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Information on EC 2.7.7.86 - cyclic GMP-AMP synthase and Organism(s) Mus musculus and UniProt Accession Q8C6L5
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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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The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
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Synonyms
cyclic gmp-amp synthase, cyclic guanosine monophosphate-adenosine monophosphate synthase, cgamp synthase, hcgas, mb21d1, chcgas, h-cgas, c6orf150, mab-21 domain-containing protein, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
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.
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 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
-
-
?
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 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
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
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
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
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
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
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 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
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
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). CGAS_MOUSE
507
0
58194
Swiss-Prot
other Location (Reliability: 4)
PDB
SCOP
CATH
UNIPROT
ORGANISM
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
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
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
free enzyme or bound to a 16 base pair complementary double stranded DNA and ATP
structure of mouse cGAS bound to an 18 bp dsDNA. cGAS interacts with dsDNA through two binding sites, forming a 2:2 complex. enzyme forms a dimer in the crystal
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
K160E
mutation dramatically reduces enzyme activity but only slightly reduces DNA binding
K240E
mutation dramatically reduces DNA binding, mutant still exhibits some catalytic activity
R158E
mutation dramatically reduces enzyme activity but only slightly reduces DNA binding
R161E
mutation dramatically reduces enzyme activity but only slightly reduces DNA binding
R222E
mutation dramatically reduces DNA binding, mutant still exhibits some catalytic activity
S165E
mutation dramatically reduces enzyme activity but only slightly reduces DNA binding
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in HEK293T cells and expressed in Escherichia coli as a SUMO (small ubiquitin-related modifier protein) fusion protein
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
Mycobacterium tuberculosis activates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase cGAS in macrophages to produce cGAMP, that activates the adaptor protein stimulator of interferon genes STING to induce type I interferons and other cytokines
medicine
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cGAS and Ifi204 cooperate to sense cytosolic dsDNA and rancisella. novicida infection to produce a strong type I IFN response
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Sun, L.; Wu, J.; Du, F.; Chen, X.; Chen, Z.J.
Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway
Science
339
786-791
2013
Mus musculus (Q8C6L5), Homo sapiens (Q8N884)
Gao, P.; Ascano, M.; Wu, Y.; Barchet, W.; Gaffney, B.L.; Zillinger, T.; Serganov, A.A.; Liu, Y.; Jones, R.A.; Hartmann, G.; Tuschl, T.; Patel, D.J.
Cyclic [G(2,5)pA(3,5)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase
Cell
153
1094-1107
2013
Mus musculus (Q8C6L5)
Collins, A.C.; Cai, H.; Li, T.; Franco, L.H.; Li, X.D.; Nair, V.R.; Scharn, C.R.; Stamm, C.E.; Levine, B.; Chen, Z.J.; Shiloh, M.U.
Cyclic GMP-AMP synthase is an innate immune DNA sensor for Mycobacterium tuberculosis
Cell Host Microbe
17
820-828
2015
Mus musculus (Q8C6L5), Mus musculus, Homo sapiens (Q8N884), Homo sapiens
Li, X.; Shu, C.; Yi, G.; Chaton, C.T.; Shelton, C.L.; Diao, J.; Zuo, X.; Kao, C.C.; Herr, A.B.; Li, P.
Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced oligomerization
Immunity
39
1019-1031
2013
Mus musculus (Q8C6L5), Mus musculus, Homo sapiens (Q8N884)
Storek, K.M.; Gertsvolf, N.A.; Ohlson, M.B.; Monack, D.M.
cGAS and Ifi204 cooperate to produce type I IFNs in response to Francisella infection
J. Immunol.
194
3236-3245
2015
Mus musculus
Motani, K.; Ito, S.; Nagata, S.
DNA-mediated cyclic GMP-AMP synthase-dependent and -independent regulation of innate immune responses
J. Immunol.
194
4914-4923
2015
Mus musculus (Q8C6L5), Mus musculus
Xia, P.; Ye, B.; Wang, S.; Zhu, X.; Du, Y.; Xiong, Z.; Tian, Y.; Fan, Z.
Glutamylation of the DNA sensor cGAS regulates its binding and synthase activity in antiviral immunity
Nat. Immunol.
17
369-378
2016
Mus musculus (Q8C6L5)
Gao, D.; Li, T.; Li, X.D.; Chen, X.; Li, Q.Z.; Wight-Carter, M.; Chen, Z.J.
Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases
Proc. Natl. Acad. Sci. USA
112
E5699-E5705
2015
Mus musculus (Q8C6L5), Mus musculus
Xu, Q.; Xiong, H.; Zhu, W.; Liu, Y.; Du, Y.
Small molecule inhibition of cyclic GMP-AMP synthase ameliorates sepsis-induced cardiac dysfunction in mice
Life Sci.
260
118315
2020
Mus musculus (Q8C6L5)
Sharma, M.; Rajendrarao, S.; Shahani, N.; Ramirez-Jarquin, U.N.; Subramaniam, S.
Cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease
Proc. Natl. Acad. Sci. USA
117
15989-15999
2020
Mus musculus (Q8C6L5), Homo sapiens (Q8N884), Homo sapiens, Mus musculus C57BL/6J (Q8C6L5)
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