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Literature summary extracted from

  • 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 (2020), J. Biol. Chem., 295, 1385-1399 .
    View publication on PubMedView publication on EuropePMC

Activating Compound

EC Number Activating Compound Comment Organism Structure
2.3.1.B41 2-(3-chloro-(4-benzamido)phenyl)-1,3-dioxoisoindoline-5-carboxylic acid i.e. CL-5A Homo sapiens
2.3.1.B41 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 Homo sapiens
2.3.1.B41 2-(3-chloro-4-(2,4-dichlorobenzamido)phenyl)-1,3-dioxoisoindoline-5-carboxylic acid i.e. CL-4 Homo sapiens
2.3.1.B41 2-(3-chloro-4-(4-chlorobenzamido)phenyl)-1,3-dioxoisoindoline-5-carboxylic acid i.e. CL-5B Homo sapiens
2.3.1.B41 2-(4-benzamidophenyl)-1,3-dioxoisoindoline-5-carboxylic acid i.e. CL-5 Homo sapiens
2.3.1.B41 2-fluoropalmitic acid
-
 Homo sapiens
2.3.1.B41 arachidonic acid
-
 Homo sapiens
2.3.1.B41 arotinoid acid i.e. TTNPB Homo sapiens
2.3.1.B41 eicosatrienoic acid
-
 Homo sapiens
2.3.1.B41 L-NASPA
-
 Homo sapiens
2.3.1.B41 lysophosphatidic acid highly activating Homo sapiens
2.3.1.B41 mead acid
-
 Homo sapiens
2.3.1.B41 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 Homo sapiens
2.3.1.B41 N-linoleoylglycine
-
 Homo sapiens

Protein Variants

EC Number Protein Variants Comment Organism
2.3.1.B41 K160A site-directed mutagenesis, the mutant's activability is similar compared to the wild-type enzyme Homo sapiens
2.3.1.B41 K81A site-directed mutagenesis, the activability of the mutant is only slightly reduced compared to the wild-type enzyme Homo sapiens
2.3.1.B41 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 Homo sapiens
2.3.1.B41 R76A site-directed mutagenesis, the activability of the mutant is only slightly reduced compared to the wild-type enzyme Homo sapiens

KM Value [mM]

EC Number KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
2.3.1.B41 additional information
-
 additional information steady-state kinetic analysis of wild-type and mutant enzymes Homo sapiens
2.3.1.B41 0.0028
-
 [histone H3 peptide]-N6-acetyl-L-lysine9 pH 7.5, 37°C, wild-type enzyme, in presence of activator lysophosphatidic acid Homo sapiens
2.3.1.B41 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 Homo sapiens
2.3.1.B41 0.0094
-
 [histone H3 peptide]-N6-acetyl-L-lysine9 pH 7.5, 37°C, wild-type enzyme, in presence of activator N-linoleoylglycine Homo sapiens
2.3.1.B41 0.015
-
 [histone H3 peptide]-N6-acetyl-L-lysine9 pH 7.5, 37°C, wild-type enzyme, in presence of activator arotinoid acid Homo sapiens
2.3.1.B41 0.247
-
 [histone H3 peptide]-N6-acetyl-L-lysine9 pH 7.5, 37°C, wild-type enzyme Homo sapiens
2.3.1.B41 0.47
-
 [histone H3 peptide]-N6-acetyl-L-lysine9 pH 7.5, 37°C, wild-type enzyme, mutant R65A Homo sapiens

Localization

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

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
2.3.1.B41 Mg2+ required Homo sapiens

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.3.1.B41 NAD+ + [histone H3 peptide]-N6-acetyl-L-lysine9 Homo sapiens
-
 nicotinamide + [histone H3 peptide]-L-lysine9 + 2'-O-acetyl-ADP-ribose
-
 ?

Organism

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

Posttranslational Modification

EC Number Posttranslational Modification Comment Organism
2.3.1.B41 lipoprotein myristic acid is a competitive inhibitor of SIRT6 demyristoylation Homo sapiens

Source Tissue

EC Number Source Tissue Comment Organism Textmining
2.3.1.B41 HEK-293 cell
-
 Homo sapiens
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.3.1.B41 NAD+ + [histone H3 peptide]-N6-acetyl-L-lysine9
-
 Homo sapiens nicotinamide + [histone H3 peptide]-L-lysine9 + 2'-O-acetyl-ADP-ribose
-
 ?

Synonyms

EC Number Synonyms Comment Organism
2.3.1.B41 histone deacetylase sirtuin 6
-
 Homo sapiens
2.3.1.B41 NAD-dependent protein deacetylase sirtuin-6 UniProt Homo sapiens
2.3.1.B41 SIRT6
-
 Homo sapiens
2.3.1.B41 sirtuin 6
-
 Homo sapiens

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
2.3.1.B41 37
-
 assay at Homo sapiens

Turnover Number [1/s]

EC Number Turnover Number Minimum [1/s] Turnover Number Maximum [1/s] Substrate Comment Organism Structure
2.3.1.B41 0.0001
-
 [histone H3 peptide]-N6-acetyl-L-lysine9 pH 7.5, 37°C, wild-type enzyme, mutant R65A Homo sapiens
2.3.1.B41 1.1
-
 [histone H3 peptide]-N6-acetyl-L-lysine9 pH 7.5, 37°C, wild-type enzyme Homo sapiens
2.3.1.B41 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 Homo sapiens
2.3.1.B41 2.8
-
 [histone H3 peptide]-N6-acetyl-L-lysine9 pH 7.5, 37°C, wild-type enzyme, in presence of activator arotinoid acid Homo sapiens
2.3.1.B41 2.8
-
 [histone H3 peptide]-N6-acetyl-L-lysine9 pH 7.5, 37°C, wild-type enzyme, in presence of activator N-linoleoylglycine Homo sapiens
2.3.1.B41 3.2
-
 [histone H3 peptide]-N6-acetyl-L-lysine9 pH 7.5, 37°C, wild-type enzyme, in presence of activator lysophosphatidic acid Homo sapiens

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
2.3.1.B41 7.5
-
 assay at Homo sapiens

General Information

EC Number General Information Comment Organism
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 Homo sapiens
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 Homo sapiens
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 Homo sapiens

kcat/KM [mM/s]

EC Number kcat/KM Value [1/mMs-1] kcat/KM Value Maximum [1/mMs-1] Substrate Comment Organism Structure
2.3.1.B41 0.00021
-
 [histone H3 peptide]-N6-acetyl-L-lysine9 pH 7.5, 37°C, wild-type enzyme, mutant R65A Homo sapiens
2.3.1.B41 4.45
-
 [histone H3 peptide]-N6-acetyl-L-lysine9 pH 7.5, 37°C, wild-type enzyme Homo sapiens
2.3.1.B41 186.7
-
 [histone H3 peptide]-N6-acetyl-L-lysine9 pH 7.5, 37°C, wild-type enzyme, in presence of activator arotinoid acid Homo sapiens
2.3.1.B41 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 Homo sapiens
2.3.1.B41 297.9
-
 [histone H3 peptide]-N6-acetyl-L-lysine9 pH 7.5, 37°C, wild-type enzyme, in presence of activator N-linoleoylglycine Homo sapiens
2.3.1.B41 1142.9
-
 [histone H3 peptide]-N6-acetyl-L-lysine9 pH 7.5, 37°C, wild-type enzyme, in presence of activator lysophosphatidic acid Homo sapiens