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Literature summary for 2.3.1.B41 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
Search for more literature for 2.3.1.B41

Activating Compound

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

Protein Variants

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

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
additional information
-
 additional information steady-state kinetic analysis of wild-type and mutant enzymes Homo sapiens
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
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
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
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
0.247
-
 [histone H3 peptide]-N6-acetyl-L-lysine9 pH 7.5, 37°C, wild-type enzyme Homo sapiens
0.47
-
 [histone H3 peptide]-N6-acetyl-L-lysine9 pH 7.5, 37°C, wild-type enzyme, mutant R65A Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
nucleus
-
 Homo sapiens 5634
-

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+ required Homo sapiens

Natural Substrates/ Products (Substrates)

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

Organism

Organism UniProt Comment Textmining
Homo sapiens Q8N6T7
-
-

Posttranslational Modification

Posttranslational Modification Comment Organism
lipoprotein myristic acid is a competitive inhibitor of SIRT6 demyristoylation Homo sapiens

Source Tissue

Source Tissue Comment Organism Textmining
HEK-293 cell
-
 Homo sapiens
-

Substrates and Products (Substrate)

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

Synonyms

Synonyms Comment Organism
histone deacetylase sirtuin 6
-
 Homo sapiens
NAD-dependent protein deacetylase sirtuin-6 UniProt Homo sapiens
SIRT6
-
 Homo sapiens
sirtuin 6
-
 Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
37
-
 assay at Homo sapiens

Turnover Number [1/s]

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

pH Optimum Minimum pH Optimum Maximum Comment Organism
7.5
-
 assay at Homo sapiens

General Information

General Information Comment Organism
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
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
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]

kcat/KM Value [1/mMs-1] kcat/KM Value Maximum [1/mMs-1] Substrate Comment Organism Structure
0.00021
-
 [histone H3 peptide]-N6-acetyl-L-lysine9 pH 7.5, 37°C, wild-type enzyme, mutant R65A Homo sapiens
4.45
-
 [histone H3 peptide]-N6-acetyl-L-lysine9 pH 7.5, 37°C, wild-type enzyme Homo sapiens
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
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
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
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