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Literature summary extracted from

  • 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 (2017), Angew. Chem. Int. Ed. Engl., 56, 1007-1011 .
    View publication on PubMed

Activating Compound

EC Number Activating Compound Comment Organism Structure
2.3.1.B41 1-(5-((3-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[1,2-a]quinoxalin-4-yl)naphthalen-2-ol
-
 Homo sapiens
2.3.1.B41 4-(pyridin-2-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline
-
 Homo sapiens
2.3.1.B41 4-(pyridin-2-yl)pyrrolo[1,2-a]quinoxaline
-
 Homo sapiens
2.3.1.B41 4-(pyridin-3-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline
-
 Homo sapiens
2.3.1.B41 4-(pyridin-3-yl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline
-
 Homo sapiens
2.3.1.B41 4-(pyridin-3-yl)pyrrolo[1,2-a]quinoxaline
-
 Homo sapiens
2.3.1.B41 4-(pyridin-4-yl)pyrrolo[1,2-a]quinoxaline
-
 Homo sapiens
2.3.1.B41 4-phenylpyrrolo[1,2-a]quinoxaline
-
 Homo sapiens
2.3.1.B41 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 Homo sapiens
2.3.1.B41 phenyl(4-phenylpyrrolo[1,2-a]quinoxalin-5(4H)-yl)methanone
-
 Homo sapiens

Application

EC Number Application Comment Organism
2.3.1.B41 medicine small molecule activators for the human sirtuins Sirt1-7 are sought as chemical tools and potential therapeutics, such as for cancer Homo sapiens

Cloned(Commentary)

EC Number Cloned (Comment) Organism
2.3.1.B41 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) Homo sapiens

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
2.3.1.B41 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 Homo sapiens

Inhibitors

EC Number Inhibitors Comment Organism Structure
2.3.1.B41 1-(4,5-dihydropyrrolo[1,2-a]quinoxalin-4-yl)naphthalen-2-ol
-
 Homo sapiens
2.3.1.B41 4-phenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline
-
 Homo sapiens
2.3.1.B41 4-phenyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline
-
 Homo sapiens
2.3.1.B41 4-phenyl-5-(phenylsulfonyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline
-
 Homo sapiens
2.3.1.B41 5-(phenylsulfonyl)-4-(pyridin-3-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline
-
 Homo sapiens
2.3.1.B41 additional information preparation of the 4-substituited-4,5-dihydropyrrolo[1,2-a]quinoxalines and 4-substituited-pyrrolo[1,2-a]quinoxalines Homo sapiens

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
2.3.1.B41 nucleosome
-
 Homo sapiens 786
-
2.3.1.B41 nucleus
-
 Homo sapiens 5634
-

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-lysine18 Homo sapiens
-
 nicotinamide + [histone H3 peptide]-L-lysine18 + 2'-O-acetyl-ADP-ribose
-
 ?
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
-
-

Purification (Commentary)

EC Number Purification (Comment) Organism
2.3.1.B41 recombinant N-terminally His-tagged human Sirt6 using from Escherichia coli by metal affinity chromatography, cation exchange chromatography, and gel filtration Homo sapiens

Source Tissue

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

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.3.1.B41 additional information Sirt6-dependent deacetylation of H3K18 and H3K9 in a histone protein preparation and in HeLa nucleosomes Homo sapiens ?
-
-
2.3.1.B41 NAD+ + [histone H3 peptide]-N6-acetyl-L-lysine18
-
 Homo sapiens nicotinamide + [histone H3 peptide]-L-lysine18 + 2'-O-acetyl-ADP-ribose
-
 ?
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 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 25 37 assay at Homo sapiens

pH Optimum

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

Cofactor

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

General Information

EC Number General Information Comment Organism
2.3.1.B41 physiological function sirtuins are protein deacylases regulating metabolism and stress responses, and are implicated in aging-related diseases. Sirtuin 6 (Sirt6)-dependent deacetylation of peptide substrates and complete nucleosomes activets by pyrrolo[1,2-a]quinoxaline derivatives Homo sapiens