Activating Compound | Comment | Organism | Structure |
---|---|---|---|
1-(5-((3-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[1,2-a]quinoxalin-4-yl)naphthalen-2-ol | - |
Homo sapiens | |
4-(pyridin-2-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline | - |
Homo sapiens | |
4-(pyridin-2-yl)pyrrolo[1,2-a]quinoxaline | - |
Homo sapiens | |
4-(pyridin-3-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline | - |
Homo sapiens | |
4-(pyridin-3-yl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline | - |
Homo sapiens | |
4-(pyridin-3-yl)pyrrolo[1,2-a]quinoxaline | - |
Homo sapiens | |
4-(pyridin-4-yl)pyrrolo[1,2-a]quinoxaline | - |
Homo sapiens | |
4-phenylpyrrolo[1,2-a]quinoxaline | - |
Homo sapiens | |
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 | |
phenyl(4-phenylpyrrolo[1,2-a]quinoxalin-5(4H)-yl)methanone | - |
Homo sapiens |
Application | Comment | Organism |
---|---|---|
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 (Comment) | Organism |
---|---|
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 (Comment) | Organism |
---|---|
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 | Comment | Organism | Structure |
---|---|---|---|
1-(4,5-dihydropyrrolo[1,2-a]quinoxalin-4-yl)naphthalen-2-ol | - |
Homo sapiens | |
4-phenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline | - |
Homo sapiens | |
4-phenyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline | - |
Homo sapiens | |
4-phenyl-5-(phenylsulfonyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline | - |
Homo sapiens | |
5-(phenylsulfonyl)-4-(pyridin-3-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline | - |
Homo sapiens | |
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 | Comment | Organism | GeneOntology No. | Textmining |
---|---|---|---|---|
nucleosome | - |
Homo sapiens | 786 | - |
nucleus | - |
Homo sapiens | 5634 | - |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
NAD+ + [histone H3 peptide]-N6-acetyl-L-lysine18 | Homo sapiens | - |
nicotinamide + [histone H3 peptide]-L-lysine18 + 2'-O-acetyl-ADP-ribose | - |
? | |
NAD+ + [histone H3 peptide]-N6-acetyl-L-lysine9 | Homo sapiens | - |
nicotinamide + [histone H3 peptide]-L-lysine9 + 2'-O-acetyl-ADP-ribose | - |
? |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | Q8N6T7 | - |
- |
Purification (Comment) | Organism |
---|---|
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 | Comment | Organism | Textmining |
---|---|---|---|
HeLa cell | - |
Homo sapiens | - |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
additional information | Sirt6-dependent deacetylation of H3K18 and H3K9 in a histone protein preparation and in HeLa nucleosomes | Homo sapiens | ? | - |
- |
|
NAD+ + [histone H3 peptide]-N6-acetyl-L-lysine18 | - |
Homo sapiens | nicotinamide + [histone H3 peptide]-L-lysine18 + 2'-O-acetyl-ADP-ribose | - |
? | |
NAD+ + [histone H3 peptide]-N6-acetyl-L-lysine9 | - |
Homo sapiens | nicotinamide + [histone H3 peptide]-L-lysine9 + 2'-O-acetyl-ADP-ribose | - |
? |
Synonyms | Comment | Organism |
---|---|---|
NAD-dependent protein deacetylase sirtuin-6 | UniProt | Homo sapiens |
SIRT6 | - |
Homo sapiens |
sirtuin 6 | - |
Homo sapiens |
Temperature Optimum [°C] | Temperature Optimum Maximum [°C] | Comment | Organism |
---|---|---|---|
25 | 37 | assay at | Homo sapiens |
pH Optimum Minimum | pH Optimum Maximum | Comment | Organism |
---|---|---|---|
7.5 | - |
assay at | Homo sapiens |
Cofactor | Comment | Organism | Structure |
---|---|---|---|
NAD+ | - |
Homo sapiens |
General Information | Comment | Organism |
---|---|---|
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 |