several neurodegenerative diseases	756392	
2.3.1.B41	malfunction	SIRT6 deficiency causes major retinal transmission defects concomitant to changes in expression of glycolytic genes and glutamate receptors, as well as elevated levels of apoptosis in inner retina cells	730790	
2.3.1.B41	malfunction	SIRT6 depletion in cardiac as well as skeletal muscle cells promotes myostatin (Mstn) expression. Upregulation of other factors implicated in muscle atrophy, such as angiotensin-II, activin and Acvr2b, in SIRT6 depleted cells is observed. Effect of SIRT6 deficiency on cardiac expression of muscle-atrophy related genes. Phenotype, detailed overview	758395	
2.3.1.B41	malfunction	SIRT6 depletion in cardiac as well as skeletal muscle cells promotes myostatin (Mstn) expression. Upregulation of other factors implicated in muscle atrophy, such as angiotensin-II, activin and Acvr2b, in SIRT6 depleted cells is observed. SIRT6-KO mice show degenerated skeletal muscle phenotype with significant fibrosis, an effect consistent with increased levels of Mstn. SIRT6 overexpression downregulates the cytokine (TNFalpha-IFNgamma)-induced Mstn expression in C2C12 cells, and promotes myogenesis. SIRT6 overexpression mitigates atrophic effect of tumor-induced cytokines in C2C12 cells. Effect of SIRT6 deficiency on cardiac expression of muscle-atrophy related genes. Phenotype, detailed overview	758395	
2.3.1.B41	malfunction	SIRT6 depletion in cardiac fibroblasts results in increased cell proliferation and extracellular matrix deposition as well as significantly higher expression of alpha-smooth muscle actin, the classical marker of myofibroblast differentiation, and increased formation of focal adhesions. Notably, SIRT6 depletion further exacerbates angiotensin II–induced myofibroblast differentiation	739733	
2.3.1.B41	malfunction	SIRT6 knockdown inhibits growth and clonogenic survival of A-375 and Hs-294T human melanoma cell lines, SIRT6 knockdown inhibits proliferation and colony formation in melanoma cells. SIRT6 knockdown results in an enhanced accumulation of cells in G0/G1 phase in both A-375 and Hs-294T human melanoma cell lines, it induces G1-phase arrest and senescence-like phenotypes in human melanoma cells. Modulations in autophagy-related genes are associated with the antiproliferative response of SIRT6 inhibition. Phenotype, overview	756871	
2.3.1.B41	malfunction	SIRT6 knockout (KO) cells show neither damage-induced telomere movement nor chromatin decondensation at damaged telomeres, while both are observed in wild-type cells. A Deacetylation mutant of SIRT6 increases damage-induced telomeric movement in SIRT6 KO cells as well as wild-type SIRT6	758437	
2.3.1.B41	malfunction	SIRT6 knockout human mesenchymal stem cells (hMSCs) exhibit accelerated functional decay, a feature distinct from typical premature cellular senescence. Rather than compromised chromosomal stability, SIRT6-null hMSCs are predominately characterized by dysregulated redox metabolism and increased sensitivity to the oxidative stress. SIRT6 forms a protein complex with both nuclear factor erythroid 2-related factor 2 (NRF2) and RNA polymerase II, which is required for the transactivation of NRF2-regulated antioxidant genes, including heme oxygenase 1 (HO-1). Overexpression of HO-1 in SIRT6 null hMSCs rescues premature cellular attrition. SIRT6-/- hMSCs are susceptible to oxidative stress. Reintroduction of wild-type SIRT6, but not of the H133Y mutant into SIRT6-/- hMSCs repress accelerated cellular senescence	756407	
2.3.1.B41	malfunction	SIRT6 loss suppresses proliferation and epidermal hyperplasia in mouse skin. Skin-specific deletion of SIRT6 in the mouse inhibits skin tumorigenesis	729520	
2.3.1.B41	malfunction	SIRT6 protein levels are not detectable in skeletal muscle (gastrocnemius and soleus) in SIRT6M -/- mice and unchanged in other tissues related to metabolic homeostasis compared with SIRT6flox/flox control mice. Mutant phenotype includes attenuated whole body energy expenditure and weakened exercise performance. Mutant mice show inactive behavior with aging, decreased activity of AMPK and reduced expression of its downstream genes in skeletal muscle of SIRT6 knockout mutant mice. Basal mitochondrial respiration and maximal mitochondrial respiratory capacity increase in C2C12 myotubes overexpressing SIRT6	-, 755766	
2.3.1.B41	metabolism	cells overexpressing Sirt6 have a lower proliferation rate with a lower percentage of cells in mitosis, roles for Sirt6 in the nucleolus and in the mitotic phase of the cell cycle	730527	
2.3.1.B41	metabolism	circadian clock relies on a transcription and translation feedback loop (TTFL). Two transcription factors, i.e. Bmal1 and Clock, activate the transcription of Period (Per) and Cryptochrome (Cry), which inhibit their own transcription when accumulated to a critical concentration. NAD+-dependent deacylase Sirt1 deacetylates Bmal1 and Per2 to regulate circadian rhythms. Sirt6 interacts with Bmal1 to regulate clock-controlled gene (CCG) expression by local chromatin remodeling. Loss of Sirt6 jeopardizes circadian phase. At molecular level, Sirt6 interacts with and deacetylates Per2, thus preventing its proteasomal degradation. Important function of Sirt6 in the direct regulation of TTFL and circadian rhythms	755978	
2.3.1.B41	metabolism	fatty acids and SIRT6 regulation, overview. Nucleosome structure may as well modulate SIRT6 activity. Role of SIRT6 metabolic homeostasis, cellular metabolism and metabolic diseases, and protein networks, detailed overview. Regulation in cancer, stress response, senescence, and aging	757931	
2.3.1.B41	metabolism	myostatin (Mstn) and SIRT6 expression exhibit reciprocal relationship, overview	758395	
2.3.1.B41	metabolism	role of SIRTs in human atherosclerosis, overview	755918	
2.3.1.B41	metabolism	SIRT6 acts as a tumor suppressor in human glioma. SIRT6 binds to poly(C)-binding protein 2 (PCBP2) promoter region and deacetylates H3K9ac, resulting in transcription regression	729145	
2.3.1.B41	metabolism	SIRT6 cooperates with SIRT5 to regulate bovine preadipocyte differentiation and lipid metabolism via the AMPKalpha signaling pathway, feedback synergistic regulation of SIRT5 and SIRT6 on differentiation and lipid deposition. In the differentiation process of bovine preadipocytes, inhibition of SIRT5 significantly promotes SIRT6 expression	755904	
2.3.1.B41	metabolism	SIRT6 may play a role in synaptic function and neuronal maturation and it may be implicated in the regulation of neuronal survival	730473	
2.3.1.B41	metabolism	SIRT6 promotes the secretion of tumor necrosis factor alpha by removing the fatty acyl modification on K19 and K20 of TNFalpha	730464	
2.3.1.B41	metabolism	SIRT6 suppresses glycolysis in bladder cancer cells	729849	
2.3.1.B41	metabolism	SIRT6 upregulates COX-2 levels and acts as an oncogene in skin carcinogenesis	729520	
2.3.1.B41	metabolism	telomere stability, movement, and chromosomal condensation are regulated by SIRT6 in the presence of oxidative damage at telomeres	758437	
2.3.1.B41	metabolism	the enzyme promotes TNF-alpha secretion by defatty acylation	739139	
2.3.1.B41	additional information	mechanisms of activated lysine deacetylation and enhanced long-chain acyl group removal by SIRT6, structure-activity relationship analysis, overview. Enzyme residue Arg65 is critical for activation by facilitating a conformational step that initiates chemical catalysis. Mechanism of SIRT6-catalyzed deacylation, overview. The substrate acyl-oxygen performs nucleophilic addition on the 1'-carbon of the nicotinamide ribose, resulting in the C1'-O-alkylamidate intermediate and release of nicotinamide. His133 acts as a general base to facilitate the intramolecular nucleophilic attack of the nicotinamide ribose 2'-hydroxyl on the O-alkylamidate carbon, affording the 1',2'-cyclic intermediate. Water-catalyzed hydrolysis of the 1',2'-cyclic intermediate yields the tetrahedral intermediate. Positively charged His133 donates a proton to the imino group of the tetrahedral intermediate, resulting in cleavage of the C-N bond and yielding the final products. O-acyl-ADPr and deacetylated lysine products are released from SIRT6	757236	
2.3.1.B41	additional information	the core domain of SIRT6 is flanked by an N-terminal, which is necessary for histone deacetylation and chromatin association, and a C-terminal, which is required for the nuclear localization of this SIRT subtype	755918	
2.3.1.B41	additional information	the extended NH2-terminal loop of SIRT6 covers the NAD+- and acyl-substrate binding sites	757931	
2.3.1.B41	additional information	the extended NH2-terminal loop of SIRT6 covers the NAD+- and acyl-substratebinding sites	757931	
2.3.1.B41	physiological function	enzyme overexpression inhibits the proliferation of ovarian cancer cells SKOV-3 and OVCAR-3. The enzyme suppresses the expression of Notch 3 both at the mRNA and protein levels in ovarian cancer cells	738169	
2.3.1.B41	physiological function	enzyme SIRT6 evolved in eukaryotes to perform multiple critical roles in modulating gene expression, metabolism, DNA repair, and lifespan. In this context, SIRT6 plays key roles as a tumor suppressor and a critical modulator of metabolic homeostasis. SIRT6 accomplishes the transfer of radiolabel from [32P]NAD+ through an intramolecular mechanism, suggesting that SIRT6 may utilize ADP-ribosylation as a method to autoregulate its own activity. By modulating H3K9 acetylation, SIRT6 appears to act as a co-repressor of transcription factors, such as nuclear factor kappaB (NF-kappaB) and hypoxia-inducible factor-1alpha (HIF-1alpha). The removal of H3K9 acetylation by SIRT6 helps to regulate telomeric chromatin and gene expression. The role of SIRT6 as a protein deacetylase seems to expand beyond histone proteins. In fact, SIRT6 can directly remove acetyl groups from non-histone proteins. For instance, SIRT6 regulates hepatic glucose production by deacetylating the K549 residue of histone acetyltransferase (HAT) GCN5 and promoting its enzymatic activity. SIRT6 can also deacetylate pyruvate kinase M2 (PKM2) at K433 residue, driving its nuclear export and suppressing PKM2 oncogenic functions. In addition to its NAD+-dependent deacetylation and ADP-ribosylation activity, SIRT6 is also able to catalyze long-chain fatty deacylation, acting as a deacylase of tumor necrosis factor-alpha (TNF-alpha) and multiple secreted proteins. SIRT6 contains a large hydrophobic pocket that may favorably interact with long-chain fatty acyl groups, such as myristoyl. Interaction with these long-chain fatty acyl groups may serve as a regulatory step to modulate the histone deacetylase activity of SIRT6. Regulation of SIRT6 in mammalian cells, SIRT6 has functions in DNA repair, gene expression, telomeric maintenance, mitosis and meiosis, and protein networks, detailed overview	757931	
2.3.1.B41	physiological function	enzyme SIRT6 evolved in eukaryotes to perform multiple critical roles in modulating gene expression, metabolism, DNA repair, and lifespan. In this context, SIRT6 plays key roles as a tumor suppressor and a critical modulator of metabolic homeostasis. SIRT6 accomplishes the transfer of radiolabel from [32P]NAD+ through an intramolecular mechanism, suggesting that SIRT6 may utilize ADP-ribosylation as a method to autoregulate its own activity. SIRT6 catalyzes ADP-ribosylation at K521 residue of PARP1 to promote DSB repair under oxidative stress. such as nuclear factor kappaB (NF-kappaB) and hypoxia-inducible factor-1alpha (HIF-1alpha). The removal of H3K9 acetylation by SIRT6 helps to regulate telomeric chromatin and gene expression. The role of SIRT6 as a protein deacetylase seems to expand beyond histone proteins. In fact, SIRT6 can directly remove acetyl groups from non-histone proteins. For instance, SIRT6 regulates hepatic glucose production by deacetylating the K549 residue of histone acetyltransferase (HAT) GCN5 and promoting its enzymatic activity. SIRT6 can also deacetylate pyruvate kinase M2 (PKM2) at K433 residue, driving its nuclear export and suppressing PKM2 oncogenic functions. In addition to its NAD+-dependent deacetylation and ADP-ribosylation activity, SIRT6 is also able to catalyze long-chain fatty deacylation, acting as a deacylase of tumor necrosis factor-alpha (TNF-alpha) and multiple secreted proteins. SIRT6 contains a large hydrophobic pocket that may favorably interact with long-chain fatty acyl groups, such as myristoyl. Interaction with these long-chain fatty acyl groups may serve as a regulatory step to modulate the histone deacetylase activity of SIRT6. Regulation of SIRT6 in mammalian cells, SIRT6 has functions in DNA repair, gene expression, telomeric maintenance, mitosis and meiosis, and protein networks, detailed overview	757931	
2.3.1.B41	physiological function	histone deacetylase SIRT6, one of the SIRT proteins, plays critical roles in controlling metabolism, genomic stability, inflammation, aging and cancer progression. SIRT6 regulates chemosensitivity in liver cancer cells via modulation of FOXO3 activity. SIRT6 interacts with FOXO3 and this interaction increases FOXO3 ubiquitination and decreases its stability. The effect of SIRT6 in preventing doxorubicin-induced cell death requires FOXO3. Overexpression of SIRT6 could not prevent doxorubicin-induced cell death in FOXO3 knockdown cells. SIRT6 plays a central role in determining doxorubicin-induced cell death via modulation of FOXO3 activity	757883	
2.3.1.B41	physiological function	histone deacetylase Sirtuin6 (Sirt6) has an essential role in the regulation of mitochondrial function in skeletal muscle and cardiomyocytes. Sirt6 also plays a specific role in mitochondrial homeostasis in podocytes. Analysis of the physiological function of Sirt6 in podocyte mitochondria and apoptosis under high-glucose conditions and mechanism, overview. Sirt6 suppresses high glucose-induced mitochondrial dysfunction and apoptosis in podocytes through AMPK activation	756973	
2.3.1.B41	physiological function	in gastrointestinal tumors, SIRT6 acts as a tumor suppressor, through different mechanisms, which include its ability to prevent the Warburg effect and genomic instability. In other types of tumors, including multiple myeloma and skin squamous cell carcinoma, high SIRT6 expression is associated with poor clinical outcome and may act pro-oncogenically. SIRT6 is involved in the regulation of a wide number of metabolic processes. SIRT6 deacetylase activity regulates the activity of NAD(P)(H) pools and nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage pathway from nicotinamide, in cancer cells. By controlling the biosynthesis of NAD+, NAMPT regulates the activity of NAD+-converting enzymes, such as CD38, poly-ADP-ribosepolymerases, and sirtuins (SIRTs). SIRT6 expression modulates the intracellular NADP(H) levels and G6PD activity. SIRT6 expression levels regulate NAD+ levels in different organs. SIRT6 regulates eNAMPT secretion. NAMPT is a direct substrate of SIRT6 deacetylation, with a mechanism that upregulates NAMPT enzymatic activity. SIRT6 affects intracellular NAMPT activity, boosts NAD(P)(H) levels, and protects against oxidative stress. In cancer, SIRT6 has been reported to play a context-dependent role. K53 is a key residue responsible for SIRT6-mediated upregulation of NAMPT activity, while K79 does not seem to be involved in SIRT6-mediated regulation of NAMPT enzymatic activity	756689	
2.3.1.B41	physiological function	neuroprotective functions for the histone deacetylase SIRT6. SIRT6 promotes DNA repair, but its activity declines with age, with a concomitant accumulation of DNA damage. SIRT6 regulates Tau protein stability and phosphorylation through increased activation of the kinase GSK3alpha/beta. SIRT6 is critical to maintain genomic stability in the brain and its loss leads to toxic Tau stability and phosphorylation. SIRT6 protects the brain from naturally accumulating DNA damage, in turn protecting against neurodegeneration	756392	
2.3.1.B41	physiological function	roles of SIRT6 and SIRT activators on the progression of atherosclerosis and ultimately on cardiac outcomes, such as myocardial infarction and mortality. Potential interactions of SIRTS with pathophysiological processes in atherosclerosis, overview	755918	
2.3.1.B41	physiological function	Sirt6 deacetylase activity regulates circadian rhythms via Per2. Sirt6 interacts with and deacetylates Per2, thus preventing its proteasomal degradation. SIRT6 regulates PER2 protein stability via the ubiquitin-proteasome pathway. Important function of Sirt6 in the direct regulation of TTFL and circadian rhythms. The deacetylase activity of SIRT6 is required for PER2 deacetylation	755978	
2.3.1.B41	physiological function	Sirt6 directly controls proliferation and differentiation of chondrocytes	730949	
2.3.1.B41	physiological function	SIRT6 downregulates the expression of mitogen-activated protein kinase pathway genes, signaling, and proliferation. In addition, inactivation of ERK2/p90RSK signaling triggered by high SIRT6 levels increases DNA repair via Chk1 and confers resistance to DNA damage	737930	
2.3.1.B41	physiological function	SIRT6 facilitates directional telomere movement upon oxidative damage. Oxidative damage at telomeres triggers directional telomere movement. The presence of the human Sir2 homologue, sirtuin 6 (SIRT6) is required for oxidative damage-induced telomeric movement. SIRT6 recruits the chromatin-remodeling protein SNF2H to damaged telomeres, which appears to promote chromatin decondensation independent of its deacetylase activity. SIRT6 is critical for directional movement in DNA damage repair. SIRT6 increases the short-term telomere mobility in response to telomere-specific oxidative damage. SIRT6 cooperates with SNF2H in the regulation of telomere chromatin structure, overview	758437	
2.3.1.B41	physiological function	SIRT6 histone deacetylase functions as a potential oncogene in human melanoma. Autophagy is important in melanoma and is associated with SIRT6. Increased SIRT6 expression may contribute to melanoma development and/or progression, potentially via senescence- and autophagy-related pathways	756871	
2.3.1.B41	physiological function	SIRT6 is a critical modulator of retinal function, likely through its effects on chromatin	730790	
2.3.1.B41	physiological function	Sirt6 is a critical regulator of endothelial senescence	729362	
2.3.1.B41	physiological function	SIRT6 is an ADP-ribosyltransferase and NAD+-dependent deacetylase of acetyl and long-chain fatty acyl groups, playing central roles in lipid and glucose metabolism. It is closely related to the occurrence of diabetes and obesity caused by overnutrition and aging. SIRT6 inhibits bovine preadipocyte differentiation and lipid synthesis, cooperating with SIRT5 to decrease lipid deposition, and repressed cell cycle arrest of preadipocytes. SIRT6 inhibits preadipocyte differentiation and lipid deposition by activating the adenosine monophosphate activated protein kinase alpha (AMPK?) pathway. SIRT6 may promote the proliferation of preadipocytes by inhibiting cell cycle arrest	755904	
2.3.1.B41	physiological function	SIRT6 is involved in mechanisms of stress protection. Function of SIRT6 in the maintenance of stress granules in response to stress	730101	
2.3.1.B41	physiological function	SIRT6 regulates metabolic homeostasis in skeletal muscle through activation of AMPK. AMPK mediates the SIRT6 effects. SIRT6 regulates AMPK activity and oxidation capacity in C2C12 myotubes	-, 755766	
2.3.1.B41	physiological function	SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. Function of SIRT6 in maintaining hMSC homeostasis by serving as a NRF2 coactivator, which represents another layer of regulation of oxidative stress-associated stem cell decay. SIRT6 is required for NRF2-depedent HO-1 expression in human mesenchymal stem cells (hMSCs)	756407	
2.3.1.B41	physiological function	SIRT6 seems to act as an oncogene, by virtue of its ability to promote DNA repair, cancer cell invasiveness and inflammation	757667	
2.3.1.B41	physiological function	sirtuin 6 (SIRT6) is involved in stress tolerance, DNA repair, inflammation, cancer, and life span. SIRT6 plays a protective role in fibrosis of different organs. It inhibits epithelial-to-mesenchymal transition during idiopathic pulmonary fibrosis. Also fibroblast-to-myofibroblast differentiation, which is characterized by increased expression of alpha-smooth muscle actin, is known to be involved in the pathogenesis of idiopathic pulmonary fibrosis. Analysis of the role of SIRT6 in the cellular model of fibroblast-to-myofibroblast differentiation induced by TGF-beta1 using human fetal lung fibroblasts (HFL1). Mechanistically, SIRT6 decreases phosphorylation and nuclear translocation of Smad2 under TGF-beta1 stimulation. SIRT6 interacts with the nuclear factor-kappaB (NF-kappaB) subunit p65 and represses TGF-beta1-induced NF-kappaB-dependent transcriptional activity, which is also dependent on its deacetylase activity. SIRT6 interacts with the nuclear factor-kappaB (NFkappaB) subunit p65 and represses TGF-beta1-induced NF-kappaB-dependent transcriptional activity, which is also dependent on its deacetylase activity	757294	
2.3.1.B41	physiological function	sirtuin 6 (SIRT6), a nicotinamide adenine dinucleotide-dependent deacetylase, participates in various age-related disorders, such as dyslipidemia and cardiovascular diseases. SIRT6 inhibits cholesterol crystal-induced vascular endothelial dysfunction via Nrf2 activation. Minute cholesterol crystals (CCs), which are generated after excess free cholesterol accumulation, form not only in mature atherosclerotic plaques but also extremely early in atherosclerosis. Endothelial dysfunction is an early feature of atherogenesis, role of SIRT6 in minute CC-induced endothelial dysfunction and the related mechanism, overview. SIRT6 rescues minute CC-induced endothelial dysfunction partly via Nrf2 activation	756672	
2.3.1.B41	physiological function	sirtuin 6 (SIRT6), a nicotinamide adenine dinucleotide-dependent deacetylase, participates in various age-related disorders, such as dyslipidemia and cardiovascular diseases. SIRT6 inhibits cholesterol crystal-induced vascular endothelial dysfunction via Nrf2 activation. Minute cholesterol crystals (CCs), which are generated after excess free cholesterol accumulation, form not only in mature atherosclerotic plaques but also extremely early in atherosclerosis. Endothelial dysfunction is an early feature of atherogenesis, role of SIRT6 in minute CC-induced endothelial dysfunction and the related mechanism, overview. SIRT6 rescues minute CC-induced endothelial dysfunction partly via Nrf2 activation. SIRT6 can protect HUVECs from minute CC-induced endothelial dysfunction	756672	
2.3.1.B41	physiological function	sirtuin 6 protects the heart from hypoxic damage. The protective mechanism of sirtuin 6 overexpression includes the activation of pAMPKalpha pathway, the increased proteinlevel of B-cell lymphoma 2, the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells, the decrease of reactive oxygen species, and the reduction in the protein level of phosphor-protein kinase B during hypoxia	738170	
2.3.1.B41	physiological function	sirtuin family members function as NAD+-dependent deacetylases that are essential for tumor metastasis and epithelial-mesenchymal transition (EMT). EMT is a pivotal mechanism involved in tumor metastasis, which is the leading cause of poor prognosis for hepatocellular carcinoma (HCC). Increased sirtuin6 expression in hepatocellular carcinoma is associated with the poor prognosis. Sirtuin6 (SIRT6) promotes the EMT of hepatocellular carcinoma by stimulating autophagic degradation of E-cadherin via the lysosomal pathway. SIRT6 deacetylates Beclin-1 in HCC cells and this event leads to the promotion of the autophagic degradation of E-cadherin. E-cadherin degradation, invasion, and migration induced by SIRT6 overexpression can be rescued by dual mutation of Beclin-1 (inhibition of acetylation), CQ (autophagy inhibitor), and knockdown of Atg7. In addition, SIRT6 promotes N-cadherin and Vimentin expression via deacetylating FOXO3a in HCC. An increased vimentin and N-cadherin expression can be observed after SIRT6 is upregulated in Hep3B and LO2 cells. In MHCC-97H cells, downregulated SIRT6 causes opposite results	757644	
2.3.1.B41	physiological function	sirtuin6 (SIRT6) is an NAD+-dependent deacetylase that targets a variety of proteins to regulate cellular processes and activities. Sirtuin family members are essential for tumor metastasis and epithelial-mesenchymal transition (EMT). Analysis of the mechanism by which SIRT6 facilitates EMT and metastasis, mechanism, overview. SIRT6 promotes HCC cell migration, invasion, and EMT. SIRT6 deacetylates Beclin-1 in HCC cells and this event leads to the promotion of the autophagic degradation of E-cadherin. SIRT6 also promotes N-cadherin and Vimentin expression via deacetylating FOXO3a in HCC. SIRT6 promotes the E-cadherin degradation in HCC via the lysosomal pathway, SIRT6 promotes the autophagic degradation of E-cadherin by deacetylating Beclin-1	757530	
2.3.1.B41	physiological function	Sirtuins (SIRTs) are NAD+-dependent deacylases that play a key role in transcription, DNA repair, metabolism, and oxidative stress resistance. Enhanced SIRT6 activity abrogates the neurotoxic phenotype of astrocytes expressing amyotrophic lateral sclerosis (ALS)-linked mutant SOD1. SIRT6 induces ARE-driven gene expression in astrocytes. And SIRT6 induces HO-1 and SRXN1 expression in astrocytes. Involvement of an additional protective pathway linking NMN treatment and increased SIRT6 activity to Nrf2 activation and upregulation of antioxidant defenses in astrocytes, overview	756691	
2.3.1.B41	physiological function	sirtuins are protein deacylases regulating metabolism and stress responses, and are implicated in aging-related diseases. Sirtuin 6 (Sirt6)-dependent deacetylation of peptide substrates and complete nucleosomes activets by pyrrolo[1,2-a]quinoxaline derivatives	755787	
2.3.1.B41	physiological function	sirtuins can deacetylate histones, and can deacetylate diverse protein substrates and regulate many processes, including metabolism and cellular stress response. Each sirtuin uniquely accommodates varying long-chain acyl substrates. SIRT6, for example, has an elongated hydrophobic pocket and is hundreds-fold more catalytically efficient toward long-chain (e.g. myristoylated) peptide substrates compared with acetylated peptide substrates	757236	
2.3.1.B41	physiological function	the enzyme controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine	739132	
2.3.1.B41	physiological function	the enzyme deacetylates histone H3-Lys18 at pericentric chromatin to prevent mitotic errors and cellular senescence	739158	
2.3.1.B41	physiological function	the enzyme is a key modulator in the phenotypic conversion of cardiac fibroblasts to myofibroblasts	739733	
2.3.1.B41	physiological function	the enzyme regulates the expression of surface antigens to evade the detection by host immune surveillance. The physiological function of PfSir2A in antigen variation may be achieved by removing medium and long chain fatty acyl groups from protein lysine residues	-, 728852	
2.3.1.B41	physiological function	the NAD+-dependent lysine deacylases, called sirtuins, are implicated in regulation of wide variety of biological functions ranging from cellular growth, stress-resistance, metabolism, genome stability to aging. Histone deacetylase SIRT6 blocks myostatin expression and development of muscle atrophy. SIRT6 controls myostatin (Mstn) expression by attenuating NF-kappaB binding to the Mstn promoter. Role for SIRT6 in maintaining muscle mass by controlling expression of atrophic factors like Mstn and activin	758395	
2.3.1.B41	physiological function	the upregulation of SIRT6 expression is required for transforming growth factor-beta1 and H2O2 /HOCl reactive oxygen species to promote the tumorigenicity of hepatocellular carcinoma cells. The enzyme contributes to inhibitory effect of ERK pathway on cellular senescence	737977