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ATP + GTP
2 diphosphate + cyclic 3',5'-AMP-GMP
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
additional information
?
-
ATP + GTP
2 diphosphate + cyclic 3',5'-AMP-GMP
-
-
-
?
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
-
-
-
?
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')
-
-
-
-
?
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')
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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(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
(4-amino-6-((4-fluorophenyl)(methyl)amino)-1,3,5-triazin-2-yl)methanol
-
(4-amino-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)methanol
-
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
4,6-dichloro-N-(4-fluorophenyl)-1,3,5-triazin-2-amine
-
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-6-((4-iodophenyl)amino)-1,3,5-triazine-2-carboxylicacid
-
4-amino-6-(4-fluoroanilino)-1,3,5-triazine-2-carboxylic acid
-
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-((4-fluorophenyl)amino)pyrimidine-4-carboxylic Acid
-
6-(1H-benzo[d]imidazol-1-yl)-N2-(4-iodophenyl)-1,3,5-triazine-2,4-diamine
-
6-(1H-indazol-1-yl)-N2-(4-iodophenyl)-1,3,5-triazine-2,4-diamine
-
6-(1H-indol-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
-
6-(aminomethyl)-N2-(4-fluorophenyl)-1,3,5-triazine-2,4-diamine
-
6-(azidomethyl)-N2-(4-iodophenyl)-1,3,5-triazine-2,4-diamine
-
6-chloro-N2-(4-fluorophenyl)-N4,N4-dimethyl-1,3,5-triazine-2,4-diamine
-
7-methoxy-N9-methyl-N9-[3-[methyl(pyridin-4-yl)amino]propyl]acridine-3,9-diamine
9-amino-6-chloro-2-methoxyacridine
-
antimalarial drug, inhibits dsDNA stimulation of cGAS. IC50 value for interferon IFN-beta 0.0053 mM
methyl 3-amino-5-((4-fluorophenyl)amino)benzoate
-
methyl 4-(dimethylamino)-6-((4-fluorophenyl)amino)-1,3,5-triazine-2-carboxylate
-
methyl 4-amino-6-((2-iodophenyl)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-ethynylphenyl)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-((4-fluorophenyl)amino)picolinate
-
methyl 4-amino-6-((4-hydroxyphenyl)amino)-1,3,5-triazine-2-carboxylate
-
methyl 4-amino-6-((4-iodophenyl)amino)-1,3,5-triazine-2-carboxylate
-
methyl 4-amino-6-((4-methoxyphenyl)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-(phenylamino)-1,3,5-triazine-2-carboxylate
-
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-(4-iodophenyl)-6-(1,3,4-oxadiazol-2-yl)-1,3,5-triazine-2,4-diamine
-
N-[2-(1-(4-amino-6-[(4-iodophenyl)amino]-1,3,5-triazin-2-yl)-1H-1,2,3-triazol-4-yl)phenyl]methanesulfonamide
-
N2-(4-fluorophenyl)-6-(methoxymethyl)-1,3,5-triazine-2,4-diamine
-
N2-(4-iodophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazine-2,4-diamine
-
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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0.0039
(4-amino-6-((4-fluorophenyl)(methyl)amino)-1,3,5-triazin-2-yl)methanol
Homo sapiens
pH 7.5, 37ยฐC
0.0043
(4-amino-6-((4-fluorophenyl)amino)-1,3,5-triazin-2-yl)methanol
Homo sapiens
pH 7.5, 37ยฐC
0.00059
4-amino-6-((4-iodophenyl)amino)-1,3,5-triazine-2-carboxylicacid
Homo sapiens
pH 7.5, 37ยฐC
0.0038
4-amino-6-(4-fluoroanilino)-1,3,5-triazine-2-carboxylic acid
Homo sapiens
pH 7.5, 37ยฐC
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, 37ยฐC
0.0023
6-(aminomethyl)-N2-(4-fluorophenyl)-1,3,5-triazine-2,4-diamine
Homo sapiens
pH 7.5, 37ยฐC
0.1
6-(azidomethyl)-N2-(4-iodophenyl)-1,3,5-triazine-2,4-diamine
Homo sapiens
pH 7.5, 37ยฐC
0.032
9-amino-6-chloro-2-methoxyacridine
Homo sapiens
-
pH 7.5, 22ยฐC
0.0131
methyl 4-amino-6-((2-iodophenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37ยฐC
0.00024 - 0.00027
methyl 4-amino-6-((3,4,5-trifluorophenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37ยฐC
0.0149
methyl 4-amino-6-((4-(trifluoromethyl)phenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37ยฐC
0.0014
methyl 4-amino-6-((4-ethynylphenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37ยฐC
0.0087
methyl 4-amino-6-((4-hydroxyphenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37ยฐC
0.00045 - 0.00066
methyl 4-amino-6-((4-iodophenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37ยฐC
0.0045
methyl 4-amino-6-((4-methoxyphenyl)amino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37ยฐC
0.005
methyl 4-amino-6-(phenylamino)-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37ยฐC
0.0015
methyl 4-amino-6-[(3,5-difluoro-4-iodophenyl)amino]-1,3,5-triazine-2-carboxylate
Homo sapiens
pH 7.5, 37ยฐC
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, 37ยฐC
0.0034
N2-(4-iodophenyl)-6-(1H-pyrazol-1-yl)-1,3,5-triazine-2,4-diamine
Homo sapiens
pH 7.5, 37ยฐC
0.013
Quinacrine
Homo sapiens
-
pH 7.5, 22ยฐC
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evolution
beta2 and beta6 of cGAS harbor the signature catalytic site residues (E200, D202 and D296) of the NTase superfamily coordinating catalytic Mg2+ ions and nucleotides
malfunction
knockout or knockdown of the enzyme blocks cytokine induction by HIV, murine leukemia virus, and simian immunodeficiency virus. cGAS mutant cell lines fail to activate IRF3 in response to HT-DNA transfection or HSV-1 infection
malfunction
aberrant activation of cGAS is associated with various autoimmune disorders
malfunction
depletion of cGAS diminishes cGAS activity and decreases the expression of inflammatory genes while suppressing the upregulation of autophagy in Huntington disease (HD) cells, while reinstating cGAS in cGAS-depleted HD cells activates cGAS activity and promotes inflammatory and autophagy responses. Phenotype, overview
malfunction
depletion of cGAS diminishes cGAS activity and decreases the expression of inflammatory genes while suppressing the upregulation of autophagy in Huntington disease (HD) cells, while reinstating cGAS in cGAS-depleted HD cells activates cGAS activity and promotes inflammatory and autophagy responses. Phenotype, overview
malfunction
dysregulation of the cGAS pathway is linked to autoimmune diseases while targeted stimulation may be of benefit in immunoncology
malfunction
overexpression of chcGAS induces Ifn-beta and Il-1beta expression. ChcGAS-induced IFN-beta and IL-1beta expression is dependent on the STING signaling pathway. Ablation of chcGAS abrogates dsDNA-stimulated IFN-beta and IL-1beta expression. Knockdown of cGAS promotes FAdV-4 infection
malfunction
small molecule inhibition of cyclic GMP-AMP synthase by RU.521 ameliorates sepsis-induced cardiac dysfunction in mice. The inflammatory responses, oxidative stress and apoptosis in hearts of sepsis mice are markedly mitigated by RU.521. The septic mice that undergo RU.521 treatment exhibit suppressed myocardial apoptosis, which is indicated by decreased caspase-3 activity
malfunction
-
depletion of cGAS diminishes cGAS activity and decreases the expression of inflammatory genes while suppressing the upregulation of autophagy in Huntington disease (HD) cells, while reinstating cGAS in cGAS-depleted HD cells activates cGAS activity and promotes inflammatory and autophagy responses. Phenotype, overview
-
metabolism
cellular intrinsic mechanism involving the cGAS-mediated cytosolic self-DNA-sensing pathway that initiates premature senescence independently of telomere shortening, overview. Micronuclei generated in response to telomeric DNA replication stress recruit cGAS and cause cellular senescence
metabolism
STING undergoes large conformational changes by binding to 2',3'-cGAMP and then recruits TANK binding kinase (TBK1), thus resulting in the phosphorylation of IFN-regulated factor 3 (IRF3) and nuclear factor-kappaB (NF-kappaB), and promoting the expression of IFNs and proinflammatory cytokines. chcGAS might be involved in sensing a DNA virus, FAdV-4, in LMH cells
metabolism
the relationship of cGAS and STING is both old (as much as much as 500 million years of co-evolution), and interesting in that cGAS is a low-activity enzyme while STING is a particularly avid binder of the cGAS product
metabolism
viral DNA sensors IFI16 and cyclic GMP-AMP synthase possess distinct functions in regulating viral gene expression, immune defenses, and apoptotic responses during herpesvirus infection. IFI16 is also proposed to stimulate other cellular pathways upon its binding to viral DNA. IFI16 is required for antiviral cytokine expression, but not for upstream activation of STING/TBK-1/IRF3 signaling
physiological function
cGAMP synthase catalyzes the production of cGAMP that in turn serves as a second messenger to activate innate immune responses
physiological function
enzyme overexpression induces spontaneous activation of STING and IRF3 phosphorylation in bystander cells
physiological function
the enzyme induces the activation of STING by producing cGAMP from GTP and ATP
physiological function
the enzyme is an innate immune sensor of HIV and other retroviruses. The enzyme binds to and activates the adaptor protein STING to induce type I interferons and other cytokines
physiological function
catalytic product cGAMP-dependent activation of stimulator of IFN genes STING induces highly upregulated CXCL10 gene expression. Formation of a distinct STING dimer is induced by 2'5'-cGAMP, but not 3',5'-3',5'cGAMP. DNase II-/- mice constitutively produce IFN-beta and CXCL10 and accumulate 2',5'-cGAMP in their fetal livers and spleens. DNase II-/- mouse embryonic fibroblasts produce 2',5'-cGAMP in a cGAS-dependent manner during apoptotic cell engulfment. cGAS deficiency does not impair the STING-dependent upregulation of CXCL10 in DNase II-/- mouse embryonic fibroblasts that is induced by apoptotic cell engulfment or DNA lipofection
physiological function
cGAS is overexpressed in rheumatoid arthritis fibroblast-like synoviocytes compared with osteoarthritis fibroblast-like synoviocytes. TNFalpha stimulation induces cGAS expression in rheumatoid arthritis fibroblast-like synoviocytes. Overexpression of cGAS promotes the proliferation and knockdown of cGAS inhibits the proliferation of rheumatoid arthritis fibroblast-like synoviocytes. cGAS overexpression enhances the production of proinflammatory cytokines and matrix metalloproteinases as well as AKT and ERK phosphorylation in TNFalpha-stimulated fibroblast-like synoviocytes. In contrast, cGAS silencing inhibits production of proinflammatory cytokines and matrix metalloproteinases as well as AKT and ERK phosphorylation in TNFalpha-stimulated fibroblast-like synoviocytes
physiological function
cGAS is required for IFN-beta expression during chlamydial infection in multiple cell types. Although infected cells deficient for STING or cGAS alone fail to induce IFN-beta, coculture of cells depleted for either STING or cGAS rescues IFN-beta expression. Cyclic GMP-AMP produced in infected cGAS(+)STING(-) cells can migrate into adjacent cells via gap junctions to function in trans in cGAS(-)STING(+) cells
physiological function
-
cyclic GMP-AMP synthase cGAS and interferon activated gene Ifi204, are both required for the STING-dependent type I IFN response to Francisella novicida infection. cGAS and Ifi204 cooperate to sense dsDNA and activate the STING-dependent type I IFN pathway. dsDNA from Francisella novicida is an important type I IFN stimulating ligand. cGASยSTING signaling leads to activation of the absent in melanoma 2 inflammasome in response to Francisella novicida infection. The absent in melanoma 2 inflammasome is beneficial to the host during Francisella novicida infection, type I IFN signaling by STING and IFN regulatory factor 3 is detrimental to the host
physiological function
exonuclease Trex1-/- mice exhibit autoimmune and inflammatory phenotypes that are associated with elevated expression of interferon-induced genes. Genetic ablation of cGas in Trex1-/- mice eliminates all detectable pathological and molecular phenotypes, including interferon-induced gene induction, autoantibody production, aberrant T-cell activation, and lethality. Even deletion of just one allele of cGas largely rescues the phenotypes of Trex1-/- mice. Deletion of cGas in mice lacking DNaseII, a lysosomal enzyme that digests DNA, rescues the lethal autoimmune phenotypes of the DNaseII-/- mice. cGAMP accumulates in mouse tissues deficient in Trex1 or DNaseII and this accumulation is dependent on cGAS
physiological function
glutamylation and deglutamylation of cGAS tightly modulate immune responses to infection with DNA viruses. Polyglutamylation of cGAS by the enzyme TTLL6 impeded its DNA-binding ability, whereas TTLL4-mediated monoglutamylation of cGAS blocks its synthase activity. Conversely, carboxypeptidase CCP6 removes the polyglutamylation of cGAS, whereas CCP5 hydrolyzes the monoglutamylation of cGAS, which together lead to the activation of cGAS
physiological function
Mycobacterium tuberculosis activates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase cGAS in macrophages to produce cGAMP. cGAS localizes with Mycobacterium tuberculosis in human cells and in human tuberculosis lesions. Knockdown or knockout of cGAS in blocks cytokine production and induction of autophagy
physiological function
Mycobacterium tuberculosis activates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase cGAS in macrophages to produce cGAMP. cGAS localizes with Mycobacterium tuberculosis in mice cells. Knockdown or knockout of cGAS in blocks cytokine production and induction of autophagy. Mice deficient in cGAS are more susceptible to lethality caused by infection with Mycobacterium tuberculosis
physiological function
the overexpression of wild-type cGAS in porcine kidney epithelial cells, but not its catalytically inactive mutants, induces IFN-beta expression, which is dependent on STING and IRF3. The downregulation of cGAS by RNAi markedly reduces IFN-beta expression after pseudorabies virus infection or poly(dA:dT) transfection
physiological function
type I interferon induction by Neisseria gonorrhoeae infection Is dependent on cGAS, but not PYHIN family member IFI16. Complete activation of IFN-beta by Neisseria gonorrhoeae infection is an additive effect of both cGAS/stimulator of IFN genes STING and toll-like receptor TLR4 pathways. cGAMP is induced after GC infection and GC DNA transfection
physiological function
cyclic GMP-AMP (cGAMP) synthase (cGAS) is a predominant DNA sensor inducing the activation of the innate immune responses that produce proinflammatory cytokines and type I interferons. Cyclic GMP-AMP synthase is essential for cytosolic double-stranded DNA and fowl adenovirus serotype 4 triggered innate immune responses in chickens. Chicken cGAS (chcGAS) participates in avian innate immunity. chcGAS is an important cytosolic DNA sensor activating innate immune responses. After binding dsDNA in the cytosol, cGAS converts adenosine 5'-triphosphate and guanosine 5'-triphosphate to 2',3'-cyclic GMP-AMP (2',3'-cGAMP), which serves as a second messenger for stimulator of interferon genes (STING)
physiological function
cyclic GMP-AMP synthase (cGAS) is activated by dsDNA binding to produce the secondary messenger 2',3'-cGAMP. cGAS is an important control point in the innate immune response. A site for small molecule binders that may cause cGAS activation at physiological ATP concentrations, and an apparent hotspot for inhibitor binding. cGAS is activated by ds-DNA binding to catalyze the cyclization of ATP and GTP to form a cyclic dinucleotide with mixed 2',5'- and 3',5'-phosphodiester linkage (2',3'-cGAMP), which in turn activates stimulator of type 1 interferon genes (STING). Activated STING causes the activation of TBK1, which phosphorylates IRF3 allowing it to translocate to the nucleus where it triggers interferon-inducible gene activation and interferon production
physiological function
cyclic GMP-AMP synthase (cGAS) plays crucial roles in autoimmune disease, anti-tumor response, anti-senescence and anti-inflammatory response
physiological function
cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease (HD). cGMP-AMP synthase (cGAS), a DNA sensor, is a critical regulator of inflammatory and autophagy responses in HD. Ribosome profiling reveals that the cGAS mRNA has high ribosome occupancy at exon 1 and codon-specific pauses at positions 171 (CCG) and 172 (CGT) in HD striatal cells. The protein levels and activity of cGAS (based on the phosphorylated STING and phosphorylated TBK1 levels), and the expression and ribosome occupancy of cGAS-dependent inflammatory genes (Ccl5 and Cxcl10) are increased in HD striatum. Phenotype, overview
physiological function
cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease (HD). cGMP-AMP synthase (cGAS), a DNA sensor, is a critical regulator of inflammatory and autophagy responses in HD. Ribosome profiling reveals that the cGAS mRNA has high ribosome occupancy at exon 1 and codon-specific pauses at positions 171 (CCG) and 172 (CGT) in HD striatal cells. The protein levels and activity of cGAS (based on the phosphorylated STING and phosphorylated TBK1 levels), and the expression and ribosome occupancy of cGAS-dependent inflammatory genes (Ccl5 and Cxcl10) are increased in HD striatum. The two major autophagy initiators, LC3A and LC3B, may be differentially regulated via cotranslational proteolytic events to initiate autophagy, which might additionally contribute to the cGAS-mediated autophagy in HD. Phenotype, overview
physiological function
dysfunctional telomeres trigger cellular senescence mediated by cyclic GMP-AMP synthase. Cyclic GMP-AMP synthase (cGAS) recognizing cytosolic chromatin fragments and then activating the stimulator of interferon genes (STING) cytosolic DNA-sensing pathway and downstream interferon signaling. Significantly, genetic and pharmacological manipulation of cGAS not only attenuates immune signaling, but also prevents premature cellular senescence in response to dysfunctional telomeres. cGAS causes premature senescence phenotype in response to dysfunctional telomeres, cGAS-STING-TBK1-IRF3 signaling, mechanism, overview
physiological function
GMP-AMP synthase (cGAS) is a cytosolic DNA sensor and plays an important role in the type I interferon response. DNA from either invading microbes or self-origin triggers the enzymatic activity of cGAS
physiological function
key role of cGAS in sepsis-induced cardiac injury
physiological function
Plasmodium falciparum (Pf, strain 3D7) genomic DNA (gDNA) delivered to the cytosol of human monocytes (THP-1 cells) binds and activates the cyclic GMP-AMP synthase (cGAS). Activated cGAS synthesizes 2',3'-cGAMP, which acts as a second messenger for STING activation and triggers STING/TBK1/IRF3 activation, resulting in type I interferon (IFN) production in human cells. This induction of type I IFN is independent of IFI16. cGAS is an important cytosolic sensor of Plasmodium falciparum genomic DNA (Pf gDNA) and reveal the role of the cGAS/STING pathway in the induction of type I IFN in response to malaria parasites
physiological function
the DNA sensor cyclic GMP-AMP synthase (cGAS) activates the canonical STING/TBK-1/IRF3 signaling axis including IFI16. Interferon-inducible protein 16 (IFI16) binds to DNA of nucleus-replicating herpesviruses and stimulates cytokine expression within infected nuclei. Recognition of viral DNA through DNA sensors is essential for the onset of antiviral responses during infection, mechanism, detailed overview. Analysis of distinct and cooperative functions of the DNA sensors IFI16 and cGAS in mediating antiviral responses to herpesviruses, i.e. HSV-1 and human cytomegalovirus (HCMV), overview. An HSV-1 mutant lacking the E3 ubiquitin ligase activity of the IE viral protein ICP0 from mutations in its ring finger domain (RF) is attenuated in its ability to induce IFI16 degradation.The pyrin domain of IFI16 mediates the interaction with ND10 bodies and cGAS. Of relevance to cellular immunity, both the antiviral ND10 body complex and the DNA sensor cGAS are PY-enriched associations during infection. ND10 body components include PML (promyelocytic leukemia protein), SUMO1, SUMO2, ATRX, SP110, and SP140L
physiological function
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cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease (HD). cGMP-AMP synthase (cGAS), a DNA sensor, is a critical regulator of inflammatory and autophagy responses in HD. Ribosome profiling reveals that the cGAS mRNA has high ribosome occupancy at exon 1 and codon-specific pauses at positions 171 (CCG) and 172 (CGT) in HD striatal cells. The protein levels and activity of cGAS (based on the phosphorylated STING and phosphorylated TBK1 levels), and the expression and ribosome occupancy of cGAS-dependent inflammatory genes (Ccl5 and Cxcl10) are increased in HD striatum. Phenotype, overview
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additional information
in the absence of dsDNA, human cGAS can adopt a cyclic dinucleotide-dependent structure similar to the second of these structural changes, where the catalytic acid containing beta-sheets have moved towards the active site while residues Gly207-Val218 remain disordered
additional information
molecular dynamics simulations and structure modeling, overview
additional information
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molecular dynamics simulations and structure modeling, overview
additional information
structure comparison of chicken enzyme with human enzyme, overview
additional information
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structure comparison of chicken enzyme with human enzyme, overview
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