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Cyclic GMP-AMP synthase

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 3165

Nomenclature: Cyclic GMP-AMP synthase

Family: Cyclic GMP-AMP synthase

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 522 6q13 CGAS cyclic GMP-AMP synthase
Mouse - 507 9 E1 Cgas cyclic GMP-AMP synthase
Rat - 358 8q31 Cgas cyclic GMP-AMP synthase
Database Links Click here for help
BRENDA
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction Click here for help
EC Number: 2.7.7.86 ATP + GTP <=> 2 diphosphate + cyclic G-P(2'-5')A-P(3'-5')

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
PF‐06928215 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 6.7 pKd 1
pKd 6.7 (Kd 2x10-7 M) [1]
Description: Binding affinity determined by SPR.
PF‐06928215 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 5.3 pIC50 1
pIC50 5.3 (IC50 4.9x10-6 M) [1]
Description: Enzyme inhibition determined by FP assay.
Immunopharmacology Comments
Cyclic GMP-AMP synthase (cGAS) directly binds to cytosolic DNA, and in response catalyses the synthesis of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Thus cGAS acts as a sensor of DNA in the cytoplasm, which is an indicator of pathogen invasion [3]. The generated cGAMP then binds to STING (stimulator of interferon genes) which is a key mediator of the innate immune system, whose activation induces production of interferons and inflammatory cytokines (via IRF3‐ and NF-κB‐dependent transcription). The cGAS-STING pathway is also associated with a number of human sterile inflammatory conditions and cancer. Pharmacological modulation of both cGAS [2] and STING is being explored for clinical potential. cGAS‐specific small molecule inhibitor development has primarily identified compounds that occupy the enzyme's active site.

References

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1. Hall J, Brault A, Vincent F, Weng S, Wang H, Dumlao D, Aulabaugh A, Aivazian D, Castro D, Chen M et al.. (2017) Discovery of PF-06928215 as a high affinity inhibitor of cGAS enabled by a novel fluorescence polarization assay. PLoS One, 12 (9): e0184843. [PMID:28934246]

2. Hertzog J, Rehwinkel J. (2020) Regulation and inhibition of the DNA sensor cGAS. EMBO Rep,: e51345 [Epub ahead of print]. [PMID:33155371]

3. Sun L, Wu J, Du F, Chen X, Chen ZJ. (2013) Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science, 339 (6121): 786-91. [PMID:23258413]

How to cite this page

Cyclic GMP-AMP synthase: Cyclic GMP-AMP synthase. Last modified on 09/11/2020. Accessed on 03/12/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3165.