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Information on EC 2.3.1.B41 - protein-long-chain fatty-acyl-lysine deacylase (NAD+) and Organism(s) Homo sapiens and UniProt Accession Q8N6T7
for references in articles please use BRENDA:EC2.3.1.B41preliminary BRENDA-supplied EC number
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EC Tree
2.3.1.B41 protein-long-chain fatty-acyl-lysine deacylase (NAD+)Specify your search results
Word Map
- 2.3.1.B41
- sirtuins
-
deacetylation
-
adp-ribosylation
- deacetylases
- cardiac
-
longevity
- sirt5
-
lifespan
- tnf
- cardiovascular
-
telomere
-
sirt1-7
- tumorigenesis
- adprt
- medicine
-
senescence-associated
- resveratrol
-
h3k56ac
- d-tyrosine
- adp-ribose
-
forkhead
-
ribosylation
-
anti-aging
- nampt
-
foxo3a
-
mono-adp-ribosylation
-
aging-associated
- adp-ribosyltransferase
-
aging-related
-
hyperacetylation
- 3-aminobenzamide
- ceramidase
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Archaea, Eukaryota
The expected taxonomic range for this enzyme is: Archaea, Eukaryota
Reaction Schemes
Synonyms
sirt6, deacylase, sirtuin 6, adp-ribosyl transferase, nad+-dependent histone deacetylase, nicotinamide adenine dinucleotide-dependent deacetylase, sirtuin-6, sirtuin6, sirt6 deacetylase, histone deacetylase sirtuin 6, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
SIRT6
-
sirtuin 6
-
additional information
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
NAD+ + [protein]-N6-palmitoyl-L-lysine = nicotinamide + [protein]-L-lysine + 2'-O-palmitoyl-ADP ribose
the enzyme prefers long chain fatty acyl groups
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
NAD+ + Ac-AK(N6-acetyl)K-7-amido-4-methylcoumarin
nicotinamide + Ac-AKK-7-amido-4-methylcoumarin + 2'-O-acetyl-ADP-ribose
the substrate is based on the human tumour suppressor protein p53
-
-
?
NAD+ + Ac-HK(N6-acetyl)K-7-amido-4-methylcoumarin
nicotinamide + Ac-HKK-7-amido-4-methylcoumarin + 2'-O-acetyl-ADP-ribose
the substrate is based on the human tumour suppressor protein p53
-
-
?
NAD+ + Ac-RHK(N6-acetyl)K-7-amido-4-methylcoumarin
nicotinamide + Ac-RHKK-7-amido-4-methylcoumarin + 2'-O-acetyl-ADP-ribose
the substrate is based on the amino acids 379-382 of the human tumour suppressor protein p53
-
-
?
NAD+ + Ac-RYQ(N6-acetyl)K-7-amido-4-methylcoumarin
nicotinamide + Ac-RYQK-7-amido-4-methylcoumarin + 2'-O-acetyl-ADP-ribose
the peptide substrate mimics the biological deacetylation site of histone H3 K56
-
-
?
NAD+ + Ac-TAR(N6-acetyl)K-7-amido-4-methylcoumarin
nicotinamide + Ac-TARK-7-amido-4-methylcoumarin + 2'-O-acetyl-ADP-ribose
the peptide substrate mimics the biological deacetylation site of histone H3 K9
-
-
?
NAD+ + QTAR(N6-dodecanoyl)KSTGG
nicotinamide + QTARKSTGG + 2'-O-dodecanoyl-ADP-ribose
dodecanoylated histone H3 peptide, about 60% compared to the activity with the decanoylated peptide
-
-
?
NAD+ + QTAR(N6-hexanoyl)KSTGG
nicotinamide + QTARKSTGG + 2'-O-hexanoyl-ADP-ribose
hexanoylated histone H3 peptide, about 20% compared to the activity with the decanoylated peptide
-
-
?
NAD+ + QTAR(N6-octanoyl)KSTGG
nicotinamide + QTARKSTGG + 2'-O-octanoyl-ADP-ribose
octanoylated histone H3 peptide, about 50% compared to the activity with the decanoylated peptide
-
-
?
NAD+ + [histone 3]-N6-acetyl-L-lysine9
nicotinamide + [histone 3]-L-lysine + 2'-O-acetyl-ADP ribose
-
-
-
?
NAD+ + [histone 3]-N6-palmitoyl-L-lysine
nicotinamide + [histone 3]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
-
-
?
NAD+ + [histone H3 peptide]-N6-acetyl-L-lysine
nicotinamide + [histone H3 peptide]-L-lysine + 2'-O-acetyl-ADP-ribose
-
-
-
?
NAD+ + [histone H3 peptide]-N6-acetyl-L-lysine18
nicotinamide + [histone H3 peptide]-L-lysine18 + 2'-O-acetyl-ADP-ribose
-
-
-
?
NAD+ + [histone H3 peptide]-N6-acetyl-L-lysine9
nicotinamide + [histone H3 peptide]-L-lysine9 + 2'-O-acetyl-ADP-ribose
-
-
-
?
NAD+ + [histone H3 peptide]-N6-butyryl-L-lysine
nicotinamide + [histone H3 peptide]-L-lysine + 2'-O-butyryl-ADP-ribose
-
-
-
?
NAD+ + [histone H3 peptide]-N6-myristoyl-L-lysine
nicotinamide + [histone H3 peptide]-L-lysine + 2'-O-myristoyl-ADP-ribose
-
-
-
?
NAD+ + [histone H3 peptide]-N6-octanoyl-L-lysine
nicotinamide + [histone H3 peptide]-L-lysine + 2'-O-octanoyl-ADP-ribose
-
-
-
?
NAD+ + [histone H3 peptide]-N6-palmitoyl-L-lysine
nicotinamide + [histone H3 peptide]-L-lysine + 2'-O-palmitoyl-ADP-ribose
-
-
-
?
NAD+ + [histone H3]-N6-acetyl-L-lysine
nicotinamide + [histone H3]-L-lysine + 2'-O-acetyl-ADP ribose
-
-
-
?
NAD+ + [histone H3]-N6-acetyl-L-lysine
nicotinamide + [histone H3]-L-lysine + 2'-O-acetyl-ADP-ribose
NAD+ + [histone H3]-N6-acetyl-L-lysine18
nicotinamide + [histone H3]-L-lysine + 2'-O-acetyl-ADP ribose
-
-
-
?
NAD+ + [histone H3]-N6-acetyl-L-lysine9
nicotinamide + [histone H3]-L-lysine + 2'-O-acetyl-ADP ribose
NAD+ + [histone H3]-N6-myristoyl-L-lysine
nicotinamide + [histone H3]-L-lysine + 2'-O-myristoyl-ADP ribose
-
-
-
?
NAD+ + [histone H3]-N6-palmitoyl-L-lysine
nicotinamide + [histone H3]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
-
-
?
NAD+ + [histone H3]-N6-palmitoyl-L-lysine9
nicotinamide + [histone H3]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
-
-
?
NAD+ + [histone H4]-N6-acetyl-L-lysine
nicotinamide + [histone H4]-L-lysine + 2'-O-acetyl-ADP-ribose
NAD+ + [protein]-N6-palmitoyl-L-lysine
nicotinamide + [protein]-L-lysine + 2'-O-palmitoyl-ADP ribose
NAD+ + [synthetic tumor necrosis factor alpha peptide]-N6-myristoyl-L-lysine19
nicotinamide + [synthetic tumor necrosis factor alpha peptide]-L-lysine19 + 2'-O-myristoyl-ADP-ribose
-
-
-
?
NAD+ + [synthetic tumor necrosis factor alpha peptide]-N6-myristoyl-L-lysine20
nicotinamide + [synthetic tumor necrosis factor alpha peptide]-L-lysine20 + 2'-O-myristoyl-ADP-ribose
-
-
-
?
NAD+ + [TNF-alpha]-N6-palmitoyl-L-lysine
nicotinamide + [TNF-alpha]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
-
-
?
NAD+ + [tumor necrosis factor alpha]-N6-acyl-L-lysine20
nicotinamide + [tumor necrosis factor alpha]-L-lysine20 + 2'-O-acyl-ADP-ribose
SIRT6 promotes the secretion of tumor necrosis factor alpha by removing the fatty acyl modification on K19 and K20 of TNFalpha
-
-
?
NAD+ + [tumor necrosis factor alpha]-N6-myristoyl-L-lysine
nicotinamide + [tumor necrosis factor alpha]-L-lysine + 2'-O-myristoyl-ADP-ribose
-
-
-
?
NAD+ + [tumor necrosis factor-alpha]-N6-acetyl-L-lysine9
nicotinamide + [tumor necrosis factor-alpha]-L-lysine + 2'-O-acetyl-ADP ribose
-
-
-
?
NAD+ + [protein]-N6-palmitoyl-L-lysine
nicotinamide + [protein]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
-
-
-
?
NAD+ + QTAR(N6-decanoyl)KSTGG
nicotinamide + QTARKSTGG + 2'-O-decanoyl-ADP-ribose
-
-
-
?
NAD+ + QTAR(N6-decanoyl)KSTGG
nicotinamide + QTARKSTGG + 2'-O-decanoyl-ADP-ribose
myristoylated histone H3 peptide, about 60% compared to the activity with the decanoylated peptide
-
-
?
NAD+ + [histone H3]-N6-acetyl-L-lysine
nicotinamide + [histone H3]-L-lysine + 2'-O-acetyl-ADP-ribose
-
-
-
?
NAD+ + [histone H3]-N6-acetyl-L-lysine
nicotinamide + [histone H3]-L-lysine + 2'-O-acetyl-ADP-ribose
the enzyme deacetylates histones H3 and H4 when they are packaged as nucleosomes, but not as free histones
-
-
?
NAD+ + [histone H3]-N6-acetyl-L-lysine9
nicotinamide + [histone H3]-L-lysine + 2'-O-acetyl-ADP ribose
-
-
-
?
NAD+ + [histone H3]-N6-acetyl-L-lysine9
nicotinamide + [histone H3]-L-lysine + 2'-O-acetyl-ADP ribose
-
-
-
-
?
NAD+ + [histone H4]-N6-acetyl-L-lysine
nicotinamide + [histone H4]-L-lysine + 2'-O-acetyl-ADP-ribose
-
-
-
?
NAD+ + [histone H4]-N6-acetyl-L-lysine
nicotinamide + [histone H4]-L-lysine + 2'-O-acetyl-ADP-ribose
the enzyme deacetylates histones H3 and H4 when they are packaged as nucleosomes, but not as free histones
-
-
?
NAD+ + [protein]-N6-palmitoyl-L-lysine
nicotinamide + [protein]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
-
-
?
NAD+ + [protein]-N6-palmitoyl-L-lysine
nicotinamide + [protein]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
-
-
-
?
NAD+ + [protein]-N6-palmitoyl-L-lysine
nicotinamide + [protein]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
-
-
?
additional information
?
-
no or very low activity with QTAR(N6-acetyl)KSTGG, QTAR(N6-propionyl)KSTGG, QTAR(N6-succinyl)KSTGG, QTAR(N6-butyryl)KSTGG, QTAR(N6-crotonyl)KSTGG
-
-
?
additional information
?
-
Sirt6 prefers long chain fatty acyl groups. Low deacetylase activity on histone H3 K9 and histone H3 K56. Selectivity for peptide sequence is not high
-
-
?
additional information
?
-
-
Sirt6 prefers long chain fatty acyl groups. Low deacetylase activity on histone H3 K9 and histone H3 K56. Selectivity for peptide sequence is not high
-
-
?
additional information
?
-
the enzyme preferentially hydrolyzes long-chain fatty acyl groups over acetyl groups in vitro
-
-
?
additional information
?
-
acetylation of nicotinamide phosphoribosyltransferase, i.e. NAMPT, on residue K53 by SIRT6
-
-
-
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
-
-
-
additional information
?
-
sirtuin6 performs H3K9 acetylation on histone H3, cf. EC 2.3.1.286
-
-
-
additional information
?
-
a myristoyl peptide and a palmitoyl peptide are incubated with sirtuin6. Sirtuin6 exhibits both SIRT6 deacetylase and deacylase activities, cf. EC 2.3.1.286
-
-
-
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
-
-
-
additional information
?
-
Sirt6-dependent deacetylation of H3K18 and H3K9 in a histone protein preparation and in HeLa nucleosomes
-
-
-
additional information
?
-
-
Sirt6-dependent deacetylation of H3K18 and H3K9 in a histone protein preparation and in HeLa nucleosomes
-
-
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
NAD+ + [histone 3]-N6-palmitoyl-L-lysine
nicotinamide + [histone 3]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
-
-
?
NAD+ + [histone H3 peptide]-N6-acetyl-L-lysine18
nicotinamide + [histone H3 peptide]-L-lysine18 + 2'-O-acetyl-ADP-ribose
-
-
-
?
NAD+ + [histone H3 peptide]-N6-acetyl-L-lysine9
nicotinamide + [histone H3 peptide]-L-lysine9 + 2'-O-acetyl-ADP-ribose
-
-
-
?
NAD+ + [histone H3]-N6-acetyl-L-lysine
nicotinamide + [histone H3]-L-lysine + 2'-O-acetyl-ADP-ribose
-
-
-
?
NAD+ + [histone H3]-N6-acetyl-L-lysine18
nicotinamide + [histone H3]-L-lysine + 2'-O-acetyl-ADP ribose
-
-
-
?
NAD+ + [histone H3]-N6-acetyl-L-lysine9
nicotinamide + [histone H3]-L-lysine + 2'-O-acetyl-ADP ribose
-
-
-
?
NAD+ + [histone H3]-N6-palmitoyl-L-lysine9
nicotinamide + [histone H3]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
-
-
?
NAD+ + [histone H4]-N6-acetyl-L-lysine
nicotinamide + [histone H4]-L-lysine + 2'-O-acetyl-ADP-ribose
-
-
-
?
NAD+ + [protein]-N6-palmitoyl-L-lysine
nicotinamide + [protein]-L-lysine + 2'-O-palmitoyl-ADP ribose
NAD+ + [TNF-alpha]-N6-palmitoyl-L-lysine
nicotinamide + [TNF-alpha]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
-
-
?
NAD+ + [tumor necrosis factor alpha]-N6-acyl-L-lysine20
nicotinamide + [tumor necrosis factor alpha]-L-lysine20 + 2'-O-acyl-ADP-ribose
SIRT6 promotes the secretion of tumor necrosis factor alpha by removing the fatty acyl modification on K19 and K20 of TNFalpha
-
-
?
NAD+ + [protein]-N6-palmitoyl-L-lysine
nicotinamide + [protein]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
-
-
-
?
NAD+ + [protein]-N6-palmitoyl-L-lysine
nicotinamide + [protein]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
-
-
?
NAD+ + [protein]-N6-palmitoyl-L-lysine
nicotinamide + [protein]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
-
-
-
?
NAD+ + [protein]-N6-palmitoyl-L-lysine
nicotinamide + [protein]-L-lysine + 2'-O-palmitoyl-ADP ribose
-
-
-
?
additional information
?
-
the enzyme preferentially hydrolyzes long-chain fatty acyl groups over acetyl groups in vitro
-
-
?
additional information
?
-
acetylation of nicotinamide phosphoribosyltransferase, i.e. NAMPT, on residue K53 by SIRT6
-
-
-
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
-
-
-
additional information
?
-
sirtuin6 performs H3K9 acetylation on histone H3, cf. EC 2.3.1.286
-
-
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(4R)-1-[(benzyloxy)carbonyl]-4-hydroxy-L-prolyl-N6-ethanethioyl-N-phenyl-L-lysinamide
0.2 mM, 56% inhibition, substrate: Ac-RYQ(N6-acetyl)K-7-amido-4-methylcoumarin
(9H-fluoren-9-yl)methyl(6-acetamido-1-(dodecylamino)-1-oxohexan-2-yl)carbamate
-
(9H-fluoren-9-yl)methyl(6-acetamido-1-(dodecylamino)-1-oxohexanyl) carbamate
-
1-(tert-butoxycarbonyl)-L-prolyl-N6-ethanethioyl-N-phenyl-L-lysinamide
0.2 mM, 32% inhibition, substrate: Ac-RYQ(N6-acetyl)K-7-amido-4-methylcoumarin
2,4-dioxo-N-(4-(pyridin-3-yloxy)phenyl)-1,2,3,4-tetrahydroquinazoline-6-sulfonamide
i.e. compound Q, a SIRT6 inhibitor with quinazolinedione-like structure, which reduces both SIRT6 deacetylase and deacylase activities
4-phenyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline
-
5-(phenylsulfonyl)-4-(pyridin-3-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline
-
6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide
i.e. EX-527. 0.2 mM, 56% inhibition, substrate: Ac-RYQ(N6-acetyl)K-7-amido-4-methylcoumarin
methyl N2-acetyl-N6-ethanethioyl-L-lysyl-L-alaninate
0.2 mM, 20% inhibition, substrate: Ac-RYQ(N6-acetyl)K-7-amido-4-methylcoumarin
N-[(5S)-5-acetamido-6-(dodecylamino)-6-oxohexyl]-N,N-dimethylmethanaminium
-
N2-[(benzyloxy)carbonyl]-N6-ethanethioyl-N-(2-fluorophenyl)-L-lysinamide
0.2 mM, 25% inhibition, substrate: Ac-RYQ(N6-acetyl)K-7-amido-4-methylcoumarin
N2-[(benzyloxy)carbonyl]-N6-ethanethioyl-N-pyridin-3-yl-L-lysinamide
0.2 mM, 54% inhibition, substrate: Ac-RYQ(N6-acetyl)K-7-amido-4-methylcoumarin
N2-[(benzyloxy)carbonyl]-N6-ethanethioyl-N-[2-(4-methoxyphenyl)-2-oxoethyl]-L-lysinamide
0.2 mM, 48% inhibition, substrate: Ac-RYQ(N6-acetyl)K-7-amino-4-methylcoumarin
N6-ethanethioyl-N-(2-oxo-2-phenylethyl)-N2-(3-phenylpropanoyl)-L-lysinamide
0.2 mM, 20% inhibition, substrate: Ac-RYQ(N6-acetyl)K-7-amido-4-methylcoumarin
N6-ethanethioyl-N-phenyl-N2-[3-(pyridin-3-yl)propanoyl]-L-lysinamide
0.2 mM, 18% inhibition, substrate: Ac-RYQ(N6-acetyl)K-7-amido-4-methylcoumarin
N6-ethanethioyl-N2-(3-phenylpropanoyl)-L-lysyl-L-alanine
0.2 mM, 20% inhibition, substrate: Ac-RYQ(N6-acetyl)K-7-amido-4-methylcoumarin
N6-ethanethioyl-N2-[3-(2-fluorophenyl)propanoyl]-N-pyridin-3-yl-L-lysinamide
0.2 mM, 58% inhibition, substrate: Ac-RYQ(N6-acetyl)K-7-amino-4-methylcoumarin
trichostatin A
TSA, a potent, zinc-chelating hydroxamate inhibitors of zinc-dependent deacylases, which potently and isoform-specifically inhibits Sirt6. Sirtuin 6 inhibition mechanism, structural basis and interaction analysis, detailed overview. The binding site are nicotinamide pocket and acyl channel, binding kinetics
quercetin
0.2 mM, 52% inhibition, substrate: Ac-RYQ(N6-acetyl)K-7-amido-4-methylcoumarin
additional information
not inhibited by linoleic acid, oleic acid, oleoylethanolamide, and myristoylethanolamide
-
additional information
identification of SIRT6 inhibitors that decrease SIRT6 deacetylase activity and evoke coherent biological effects in cells. These inhibitors include a family of compounds with a quinazolinedione-based structure and a family of compounds with salicylate-based structure, with an IC50 for the SIRT6-catalyzed deacetylase activity in the low micromolar range. Relative enzyme activity in presencee of inhibitors compared to control, overview. No inhibition by (9H-fluoren-9-yl)methyl [(2S)-6-[(tert-butoxycarbonyl)amino]-1-(dodecylamino)-1-oxohexan-2-yl]carbamate and tert-butyl [(5S)-5-acetamido-6-(dodecylamino)-6-oxohexyl]carbamate
-
additional information
preparation of the 4-substituited-4,5-dihydropyrrolo[1,2-a]quinoxalines and 4-substituited-pyrrolo[1,2-a]quinoxalines
-
additional information
-
preparation of the 4-substituited-4,5-dihydropyrrolo[1,2-a]quinoxalines and 4-substituited-pyrrolo[1,2-a]quinoxalines
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1-(5-((3-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[1,2-a]quinoxalin-4-yl)naphthalen-2-ol
-
2-(3-chloro-(4-benzamido)phenyl)-1,3-dioxoisoindoline-5-carboxylic acid
i.e. CL-5A
2-(3-chloro-4-(2,4,6-trichloro-N-(2,4,6-trichlorobenzoyl)benzamido)phenyl)-1,3-dioxoisoindoline-5-carboxylic acid
i.e. CL5D, SIRT6 displays ordered binding and CL5D does not improve H3K9ac binding
2-(3-chloro-4-(2,4-dichlorobenzamido)phenyl)-1,3-dioxoisoindoline-5-carboxylic acid
i.e. CL-4
2-(3-chloro-4-(4-chlorobenzamido)phenyl)-1,3-dioxoisoindoline-5-carboxylic acid
i.e. CL-5B
4-(pyridin-3-yl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline
-
additional information
the enzyme activity is not stimulated by N-stearoylethanolamine and N-arachidonoylethanolamine
-
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
-
additional information
screening for SIRT6 activator small molecules, dose-response and Michaelis-Menten parameters of activation by the SIRT6 activators, overview. Structure-activity relationship analysis yields activators with improved potency and selectivity for SIRT6. Enzyme residue Arg65 is critical for activation by facilitating a conformational step that initiates chemical catalysis. Arg65 mediates a conformational change after substrate binding and that the rate of this change is enhanced by small-molecule activation of deacetylation and during demyristoylation
-
additional information
structural basis of sirtuin 6 activation by synthetic small molecules, overview. Synthesis and screening of pyrrolo[1,2-a]quinoxaline derivatives, yielding synthetic Sirt6 activators performing direct, substrate-independent compound binding to the Sirt6 catalytic core and potent activation of Sirt6-dependent deacetylation of peptide substrates and complete nucleosomes. Crystal structures of Sirt6/activator complexes reveal that the compounds bind to a Sirt6-specific acyl channel pocket and identify key interactions. Weak and possibly non-specific activating effects are also reported for the plant metabolite fatty acids (Sirt6). Preparation of the 4-substituited-4,5-dihydropyrrolo[1,2-a]quinoxalines and 4-substituited-pyrrolo[1,2-a]quinoxalines. Sirt6 activator-binding site and mechanism, microscale thermophoresis binding experiments, overview
-
additional information
-
structural basis of sirtuin 6 activation by synthetic small molecules, overview. Synthesis and screening of pyrrolo[1,2-a]quinoxaline derivatives, yielding synthetic Sirt6 activators performing direct, substrate-independent compound binding to the Sirt6 catalytic core and potent activation of Sirt6-dependent deacetylation of peptide substrates and complete nucleosomes. Crystal structures of Sirt6/activator complexes reveal that the compounds bind to a Sirt6-specific acyl channel pocket and identify key interactions. Weak and possibly non-specific activating effects are also reported for the plant metabolite fatty acids (Sirt6). Preparation of the 4-substituited-4,5-dihydropyrrolo[1,2-a]quinoxalines and 4-substituited-pyrrolo[1,2-a]quinoxalines. Sirt6 activator-binding site and mechanism, microscale thermophoresis binding experiments, overview
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0024
[synthetic tumor necrosis factor alpha peptide]-N6-myristoyl-L-lysine19
pH 8.0, 37°C
-
0.0045
[synthetic tumor necrosis factor alpha peptide]-N6-myristoyl-L-lysine20
pH 8.0, 37°C
-
additional information
additional information
steady-state kinetic analysis of wild-type and mutant enzymes
-
0.0028
[histone H3 peptide]-N6-acetyl-L-lysine9
pH 7.5, 37°C, wild-type enzyme, in presence of activator lysophosphatidic acid
-
0.0052
[histone H3 peptide]-N6-acetyl-L-lysine9
pH 7.5, 37°C, wild-type enzyme, in presence of activator 2-(3-chloro-4-(2,4,6-trichloro-N-(2,4,6-trichlorobenzoyl)benzamido)phenyl)-1,3-dioxoisoindoline-5-carboxylic acid
-
0.0094
[histone H3 peptide]-N6-acetyl-L-lysine9
pH 7.5, 37°C, wild-type enzyme, in presence of activator N-linoleoylglycine
-
0.015
[histone H3 peptide]-N6-acetyl-L-lysine9
pH 7.5, 37°C, wild-type enzyme, in presence of activator arotinoid acid
-
0.247
[histone H3 peptide]-N6-acetyl-L-lysine9
pH 7.5, 37°C, wild-type enzyme
-
0.47
[histone H3 peptide]-N6-acetyl-L-lysine9
pH 7.5, 37°C, wild-type enzyme, mutant R65A
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.002
[synthetic tumor necrosis factor alpha peptide]-N6-myristoyl-L-lysine19
pH 8.0, 37°C
-
0.005
[synthetic tumor necrosis factor alpha peptide]-N6-myristoyl-L-lysine20
pH 8.0, 37°C
-
0.0001
[histone H3 peptide]-N6-acetyl-L-lysine9
pH 7.5, 37°C, wild-type enzyme, mutant R65A
-
1.1
[histone H3 peptide]-N6-acetyl-L-lysine9
pH 7.5, 37°C, wild-type enzyme
-
1.5
[histone H3 peptide]-N6-acetyl-L-lysine9
pH 7.5, 37°C, wild-type enzyme, in presence of activator 2-(3-chloro-4-(2,4,6-trichloro-N-(2,4,6-trichlorobenzoyl)benzamido)phenyl)-1,3-dioxoisoindoline-5-carboxylic acid
-
2.8
[histone H3 peptide]-N6-acetyl-L-lysine9
pH 7.5, 37°C, wild-type enzyme, in presence of activator arotinoid acid
-
2.8
[histone H3 peptide]-N6-acetyl-L-lysine9
pH 7.5, 37°C, wild-type enzyme, in presence of activator N-linoleoylglycine
-
3.2
[histone H3 peptide]-N6-acetyl-L-lysine9
pH 7.5, 37°C, wild-type enzyme, in presence of activator lysophosphatidic acid
-
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.83
[synthetic tumor necrosis factor alpha peptide]-N6-myristoyl-L-lysine19
pH 8.0, 37°C
-
1.1
[synthetic tumor necrosis factor alpha peptide]-N6-myristoyl-L-lysine20
pH 8.0, 37°C
-
0.00021
[histone H3 peptide]-N6-acetyl-L-lysine9
pH 7.5, 37°C, wild-type enzyme, mutant R65A
-
4.45
[histone H3 peptide]-N6-acetyl-L-lysine9
pH 7.5, 37°C, wild-type enzyme
-
186.7
[histone H3 peptide]-N6-acetyl-L-lysine9
pH 7.5, 37°C, wild-type enzyme, in presence of activator arotinoid acid
-
288.5
[histone H3 peptide]-N6-acetyl-L-lysine9
pH 7.5, 37°C, wild-type enzyme, in presence of activator 2-(3-chloro-4-(2,4,6-trichloro-N-(2,4,6-trichlorobenzoyl)benzamido)phenyl)-1,3-dioxoisoindoline-5-carboxylic acid
-
297.9
[histone H3 peptide]-N6-acetyl-L-lysine9
pH 7.5, 37°C, wild-type enzyme, in presence of activator N-linoleoylglycine
-
1142.9
[histone H3 peptide]-N6-acetyl-L-lysine9
pH 7.5, 37°C, wild-type enzyme, in presence of activator lysophosphatidic acid
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
729145, 729362, 729520, 729679, 729849, 729972, 730024, 730464, 730498, 730527, 730790, 737930, 737977, 738060, 738169, 738283, 739139, 739158, 739225, 755787, 755918, 756392, 756407, 756672, 756689, 756691, 756871, 756879, 756973, 757236, 757294, 757398, 757530, 757667, 757883, 757931, 758395, 758437
SwissProt
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
muscle invasive urothelial carcinoma of the bladder. Decline of SIRT6 expression when bladder cancer progresses from stage T2 to stage T4
lung, level of SIRT6 in in vitro model of myofibroblast differentiation, overview
SIRT6 is highly expressed in the retina, controlling levels of histone H3K9 and H3K56 acetylation
-
increased SIRT6 expression in HCC, SIRT6 expression pattern and its association with HCC metastasis, overview
additional information
SIRT6 is highly expressed in human brains but reduced in Alzheimer's disease patients, SIRT6 mRNA and protein levels are reduced in patients with Alzheimer's disease in temporal cortex and hippocampus
HCC cell, SIRT6 upregulation is quite prevalent in HCC tissues and closely correlated with worse overall survival, disease-relapse free survival, and HCC metastasis
additional information
most of the melanoma cell lines exhibit significantly higher expression of SIRT6 protein and mRNA as assessed by immunoblot and RT-qPCR analyses, respectively
additional information
-
most of the melanoma cell lines exhibit significantly higher expression of SIRT6 protein and mRNA as assessed by immunoblot and RT-qPCR analyses, respectively
additional information
SIRT6 and PP2A regulatory subunit (PPP2AR1A, the main Tau phosphatase) expression are positively correlated in normal brains, but this correlation is lost in Alzheimer's disease brains
additional information
-
SIRT6 and PP2A regulatory subunit (PPP2AR1A, the main Tau phosphatase) expression are positively correlated in normal brains, but this correlation is lost in Alzheimer's disease brains
additional information
Sirt6 expression and Sirt6-wild-type-1 colocalization is suppressed in the glomeruli of patients with diabetic nephropathy (DN)
additional information
-
Sirt6 expression and Sirt6-wild-type-1 colocalization is suppressed in the glomeruli of patients with diabetic nephropathy (DN)
additional information
SIRT6 expression levels regulate NAD+ levels in different organs
additional information
SIRT6 promoted HCC metastasis, expression analysis in HCC cell lines, overview. SIRT6 expression is significantly increased. SIRT6 is also upregulated in Hep3B and LO2 cells
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
Sirt6 is enriched in the nucleolus in the G1 phase of the cell cycle, while S phase nucleoli are almost entirely free of Sirt6
SIRT6 activity is nucleosome dependent, and suggest that its binding to the nucleosome might convert it into an active structure
the C-terminus of SIRT6 is required for nuclear localization of the enzyme
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
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
additional information
evolution
SIRT6 belongs to the mammalian homologues of Sir2 histone NAD+-dependent deacylase family
evolution
sirtuin 6 (SIRT6) is a member of the sirtuin family of nicotinamide adenine dinucleotide?dependent protein deacetylases
evolution
sirtuin6 is a member of the sirtuin family which function as NAD+-dependent deacetylases
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
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
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
malfunction
knock-down of SIRT6 does not sensitize bladder cancer cell lines to DNA damaging drugs
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
malfunction
enzyme inactivation in cells leads to histone H3-Lys18 hyperacetylation and aberrant accumulation of pericentric transcripts
malfunction
inhibiting SIRT6 activity enhances anti-multiple myeloma activity of doxorubicin in vivo
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
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
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
malfunction
in SIRT6-overexpressing cells, NAD(H) levels are upregulated, as a consequence of NAMPT activation
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
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
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
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
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
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
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
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
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
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
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
metabolism
SIRT6 promotes the secretion of tumor necrosis factor alpha by removing the fatty acyl modification on K19 and K20 of TNFalpha
metabolism
SIRT6 upregulates COX-2 levels and acts as an oncogene in skin carcinogenesis
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
metabolism
myostatin (Mstn) and SIRT6 expression exhibit reciprocal relationship, overview
metabolism
telomere stability, movement, and chromosomal condensation are regulated by SIRT6 in the presence of oxidative damage at telomeres
physiological function
SIRT6 is a critical modulator of retinal function, likely through its effects on chromatin
physiological function
Sirt6 is a critical regulator of endothelial senescence
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
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
physiological function
the enzyme deacetylates histone H3-Lys18 at pericentric chromatin to prevent mitotic errors and cellular senescence
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
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
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
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
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
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
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
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
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
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)
physiological function
SIRT6 seems to act as an oncogene, by virtue of its ability to promote DNA repair, cancer cell invasiveness and inflammation
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
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
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
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
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
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
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
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
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
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
additional information
the extended NH2-terminal loop of SIRT6 covers the NAD+- and acyl-substrate binding sites
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
lipoprotein
myristic acid is a competitive inhibitor of SIRT6 demyristoylation
nitrosylation
tyrosine 257 in sirtuin 6 is nitrated after 3-morpholinosydnonimine treatment
additional information
SIRT6 SUMOylation appears to specifically regulate SIRT6 deacetylation on H3K56 but not H3K9
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
analysis of in silico cocrystal structure of SIRT6 bound to ADP-ribose and a H3K9 myristoylated peptide, PDB ID 3ZG6
hanging drop vapor diffusion at 20°C. Crystal structures in complex with ADP-ribose and the non-hydrolyzable analog of O-acetyl-ADP-ribose, 2'-N-acetyl-ADP-ribose
hanging drop vapor diffusion method at 18°C, crystal structure of Sirt6 in complex with a histone H3 K9 myristoyl peptide and ADPribose at 2.2 A resolution
purified recombinant Sirt6 in complex with UBCS compounds, hanging drop vapour diffusion method, mixing of 10 mg/ml Sirt6-13-308, and 10 mM ADP-ribose at 20°C in with reservoir solution comtaining 1.6 M (NH4)2SO4, 10% PEG 400, and Bis-Tris, pH 5.7, crystals appear within 24 h and are subsequently soaked by adding 100 mM UBCS compound, incubation for one week, X-ray diffraction structure determination and analysis at 1.87-2.10 A resolution, molecular replacement using the protein part of a Sirt6/ADP-ribose structure (PDB code 3K35) as a search model, modeling
Sirt6/ADP-ribose/trichostatin A complex, hanging drop vapor diffusion method, 10 mg/ml purified recombinant protein Sirt6 and 10 mM ADP-ribose in 50 mM Na-phosphate buffer, pH 7.5, 0.6 mM DTT, and 5% DMSO are mixed with an equal volume of reservoir solution containing 1.6 M (NH4)2SO4, 10% PEG 400, and Bis-Tris buffer, pH 5.7, at 20°C, X-ray diffraction structure determination and analysis at 1.70 A resolution, molecular replacement using a Sirt6/ADP-ribose structure (PDB ID 3K35) as search model, modeling
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D63H
naturally occuring mutation in SIRT6, the homozygous inactivating mutation of histone deacetylase SIRT6 results in severe congenital anomalies and perinatal lethality in four affected fetuses, it causes human perinatal lethality, missense mutation SIRT6 p.D63H in affected fetal amniocytes. SIRT6 D63H mutant mESCs fail to form EBs and retain pluripotent gene expression. The amino acid change at Asp63 to a histidine results in virtually complete loss of H3K9 deacetylase and demyristoylase functions. Asp63 is located in the NAD+-binding pocket, forming hydrogen bonds with neighboring amino acids and thus providing structure to the NAD+-binding loop
G60A
H131Y
the mutant enzyme can still bind NAD+ but has a decreased ability to bind ADP-ribose
H133Y
K160A
site-directed mutagenesis, the mutant's activability is similar compared to the wild-type enzyme
K81A
site-directed mutagenesis, the activability of the mutant is only slightly reduced compared to the wild-type enzyme
R65A
R76A
site-directed mutagenesis, the activability of the mutant is only slightly reduced compared to the wild-type enzyme
Y12F
the mutant exhibits deacetylase activity similar to that of the wild type enzyme
Y148F
the mutant shows 57% decrease of activity compared to the wild type enzyme
Y257F
the mutant shows 73% decrease of activity compared to the wild type enzyme
Y5F
the mutant exhibits deacetylase activity similar to that of the wild type enzyme
additional information
G60A
the mutant is a lysine defatty acylase in vitro with substantially decreased deacetylase activity in vitro and no detectable deacetylase activity in cells
G60A
the SIRT6 G60A mutant retains an efficient defatty-acylase activity, but has significantly decreased deacetylase activity
H133Y
when human Sirt6 wild-type enzyme is overexpressed in Sirt6 KO MEF cells, tumor necrosis factor alpha has lower fatty acylation level than tumor necrosis factor alpha from cells without overexpression of human Sirt6, while overexpression of human Sirt6 H133Y catalytic mutant does not have much effect on tumor necrosis factor alpha fatty acylation
H133Y
catalytically inactive SIRT6 mutant, the SIRT6 H133Y mutant without histone deacetylase activity fails to inhibit phosphorylation and nuclear translocation of Smad2
R65A
the mutant shows only ADP-ribosyltransferase activity but no deacetylase activity
R65A
site-directed mutagenesis, the SIRT6 variant cannot be stimulated toward deacetylation by activator compounds. The R65A variant is similarly deficient in the ability to display enhanced catalysis with myristoylated substrates, suggesting that common catalytic steps are hampered
additional information
enzyme knockout by SIRT6 siRNA expression. SIRT6 overexpression in hepatocellular carcinoma cells reduces E-cadherin levels
additional information
generation of SIRT6 knockout human mesenchymal stem cells (hMSCs) by targeted gene editing. For generation of SIRT6-deficient human embryonic stem cells (hESCs), the exon 1 of SIRT6 gene is removed in hESCs by a transcription activator-like effector nuclease. SIRT6-deficient 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). Phenotype, overview
additional information
-
generation of SIRT6 knockout human mesenchymal stem cells (hMSCs) by targeted gene editing. For generation of SIRT6-deficient human embryonic stem cells (hESCs), the exon 1 of SIRT6 gene is removed in hESCs by a transcription activator-like effector nuclease. SIRT6-deficient 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). Phenotype, overview
additional information
generation of SIRT6 knockout MEF cells which exhibit an increased basal level of mobility compared to that in wild-type cells before damage. But the cells do not show the damage-induced increase in total movement after damage
additional information
-
generation of SIRT6 knockout MEF cells which exhibit an increased basal level of mobility compared to that in wild-type cells before damage. But the cells do not show the damage-induced increase in total movement after damage
additional information
generation of SIRT6-overexpressing human umbilical vein endothelial cells (HUVECS), significantly fewer THP-1 cells adher to SIRT6-overexpressing HUVECs exposed to minute CCs compared to control HUVECs
additional information
lentiviral short hairpin RNA-mediated knockdown of SIRT6 in A-375 and Hs 294T human melanoma cells significantly decreased cell growth, viability, and colony formation, induced G1-phase arrest and increased senescence-associated beta-galactosidase staining. SIRT6 knockdown in A375 cells causes significant modulation in several genes and/or proteins, i.e. it decreases in AKT1, ATG12, ATG3, ATG7, BAK1, BCL2L1, CLN3, CTSB, CTSS, DRAM2, HSP90AA1, IRGM, NPC1, SQSTM1, TNF, and BECN1 expression and increases in GAA, ATG10 expression
additional information
-
lentiviral short hairpin RNA-mediated knockdown of SIRT6 in A-375 and Hs 294T human melanoma cells significantly decreased cell growth, viability, and colony formation, induced G1-phase arrest and increased senescence-associated beta-galactosidase staining. SIRT6 knockdown in A375 cells causes significant modulation in several genes and/or proteins, i.e. it decreases in AKT1, ATG12, ATG3, ATG7, BAK1, BCL2L1, CLN3, CTSB, CTSS, DRAM2, HSP90AA1, IRGM, NPC1, SQSTM1, TNF, and BECN1 expression and increases in GAA, ATG10 expression
additional information
overexpression of SIRT6 in HFL1 cells infected with an adenoviral vector encoding SIRT6 or knockdown by an adenoviral vector encoding SIRT6 short hairpin RNA
additional information
-
overexpression of SIRT6 in HFL1 cells infected with an adenoviral vector encoding SIRT6 or knockdown by an adenoviral vector encoding SIRT6 short hairpin RNA
additional information
SIRT6 overexpression abrogates the toxicity of primary astrocytes expressing ALS-linked mutant SOD1 G93A. SIRT6 plays a central role in the protection conferred by enhancing NAD+ availability in hSOD1G93A astrocytes
additional information
-
SIRT6 overexpression abrogates the toxicity of primary astrocytes expressing ALS-linked mutant SOD1 G93A. SIRT6 plays a central role in the protection conferred by enhancing NAD+ availability in hSOD1G93A astrocytes
additional information
specific downregulation of histone deacetylase sirtuin 6 (SIRT6), overexpression of SIRT6. In Hep-G2 cells, doxorubicin treatment results in significant increases in SIRT1 and SIRT4 mRNA expression and downregulation of SIRT6 mRNA level by 36 h
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged enzyme from Escherichia coli by nickel affinity chromatography, tag cleavage by TEV protease, reverse affinity chromatography, action exchange chromatography, and gel filtration
recombinant N-terminally His-tagged human Sirt6 using from Escherichia coli by metal affinity chromatography, cation exchange chromatography, and gel filtration
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene SIRT6, His-tagged full-length Sirt6 (residues 1-355) in pQE80L.1 vector is expressed in Escherichia coli strain M15[pREP4] and His-tagged Sirt6(13-308) in vector pET151-D-TOPO in Escherichia coli strain Rosetta2 (DE3) pLysS
gene SIRT6, recombinant expression of N-terminally His-tagged human Sirt6 using vector pQE80L.1 (internal pQE80 derivative with TEV cleavage site) in Escherichia coli M15[pREP4] (construct 1-355) or vector pET151-D-TOPO in Escherichia coli Rosetta2 (DE3) pLysS (shortened constructs)
gene SIRT6, recombinant overexpression of wild-type SIRT6 and catalytically inactive SIRT6 mutant H133Y using retroviral transduction in BxPC-3 and MCF-7 cells
gene SIRT6, transient overexpression of FLAG-tagged SIRT6 in HeLa cells, quantitative reverse transcription PCR enzyme expression analysis
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
decline of SIRT6 expression when bladder cancer progresses from stage T2 to stage T4
enzyme expression in HCC cells is upregulated by transforming growth factor-beta1, H2O2, and HOCl
enzyme expression is significantly reduced in human ovarian cancer tissues compared to the normal tissues
H2O2 treatment significantly reduces Sirt6 protein. Stress-induced downregulation of Sirt6 is likely involved in the pathogenesis of diabetic retinopathy
high-glucose causes Sirt6 and p-AMPK downregulation in podocytes. High-glucose conditions decrease Sirt6 expression levels significantly
in Hep-G2 cells, doxorubicin treatment results in significant increases in SIRT1 and SIRT4 mRNA expression and downregulation of SIRT6 mRNA level by 36 h
minute cholesterol crystals significantly suppress SIRT6 expression in endothelial cells
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
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
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
the oncogenic role of SIRT6 in skin cancer suggest SIRT6 as a potential target for developing chemopreventive strategies to reduce the skin cancer
medicine
SIRT6 and its downstream signaling can be targeted in Alzheimer's disease and age related neurodegeneration
medicine
SIRT6 as a potential therapeutic target to prevent astrocyte-mediated motor neuron death in amyotrophic lateral sclerosis (ALS)
medicine
small molecule activators for the human sirtuins Sirt1-7 are sought as chemical tools and potential therapeutics, such as for cancer
medicine
the enzyme is a potential therapeutic target for therapy of cancer and other metabolic diseases
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Chen, X.; Hao, B.; Liu, Y.; Dai, D.; Han, G.; Li, Y.; Wu, X.; Zhou, X.; Yue, Z.; Wang, L.; Cao, Y.; Liu, J.
The histone deacetylase SIRT6 suppresses the expression of the RNA-binding protein PCBP2 in glioma
Biochem. Biophys. Res. Commun.
446
364-369
2014
Homo sapiens (Q8N6T7), Homo sapiens
Liu, R.; Liu, H.; Ha, Y.; Tilton, R.G.; Zhang, W.
Oxidative stress induces endothelial cell senescence via downregulation of Sirt6
Biomed Res. Int.
2014
902842
2014
Homo sapiens (Q8N6T7), Homo sapiens
Ming, M.; Han, W.; Zhao, B.; Sundaresan, N.R.; Deng, C.X.; Gupta, M.P.; He, Y.Y.
SIRT6 promotes COX-2 expression and acts as an oncogene in skin cancer
Cancer Res.
74
5925-5933
2014
Mus musculus (P59941), Mus musculus, Homo sapiens (Q8N6T7), Homo sapiens
Kokkonen, P.; Rahnasto-Rilla, M.; Mellini, P.; Jarho, E.; Lahtela-Kakkonen, M.; Kokkola, T.
Studying SIRT6 regulation using H3K56 based substrate and small molecules
Eur. J. Pharm. Sci.
63
71-76
2014
Homo sapiens (Q8N6T7)
Wu, M.; Dickinson, S.I.; Wang, X.; Zhang, J.
Expression and function of SIRT6 in muscle invasive urothelial carcinoma of the bladder
Int. J. Clin. Exp. Pathol.
7
6504-6513
2014
Homo sapiens (Q8N6T7)
Pan, P.W.; Feldman, J.L.; Devries, M.K.; Dong, A.; Edwards, A.M.; Denu, J.M.
Structure and biochemical functions of SIRT6
J. Biol. Chem.
286
14575-14587
2011
Homo sapiens (Q8N6T7), Homo sapiens
Feldman, J.L.; Baeza, J.; Denu, J.M.
Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins
J. Biol. Chem.
288
31350-31356
2013
Homo sapiens (Q8N6T7)
Jiang, H.; Khan, S.; Wang, Y.; Charron, G.; He, B.; Sebastian, C.; Du, J.; Kim, R.; Ge, E.; Mostoslavsky, R.; Hang, H.C.; Hao, Q.; Lin, H.
SIRT6 regulates TNF-alpha secretion through hydrolysis of long-chain fatty acyl lysine
Nature
496
110-113
2013
Homo sapiens (Q8N6T7), Homo sapiens
Gil, R.; Barth, S.; Kanfi, Y.; Cohen, H.Y.
SIRT6 exhibits nucleosome-dependent deacetylase activity
Nucleic Acids Res.
41
8537-8545
2013
Homo sapiens (Q8N6T7)
Ardestani, P.M.; Liang, F.
Sub-cellular localization, expression and functions of Sirt6 during the cell cycle in HeLa cells
Nucleus
3
442-451
2012
Homo sapiens (Q8N6T7)
Silberman, D.M.; Ross, K.; Sande, P.H.; Kubota, S.; Ramaswamy, S.; Apte, R.S.; Mostoslavsky, R.
SIRT6 is required for normal retinal function
PLoS One
9
e98831
2014
Homo sapiens (Q8N6T7)
Cea, M.; Cagnetta, A.; Adamia, S.; Acharya, C.; Tai, Y.T.; Fulciniti, M.; Ohguchi, H.; Munshi, A.; Acharya, P.; Bhasin, M.K.; Zhong, L.; Carrasco, R.; Monacelli, F.; Ballestrero, A.; Richardson, P.; Gobbi, M.; Lemoli, R.M.; Munshi, N.; Hideshima, T.; Nencioni, A.; Chauhan, D.; Anderson, K.C.
Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells
Blood
127
1138-1150
2016
Homo sapiens (Q8N6T7), Homo sapiens
Feng, X.X.; Luo, J.; Liu, M.; Yan, W.; Zhou, Z.Z.; Xia, Y.J.; Tu, W.; Li, P.Y.; Feng, Z.H.; Tian, D.A.
Sirtuin 6 promotes transforming growth factor-beta1/H2O2/HOCl-mediated enhancement of hepatocellular carcinoma cell tumorigenicity by suppressing cellular senescence
Cancer Sci.
106
559-566
2015
Homo sapiens (Q8N6T7)
Rahnasto-Rilla, M.; Kokkola, T.; Jarho, E.; Lahtela-Kakkonen, M.; Moaddel, R.
N-acylethanolamines bind to SIRT6
ChemBioChem
17
77-81
2016
Homo sapiens (Q8N6T7)
Zhang, J.; Yin, X.J.; Xu, C.J.; Ning, Y.X.; Chen, M.; Zhang, H.; Chen, S.F.; Yao, L.Q.
The histone deacetylase SIRT6 inhibits ovarian cancer cell proliferation via down-regulation of Notch 3 expression
Eur. Rev. Med. Pharmacol. Sci.
19
818-824
2015
Homo sapiens (Q8N6T7), Homo sapiens
Hu, S.; Liu, H.; Ha, Y.; Luo, X.; Motamedi, M.; Gupta, M.P.; Ma, J.X.; Tilton, R.G.; Zhang, W.
Posttranslational modification of Sirt6 activity by peroxynitrite
Free Radic. Biol. Med.
79
176-185
2015
Homo sapiens (Q8N6T7), Homo sapiens
Zhang, X.; Khan, S.; Jiang, H.; Antonyak, M.A.; Chen, X.; Spiegelman, N.A.; Shrimp, J.H.; Cerione, R.A.; Lin, H.
Identifying the functional contribution of the defatty-acylase activity of SIRT6
Nat. Chem. Biol.
12
614-620
2016
Homo sapiens (Q8N6T7)
Tasselli, L.; Xi, Y.; Zheng, W.; Tennen, R.I.; Odrowaz, Z.; Simeoni, F.; Li, W.; Chua, K.F.
SIRT6 deacetylates H3K18Ac at pericentric chromatin to prevent mitotic errors and cellular senescence
Nat. Struct. Mol. Biol.
23
434-440
2016
Homo sapiens (Q8N6T7), Homo sapiens
Liu, J.; Zheng, W.
Cyclic peptide-based potent human SIRT6 inhibitors
Org. Biomol. Chem.
14
5928-5935
2016
Homo sapiens (Q8N6T7), Homo sapiens
You, W.; Rotili, D.; Li, T.M.; Kambach, C.; Meleshin, M.; Schutkowski, M.; Chua, K.F.; Mai, A.; Steegborn, C.
Structural basis of sirtuin 6 activation by synthetic small molecules
Angew. Chem. Int. Ed. Engl.
56
1007-1011
2017
Homo sapiens (Q8N6T7), Homo sapiens
Sosnowska, B.; Mazidi, M.; Penson, P.; Gluba-Brzozka, A.; Rysz, J.; Banach, M.
The sirtuin family members SIRT1, SIRT3 and SIRT6 their role in vascular biology and atherogenesis
Atherosclerosis
265
275-282
2017
Homo sapiens (Q8N6T7), Homo sapiens
Kaluski, S.; Portillo, M.; Besnard, A.; Stein, D.; Einav, M.; Zhong, L.; Ueberham, U.; Arendt, T.; Mostoslavsky, R.; Sahay, A.; Toiber, D.
Neuroprotective functions for the histone deacetylase SIRT6
Cell Rep.
18
3052-3062
2017
Mus musculus (P59941), Homo sapiens (Q8N6T7), Homo sapiens
Pan, H.; Guan, Di; Liu, X.; Li, J.; Wang, L.; Wu5, J.; Zhou1, J.; Zhang, W.; Ren, R.; Zhang, W.; Li, Y.; Yang, J.; Hao, Y.; Yuan, T.; Yuan, G.; Wang, H.; Ju, Z.; Mao, Z.; Li, J.; Qu, J.; Tang, F.; Liu, G.-H.
SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2
Cell Res.
26
190-205
2016
Homo sapiens (Q8N6T7), Homo sapiens
Jin, Z.; Xiao, Y.; Yao, F.; Wang, B.; Zheng, Z.; Gao, H.; Lv, X.; Chen, L.; He, Y.; Wang, W.; Lin, R.
SIRT6 inhibits cholesterol crystal-induced vascular endothelial dysfunction via Nrf2 activation
Exp. Cell Res.
387
111744
2020
Mus musculus (P59941), Homo sapiens (Q8N6T7)
Sociali, G.; Grozio, A.; Caffa, I.; Schuster, S.; Becherini, P.; Damonte, P.; Sturla, L.; Fresia, C.; Passalacqua, M.; Mazzola, F.; Raffaelli, N.; Garten, A.; Kiess, W.; Cea, M.; Nencioni, A.; Bruzzone, S.
SIRT6 deacetylase activity regulates NAMPT activity and NAD(P)(H) pools in cancer cells
FASEB J.
33
3704-3717
2019
Homo sapiens (Q8N6T7)
Harlan, B.; Pehar, M.; Killoy, K.; Vargas, M.
Enhanced SIRT6 activity abrogates the neurotoxic phenotype of astrocytes expressing ALS-linked mutant SOD1
FASEB J.
33
7084-7091
2019
Homo sapiens (Q8N6T7), Homo sapiens
Garcia-Peterson, L.; Ndiaye, M.; Singh, C.; Chhabra, G.; Huang, W.; Ahmad, N.
SIRT6 histone deacetylase functions as a potential oncogene in human melanoma
Genes Cancer
8
701-712
2017
Homo sapiens (Q8N6T7), Homo sapiens
Ferrer, C.; Alders, M.; Postma, A.; Park, S.; Klein, M.; Cetinbas, M.; Pajkrt, E.; Glas, A.; van Koningsbruggen, S.; Christoffels, V.; Mannens, M.; Knegt, L.; Etchegaray, J.; Sadreyev, R.; Denu, J.; Mostoslavsky, G.; van Maarle, M.; Mostoslavsky, R.
An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality
Genes Dev.
32
373-388
2018
Mus musculus (P59941), Mus musculus, Homo sapiens (Q8N6T7), Homo sapiens
Fan, Y.; Yang, Q.; Yang, Y.; Gao, Z.; Ma, Y.; Zhang, L.; Liang, W.; Ding, G.
Sirt6 suppresses high glucose-induced mitochondrial dysfunction and apoptosis in podocytes through AMPK activation
Int. J. Biol. Sci.
15
701-713
2019
Mus musculus (P59941), Homo sapiens (Q8N6T7), Homo sapiens, Mus musculus C57BL/6 (P59941)
Klein, M.A.; Liu, C.; Kuznetsov, V.I.; Feltenberger, J.B.; Tang, W.; Denu, J.M.
Mechanism of activation for the sirtuin 6 protein deacylase
J. Biol. Chem.
295
1385-1399
2020
Homo sapiens (Q8N6T7)
Zhang, Q.; Tu, W.; Tian, K.; Han, L.; Wang, Q.; Chen, P.; Zhou, X.
Sirtuin 6 inhibits myofibroblast differentiation via inactivating transforming growth factor-beta1/Smad2 and nuclear factor-kappaB signaling pathways in human fetal lung fibroblasts
J. Cell. Biochem.
120
93-104
2019
Homo sapiens (Q8N6T7), Homo sapiens
You, W.; Steegborn, C.
Structural basis of sirtuin 6 inhibition by the hydroxamate trichostatin A implications for protein deacylase drug development
J. Med. Chem.
61
10922-10928
2018
Homo sapiens (Q8N6T7)
Cai, J.; Liu, Z.; Huang, X.; Shu, S.; Hu, X.; Zheng, M.; Tang, C.; Liu, Y.; Chen, G.; Sun, L.; Liu, H.; Liu, F.; Cheng, J.; Dong, Z.
The deacetylase sirtuin 6 protects against kidney fibrosis by epigenetically blocking beta-catenin targetgene expression
Kidney Int.
97
106-118
2020
Homo sapiens (Q8N6T7)
Han, L.; Jia, L.; Wu, F.; Huang, C.
Sirtuin6 (SIRT6) promotes the EMT of hepatocellular carcinoma by stimulating autophagic degradation of E-cadherin
Mol. Cancer Res.
17
2267-2280
2019
Homo sapiens
Sociali, G.; Liessi, N.; Grozio, A.; Caffa, I.; Parenti, M.; Ravera, S.; Tasso, B.; Benzi, A.; Nencioni, A.; Del Rio, A.; Robina, I.; Millo, E.; Bruzzone, S.
Differential modulation of SIRT6 deacetylase and deacylase activities by lysine-based small molecules
Mol. Divers.
24
655-671
2019
Homo sapiens (Q8N6T7)
Hu, J.; Deng, F.; Hu, X.; Zhang, W.; Zeng, X.; Tian, X.
Histone deacetylase SIRT6 regulates chemosensitivity in liver cancer cells via modulation of FOXO3 activity
Oncol. Rep.
40
3635-3644
2018
Homo sapiens (Q8N6T7)
Chang, A.; Ferrer, C.; Mostoslavsky, R.
SIRT6, a mammalian deacylase with multitasking abilities
Physiol. Rev.
100
145-169
2020
Mus musculus (P59941), Homo sapiens (Q8N6T7)
Samant, S.; Kanwal, A.; Pillai, V.; Bao, R.; Gupta, M.
The histone deacetylase SIRT6 blocks myostatin expression and development of muscle atrophy
Sci. Rep.
7
11744
2017
Mus musculus (P59941), Homo sapiens (Q8N6T7)
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