Information on EC 2.7.7.86 - cyclic GMP-AMP synthase

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
2.7.7.86
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RECOMMENDED NAME
GeneOntology No.
cyclic GMP-AMP synthase
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
ATP + GTP = 2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
show the reaction diagram
overall reaction
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-
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ATP + GTP = pppGp(2'-5')A + diphosphate
show the reaction diagram
(1a)
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pppGp(2'-5')A = cyclic Gp(2'-5')Ap(3'-5') + diphosphate
show the reaction diagram
(1b)
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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.
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
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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
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + GTP
2 diphosphate + cyclic 3',5'-AMP-GMP
show the reaction diagram
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
show the reaction diagram
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + GTP
2 diphosphate + cyclic 3',5'-AMP-GMP
show the reaction diagram
ATP + GTP
2 diphosphate + cyclic Gp(2'-5')Ap(3'-5')
show the reaction diagram
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Mg2+
-
required for activity
Mn2+
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required for activity
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
9-amino-6-chloro-2-methoxyacridine
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antimalarial drug, inhibits dsDNA stimulation of cGAS. IC50 value for interferon IFN-beta 0.0053 mM
Quinacrine
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antimalarial drug, inhibits dsDNA stimulation of cGAS. IC50 value for interferon IFN-beta 0.0037 mM
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
dsDNA
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.032
9-amino-6-chloro-2-methoxyacridine
Homo sapiens;
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pH 7.5, 22°C
0.013
Quinacrine
Homo sapiens;
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pH 7.5, 22°C
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
mRNA is abundant in the spleen, duodenum, jejunum, and ileum
Manually annotated by BRENDA team
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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
Manually annotated by BRENDA team
mRNA is abundant in the spleen, duodenum, jejunum, and ileum
Manually annotated by BRENDA team
mRNA is abundant in the spleen, duodenum, jejunum, and ileum
Manually annotated by BRENDA team
mRNA is abundant in the spleen, duodenum, jejunum, and ileum
Manually annotated by BRENDA team
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rheumatoid arthritis synoviocyte
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
membrane of endoplasmic reticulum
Manually annotated by BRENDA team
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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
Manually annotated by BRENDA team
PDB
SCOP
CATH
UNIPROT
ORGANISM
Homo sapiens;
Mus musculus;
Sus scrofa;
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
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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
sitting drop vapor diffusion method, using 18% (w/v) PEG3350, 0.2 M ammonium nitrate, 0.5 M NaCl, and 0.02 mM CYMAL-7
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structure of cGAS catalytic domain
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free enzyme or bound to a 16 base pair complementary double stranded DNA and ATP
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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
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Ni-NTA column chromatography, HiTrap heparin column chromatography, and Superdex 200 gel filtration
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli Rosetta2 (DE3) cells
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expressed in HEK-293 cells
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expressed in HEK293T cells
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expressed in HEK293T cells and expressed in Escherichia coli as a SUMO (small ubiquitin-related modifier protein) fusion protein
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
K160E
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mutation dramatically reduces enzyme activity but only slightly reduces DNA binding
K240E
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mutation dramatically reduces DNA binding, mutant still exhibits some catalytic activity
R158E
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mutation dramatically reduces enzyme activity but only slightly reduces DNA binding
R161E
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mutation dramatically reduces enzyme activity but only slightly reduces DNA binding
R222E
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mutation dramatically reduces DNA binding, mutant still exhibits some catalytic activity
S165E
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mutation dramatically reduces enzyme activity but only slightly reduces DNA binding
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine