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Information on EC 2.7.7.86 - cyclic GMP-AMP synthase
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2.7.7.86 cyclic GMP-AMP synthaseIUBMB Comments
Cyclic Gp(2'-5')Ap(3'-5') is a signalling molecule in mammalian cells that triggers the production of type I interferons and other cytokines.
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Word Map
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
Synonyms
cyclic gmp-amp synthase, cyclic guanosine monophosphate-adenosine monophosphate synthase, cgamp synthase, hcgas, mb21d1, chcgas, h-cgas, mab-21 domain-containing protein, c6orf150, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
cGAMP synthase
cGAS
MB21D1
cGAS
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + GTP = pppGp(2'-5')A + diphosphate
(1a)
-
-
-
pppGp(2'-5')A = cyclic Gp(2'-5')Ap(3'-5') + diphosphate
(1b)
-
-
-
ATP + GTP = 2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
-
ATP + GTP = 2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
catalytic mechanism of cyclic GMP-AMP synthase (cGAS). AMP-2'-GTP is produced in significant abundance initially, while 2',3'-cGAMP is not suggesting a mechanism where the majority of substrate flows through AMP-2'-GTP, which is released to solution and then must rebind in competition with ATP and GTP to form 2',3'-cGAMP. AMP-2'-GTP is not subject to ATP or GTP competition
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SYSTEMATIC NAME
IUBMB Comments
ATP:GTP adenylyltransferase (cyclizing)
Cyclic Gp(2'-5')Ap(3'-5') is a signalling molecule in mammalian cells that triggers the production of type I interferons and other cytokines.
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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
ATP + GTP
2 diphosphate + cyclic 3',5'-AMP-GMP
cyclic 3',5'-AMP-GMP is a signalling molecule in mammalian cells that triggers the production of type I interferons and other cytokines
-
-
?
ATP + GTP
2 diphosphate + cyclic 3',5'-AMP-GMP
cyclic 3',5'-AMP-GMP is a signalling molecule in mammalian cells that triggers the production of type I interferons and other cytokines
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
-
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
-
product is cyclic Gp(2'-5')Ap(3'-5')
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
-
product is cyclic Gp(2'-5')Ap(3'-5')
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
over 78% conversion within 40 min
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
additional information
?
-
interaction of cGAS and viral DNA sensor IFI16, the pyrin domain of IFI16 mediates the interaction with ND10 bodies and enzyme cGAS
-
-
-
additional information
?
-
-
interaction of cGAS and viral DNA sensor IFI16, the pyrin domain of IFI16 mediates the interaction with ND10 bodies and enzyme cGAS
-
-
-
additional information
?
-
a diphosphatase-coupled cGAS activity assay is performed
-
-
-
additional information
?
-
-
a diphosphatase-coupled cGAS activity assay is performed
-
-
-
additional information
?
-
quantification of cyclic Gp(2'-5')Ap(3'-5')(2',3'-cGAMP)WS is performed by LC-MS/MS
-
-
-
additional information
?
-
the substrate orientation is thermodynamically preferred for 2',3'-cGAMP, kinetics, overview. cGAS can produce 2',3'-cGAMP without releasing AMP-2'-GTP to solution. AMP-2'-GTP is produced in significant abundance initially, while 2',3'-cGAMP is not
-
-
-
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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
ATP + GTP
2 diphosphate + cyclic 3',5'-AMP-GMP
cyclic 3',5'-AMP-GMP is a signalling molecule in mammalian cells that triggers the production of type I interferons and other cytokines
-
-
?
ATP + GTP
2 diphosphate + cyclic 3',5'-AMP-GMP
cyclic 3',5'-AMP-GMP is a signalling molecule in mammalian cells that triggers the production of type I interferons and other cytokines
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
-
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
over 78% conversion within 40 min
-
-
?
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
overall reaction
-
-
?
additional information
?
-
interaction of cGAS and viral DNA sensor IFI16, the pyrin domain of IFI16 mediates the interaction with ND10 bodies and enzyme cGAS
-
-
-
additional information
?
-
-
interaction of cGAS and viral DNA sensor IFI16, the pyrin domain of IFI16 mediates the interaction with ND10 bodies and enzyme cGAS
-
-
-
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(1R,2S)-2-(7-oxo-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamido)cyclohexane-1-carboxylic acid
-
(3R)-1-(pyrrolo[1,2-a]quinoxalin-4-yl)piperidine-3-carboxylic acid
16.8% inhibition at 0.1 mM
1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinoline-6,7-dicarboxylic acid
39.9% inhibition at 0.1 mM
1-[9-(6-aminopyridin-3-yl)-6,7-dichloro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl]-2-hydroxyethan-1-one
3-[1-(6,7-dichloro-1H-benzimidazol-2-yl)-5-hydroxy-3-methyl-pyrazol-4-yl]-3H-isobenzofuran-1-one
-
3-[5-(carboxymethyl)-3-oxo-3,5-dihydro[1,2,4]triazino[2,3-a]benzimidazol-2-yl]propanoic acid
29.9% inhibition at 0.1 mM
4-(dimethylamino)-6-((4-fluorophenyl)amino)-1,3,5-triazine-2-carbonitrile
-
4-amino-6-((4-fluorophenyl)amino)-N-methyl-1,3,5-triazine-2-carboxamide
-
4-amino-N-benzyl-6-((4-fluorophenyl)amino)-1,3,5-triazine-2-carboxamide
-
4-[(4-fluorophenyl)amino]-6-(methylamino)-1,3,5-triazine-2-carbonitrile
-
4-[2-(2-methyl[1,2,4]triazolo[1,5-c]quinazolin-5-yl)hydrazinyl]-4-oxobutanoic acid
21.8% inhibition at 0.1 mM
6-(1H-benzo[d]imidazol-1-yl)-N2-(4-iodophenyl)-1,3,5-triazine-2,4-diamine
-
6-(4-(2-aminophenyl)-1H-1,2,3-triazol-1-yl)-N2-(4-iodophenyl)-1,3,5-triazine-2,4-diamine
-
6-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)-N2-(4-iodophenyl)-1,3,5-triazine-2,4-diamine
-
9-amino-6-chloro-2-methoxyacridine
-
antimalarial drug, inhibits dsDNA stimulation of cGAS. IC50 value for interferon IFN-beta 0.0053 mM
methyl 4-(dimethylamino)-6-((4-fluorophenyl)amino)-1,3,5-triazine-2-carboxylate
-
methyl 4-amino-6-((3,4,5-trifluorophenyl)amino)-1,3,5-triazine-2-carboxylate
-
methyl 4-amino-6-((4-(trifluoromethyl)phenyl)amino)-1,3,5-triazine-2-carboxylate
-
methyl 4-amino-6-((4-fluorophenyl)(methyl)amino)-1,3,5-triazine-2-carboxylate
-
methyl 4-amino-6-(3,5-difluoro-4-iodoanilino)-1,3,5-triazine-2-carboxylate
i.e. CU-76, selectively inhibits the DNA pathway in human cells but has no effect on the RIG-I-MAVS or Toll-like receptor pathways
-
methyl 4-amino-6-(4-iodoanilino)-1,3,5-triazine-2-carboxylate
i.e. CU-32, selectively inhibits the DNA pathway in human cells but has no effect on the RIG-I-MAVS or Toll-like receptor pathways
-
methyl 4-amino-6-[(3,5-difluoro-4-iodophenyl)amino]-1,3,5-triazine-2-carboxylate
-
methyl 4-[(4-fluorophenyl)amino]-6-(methylamino)-1,3,5-triazine-2-carboxylate
-
N-[2-(1-(4-amino-6-[(4-iodophenyl)amino]-1,3,5-triazin-2-yl)-1H-1,2,3-triazol-4-yl)phenyl]methanesulfonamide
-
Quinacrine
-
antimalarial drug, inhibits dsDNA stimulation of cGAS. IC50 value for interferon IFN-beta 0.0037 mM
(1R,2S)-2-(7-oxo-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamido)cyclohexane-1-carboxylic acid
PF-06928215, a commercial inhibitor, enzyme binding structure analysis, the pyrazolopyrimidine of PF-06928215 is sandwiched between the guanidinium group of R376 and the aromatic ring of Y436, mimicking the nucleobase. The benzene is anchored in a hydrophobic subpocket lined by the side chains of F488 and L490, molecular dynamics simulations, overview
-
(1R,2S)-2-(7-oxo-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamido)cyclohexane-1-carboxylic acid
PF-06928215, a commercial inhibitor
-
1-[9-(6-aminopyridin-3-yl)-6,7-dichloro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl]-2-hydroxyethan-1-one
-
1-[9-(6-aminopyridin-3-yl)-6,7-dichloro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl]-2-hydroxyethan-1-one
-
-
3-[1-(6,7-dichloro-1H-benzimidazol-2-yl)-5-hydroxy-3-methyl-pyrazol-4-yl]-3H-isobenzofuran-1-one
RU-521 or RU.521
-
3-[1-(6,7-dichloro-1H-benzimidazol-2-yl)-5-hydroxy-3-methyl-pyrazol-4-yl]-3H-isobenzofuran-1-one
-
RU-521 or RU.521
-
3-[1-(6,7-dichloro-1H-benzimidazol-2-yl)-5-hydroxy-3-methyl-pyrazol-4-yl]-3H-isobenzofuran-1-one
RU-521 or RU.521
-
3-[1-(6,7-dichloro-1H-benzimidazol-2-yl)-5-hydroxy-3-methyl-pyrazol-4-yl]-3H-isobenzofuran-1-one
RU-521 or RU.521, markedly mitigates the inflammatory responses, oxidative stress and apoptosis in hearts of sepsis mice. RU.521 attenuates myocardial apoptosis in the hearts of mice with sepsis
-
7-methoxy-N9-methyl-N9-[3-[methyl(pyridin-4-yl)amino]propyl]acridine-3,9-diamine
-
7-methoxy-N9-methyl-N9-[3-[methyl(pyridin-4-yl)amino]propyl]acridine-3,9-diamine
-
-
additional information
in silico screening-based discovery of inhibitors of human cyclic GMP-AMP synthase, cross-validation study of molecular docking and experimental testing, usage of catalytic domain of human cGAS (h-cGASCD) for virtual screening, overview
-
additional information
-
in silico screening-based discovery of inhibitors of human cyclic GMP-AMP synthase, cross-validation study of molecular docking and experimental testing, usage of catalytic domain of human cGAS (h-cGASCD) for virtual screening, overview
-
additional information
discovery of small-molecule cyclic GMP-AMP synthase inhibitors, sceening and molecular docking study using structure PDB ID 4O6A, overview
-
additional information
-
discovery of small-molecule cyclic GMP-AMP synthase inhibitors, sceening and molecular docking study using structure PDB ID 4O6A, overview
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Plasmodium falciparum genomic DNA
activates cGAS in vivo in THP-1 cells, no effect in enzyme-deficient cGAS-/- THP-1 cells. 2',3'-cGAMP is produced in Pf gDNA-transfected THP-1 cells but not in control THP-1 cells
-
dsDNA
presence of dsDNA activates cGAS. dsDNA of 12 bp in length does not activate mcGAS efficiently, dsDNA of 18 bp in length has about 90% activity compared to salmon sperm DNA. Interactions of both DNA binding aites are essential for activation. The two sites bind cooperatively and site B plays a crucial role in binding. DNA binding by induces higher-order complex formation in solution
-
dsDNA
cGAS is activated by dsDNA, a site for small molecule binders may cause cGAS activation at physiological ATP concentrations. dsDNA in the cytosol may occur from infection or mitochondrial damage
-
dsDNA
presence of dsDNA activates cGAS. dsDNA of 12 bp in length does not activate mcGAS efficiently, dsDNA of 18 bp in length has about 90% activity compared to salmon sperm DNA. Interactions of both DNA binding aites are essential for activation. The two sites bind cooperatively and site B plays a crucial role in binding. DNA binding by induces higher-order complex formation in solution
-
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
Michaelis-Menten kinetics, kinetic analysis by different methods with full-length and truncated enzyme, overview
-
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0039
(4-amino-6-((4-fluorophenyl)(methyl)amino)-1,3,5-triazin-2-yl)methanol
Homo sapiens
pH 7.5, 37°C
0.0043
(4-amino-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)methanol
Homo sapiens
pH 7.5, 37°C
0.00059
4-amino-6-((4-iodophenyl)amino)-1,3,5-triazine-2-carboxylicacid
Homo sapiens
pH 7.5, 37°C
0.0038
4-amino-6-(4-fluoroanilino)-1,3,5-triazine-2-carboxylic acid
Homo sapiens
pH 7.5, 37°C
0.00023
6-(4-(2-aminophenyl)-1H-1,2,3-triazol-1-yl)-N2-(4-iodophenyl)-1,3,5-triazine-2,4-diamine
Homo sapiens
pH 7.5, 37°C
0.0023
6-(aminomethyl)-N2-(4-fluorophenyl)-1,3,5-triazine-2,4-diamine
Homo sapiens
pH 7.5, 37°C
0.1
6-(azidomethyl)-N2-(4-iodophenyl)-1,3,5-triazine-2,4-diamine
Homo sapiens
pH 7.5, 37°C
0.0131
methyl 4-amino-6-((2-iodophenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37°C
0.00024 - 0.00027
methyl 4-amino-6-((3,4,5-trifluorophenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37°C
0.0149
methyl 4-amino-6-((4-(trifluoromethyl)phenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37°C
0.0014
methyl 4-amino-6-((4-ethynylphenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37°C
0.0087
methyl 4-amino-6-((4-hydroxyphenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37°C
0.00045 - 0.00066
methyl 4-amino-6-((4-iodophenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37°C
0.0045
methyl 4-amino-6-((4-methoxyphenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37°C
0.005
methyl 4-amino-6-(phenylamino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37°C
0.0015
methyl 4-amino-6-[(3,5-difluoro-4-iodophenyl)amino]-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37°C
0.0025
N-2-(4-iodophenyl)-6-(1,3,4-oxadiazol-2-yl)-1,3,5-triazine-2,4-diamine
Homo sapiens
pH 7.5, 37°C
0.0034
N2-(4-iodophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazine-2,4-diamine
Homo sapiens
pH 7.5, 37°C
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.5
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
SwissProt
brenda
-
SwissProt
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
primary human endothelial cells mount robust IFN-I responses to human Cytomegalovirus that are dependent upon cyclic GMP-AMP synthase cGAS, STING, and interferon regulatory factor IRF3 signaling
brenda
mRNA is abundant in the spleen, duodenum, jejunum, and ileum
brenda
mRNA is abundant in the spleen, duodenum, jejunum, and ileum
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
upon infection with Chlamydia trachomatis cGAS localizes in punctate regions on the cytosolic side of the chlamydial inclusion membrane in association with stimulator of genes STING
brenda
telomeric DNA and cGAS are co-localized in a limited number of micronuclei
brenda
additional information