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Literature summary extracted from

  • Chang, A.; Ferrer, C.; Mostoslavsky, R.
    SIRT6, a mammalian deacylase with multitasking abilities (2020), Physiol. Rev., 100, 145-169 .
    View publication on PubMedView publication on EuropePMC

Activating Compound

EC Number Activating Compound Comment Organism Structure
2.3.1.B41 additional information binding of free fatty acids to SIRT6 significantly enhances SIRT6's in vitro histone deacetylase activity Mus musculus
2.3.1.B41 additional information binding of free fatty acids to SIRT6 significantly enhances SIRT6's in vitro histone deacetylase activity. Given Sirt6 critical roles in multiple molecular pathways, including DNA repair, telomere maintenance, glycolysis, gluconeogenesis, lipid metabolism, inflammation, and tumor suppression, it is clear that attempts to enhance the activity of SIRT6 could provide therapeutic benefits, development of SIRT6 activators, overview Homo sapiens

Application

EC Number Application Comment Organism
2.3.1.B41 medicine the enzyme is a potential therapeutic target for therapy of cancer and other metabolic diseases Homo sapiens
2.3.1.B41 medicine the enzyme is a potential therapeutic target for therapy of cancer and other metabolic diseases Mus musculus

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
2.3.1.B41 nucleus
-
 Homo sapiens 5634
-
2.3.1.B41 nucleus
-
 Mus musculus 5634
-

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.3.1.B41 additional information Mus musculus SIRT6 is a specific deacetylase for H3K9, see EC 2.3.1.286. It also deacetylates H3K56 and H3K18, as well as KAP1, CtIP, PGC-1alpha, TRF2, GCN5, SNF2H, and PKM2 ?
-
-
2.3.1.B41 additional information Homo sapiens SIRT6 is a specific deacetylase for H3K9, see EC 2.3.1.286. It also deacetylates H3K56 and H3K18, as well as KAP1, CtIP, PGC-1alpha, TRF2, GCN5, SNF2H, and PKM2, cf. EC 2.3.1.286 ?
-
-
2.3.1.B41 NAD+ + [protein]-N6-palmitoyl-L-lysine Homo sapiens
-
 nicotinamide + [protein]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
 ?
2.3.1.B41 NAD+ + [protein]-N6-palmitoyl-L-lysine Mus musculus
-
 nicotinamide + [protein]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
 ?
2.3.1.B41 NAD+ + [TNF-alpha]-N6-palmitoyl-L-lysine Homo sapiens
-
 nicotinamide + [TNF-alpha]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
 ?
2.3.1.B41 NAD+ + [TNF-alpha]-N6-palmitoyl-L-lysine Mus musculus
-
 nicotinamide + [TNF-alpha]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
2.3.1.B41 Homo sapiens Q8N6T7
-
-
2.3.1.B41 Mus musculus P59941
-
-

Posttranslational Modification

EC Number Posttranslational Modification Comment Organism
2.3.1.B41 additional information SIRT6 SUMOylation appears to specifically regulate SIRT6 deacetylation on H3K56 but not H3K9 Homo sapiens
2.3.1.B41 additional information SIRT6 SUMOylation appears to specifically regulate SIRT6 deacetylation on H3K56 but not H3K9 Mus musculus

Source Tissue

EC Number Source Tissue Comment Organism Textmining
2.3.1.B41 embryo
-
 Mus musculus
-
2.3.1.B41 neural stem cell
-
 Homo sapiens
-
2.3.1.B41 neural stem cell
-
 Mus musculus
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.3.1.B41 additional information SIRT6 is a specific deacetylase for H3K9, see EC 2.3.1.286. It also deacetylates H3K56 and H3K18, as well as KAP1, CtIP, PGC-1alpha, TRF2, GCN5, SNF2H, and PKM2 Mus musculus ?
-
-
2.3.1.B41 additional information SIRT6 is a specific deacetylase for H3K9, see EC 2.3.1.286. It also deacetylates H3K56 and H3K18, as well as KAP1, CtIP, PGC-1alpha, TRF2, GCN5, SNF2H, and PKM2, cf. EC 2.3.1.286 Homo sapiens ?
-
-
2.3.1.B41 additional information SIRT6 can undergo intramolecular mono-ADP-ribosylation utilizing NAD+ as a substrate, i.e. mono-ADP-ribosylation. SIRT6 also performs ADP-ribosyl transferase activity on other protein substrates, overview. Weak deacetylase activity of SIRT6 in vitro Homo sapiens ?
-
-
2.3.1.B41 additional information SIRT6 can undergo intramolecular mono-ADP-ribosylation utilizing NAD+ as a substrate. Purified mouse SIRT6 successfully catalyzes the transfer of radiolabel from [32P]NAD+ onto itself, i.e. mono-ADP-ribosylation. also performs ADP-ribosyl transferase activity on other protein substrates, overview. Weak deacetylase activity of SIRT6 in vitro Mus musculus ?
-
-
2.3.1.B41 NAD+ + [protein]-N6-palmitoyl-L-lysine
-
 Homo sapiens nicotinamide + [protein]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
 ?
2.3.1.B41 NAD+ + [protein]-N6-palmitoyl-L-lysine
-
 Mus musculus nicotinamide + [protein]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
 ?
2.3.1.B41 NAD+ + [TNF-alpha]-N6-palmitoyl-L-lysine
-
 Homo sapiens nicotinamide + [TNF-alpha]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
 ?
2.3.1.B41 NAD+ + [TNF-alpha]-N6-palmitoyl-L-lysine
-
 Mus musculus nicotinamide + [TNF-alpha]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
 ?

Synonyms

EC Number Synonyms Comment Organism
2.3.1.B41 ADP-ribosyl transferase
-
 Homo sapiens
2.3.1.B41 ADP-ribosyl transferase
-
 Mus musculus
2.3.1.B41 chromatin deacylase
-
 Homo sapiens
2.3.1.B41 chromatin deacylase
-
 Mus musculus
2.3.1.B41 deacylase
-
 Homo sapiens
2.3.1.B41 deacylase
-
 Mus musculus
2.3.1.B41 histone deacetylase
-
 Homo sapiens
2.3.1.B41 histone deacetylase
-
 Mus musculus
2.3.1.B41 More see also EC 2.3.1.286 Homo sapiens
2.3.1.B41 More see also EC 2.3.1.286 Mus musculus
2.3.1.B41 SIRT6
-
 Homo sapiens
2.3.1.B41 SIRT6
-
 Mus musculus

Cofactor

EC Number Cofactor Comment Organism Structure
2.3.1.B41 NAD+
-
 Homo sapiens
2.3.1.B41 NAD+
-
 Mus musculus

Expression

EC Number Organism Comment Expression
2.3.1.B41 Mus musculus several factors regulate the expression of the SIRT6 gene. PARP1 may inhibit the expression of SIRT6, and the presence of PJ-34, a PARP1 inhibitor, results in enhanced mRNA level of nuclear SIRT6. A role for the transcription factor E2F1 as an enhancer of glycolysis and inhibitor of the expression of SIRT6. E2F1 directly binds the SIRT6 promoter and suppresses SIRT6 promoter activity under both normoxic and hypoxic culture conditions. In embryos and neural stem cells, SIRT6 expression becomes suppressed by maternal diabetes in vivo or high glucose in vitro through oxidative stress down
2.3.1.B41 Homo sapiens several factors regulate the expression of the SIRT6 gene. PARP1 may inhibit the expression of SIRT6, and the presence of PJ-34, a PARP1 inhibitor, results in enhanced mRNA level of nuclear SIRT6. A role for the transcription factor E2F1 as an enhancer of glycolysis and inhibitor of the expression of SIRT6. E2F1 directly binds the SIRT6 promoter and suppresses SIRT6 promoter activity under both normoxic and hypoxic culture conditions. In neural stem cells, SIRT6 expression becomes suppressed by maternal diabetes in vivo or high glucose in vitro through oxidative stress down
2.3.1.B41 Homo sapiens several factors regulate the expression of the SIRT6 gene. Notably, in a tumor-suppressing pathway, c-FOS binds to an AP-1 binding site (TAAGTCA) at the SIRT6 promoter, activating SIRT6 gene expression. In addition to the positive regulators of SIRT6, various chromatin factors negatively control the gene expression of SIRT6. presence of PJ-34, a PARP1 inhibitor, results in enhanced mRNA level of nuclear SIRT6 up
2.3.1.B41 Mus musculus several factors regulate the expression of the SIRT6 gene. Notably, in a tumor-suppressing pathway, c-FOS binds to an AP-1 binding site (TAAGTCA) at the SIRT6 promoter, activating SIRT6 gene expression. In addition to the positive regulators of SIRT6, various chromatin factors negatively control the gene expression of SIRT6. presence of PJ-34, a PARP1 inhibitor, results in enhanced mRNA level of nuclear SIRT6 up

General Information

EC Number General Information Comment Organism
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 Homo sapiens
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 Mus musculus
2.3.1.B41 additional information the extended NH2-terminal loop of SIRT6 covers the NAD+- and acyl-substrate binding sites Homo sapiens
2.3.1.B41 additional information the extended NH2-terminal loop of SIRT6 covers the NAD+- and acyl-substratebinding sites Mus musculus
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 Homo sapiens
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 Mus musculus