Enzymes
UniProtKB help_outline | 2 proteins |
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- Name help_outline 2',3'-cGAMP Identifier CHEBI:143093 Charge -2 Formula C20H22N10O13P2 InChIKeyhelp_outline XRILCFTWUCUKJR-INFSMZHSSA-L SMILEShelp_outline P1(O[C@@H]2[C@H](O[C@H]([C@@H]2O)N3C=NC=4C(=NC=NC43)N)COP(=O)(O[C@H]5[C@@H](O[C@@H]([C@H]5O)CO1)N6C=NC=7C(NC(=NC76)N)=O)[O-])(=O)[O-] 2D coordinates Mol file for the small molecule Search links Involved in 9 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline H2O Identifier CHEBI:15377 (Beilstein: 3587155; CAS: 7732-18-5) help_outline Charge 0 Formula H2O InChIKeyhelp_outline XLYOFNOQVPJJNP-UHFFFAOYSA-N SMILEShelp_outline [H]O[H] 2D coordinates Mol file for the small molecule Search links Involved in 6,048 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline AMP Identifier CHEBI:456215 Charge -2 Formula C10H12N5O7P InChIKeyhelp_outline UDMBCSSLTHHNCD-KQYNXXCUSA-L SMILEShelp_outline Nc1ncnc2n(cnc12)[C@@H]1O[C@H](COP([O-])([O-])=O)[C@@H](O)[C@H]1O 2D coordinates Mol file for the small molecule Search links Involved in 487 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline GMP Identifier CHEBI:58115 Charge -2 Formula C10H12N5O8P InChIKeyhelp_outline RQFCJASXJCIDSX-UUOKFMHZSA-L SMILEShelp_outline Nc1nc2n(cnc2c(=O)[nH]1)[C@@H]1O[C@H](COP([O-])([O-])=O)[C@@H](O)[C@H]1O 2D coordinates Mol file for the small molecule Search links Involved in 39 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline H+ Identifier CHEBI:15378 Charge 1 Formula H InChIKeyhelp_outline GPRLSGONYQIRFK-UHFFFAOYSA-N SMILEShelp_outline [H+] 2D coordinates Mol file for the small molecule Search links Involved in 9,176 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
Cross-references
RHEA:58808 | RHEA:58809 | RHEA:58810 | RHEA:58811 | |
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Reaction direction help_outline | undefined | left-to-right | right-to-left | bidirectional |
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Gene Ontology help_outline |
Publications
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Hydrolysis of 2'3'-cGAMP by ENPP1 and design of nonhydrolyzable analogs.
Li L., Yin Q., Kuss P., Maliga Z., Millan J.L., Wu H., Mitchison T.J.
Agonists of mouse STING (TMEM173) shrink and even cure solid tumors by activating innate immunity; human STING (hSTING) agonists are needed to test this therapeutic hypothesis in humans. The endogenous STING agonist is 2'3'-cGAMP, a second messenger that signals the presence of cytosolic double-st ... >> More
Agonists of mouse STING (TMEM173) shrink and even cure solid tumors by activating innate immunity; human STING (hSTING) agonists are needed to test this therapeutic hypothesis in humans. The endogenous STING agonist is 2'3'-cGAMP, a second messenger that signals the presence of cytosolic double-stranded DNA. We report activity-guided partial purification and identification of ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP1) to be the dominant 2'3'-cGAMP hydrolyzing activity in cultured cells. The hydrolysis activity of ENPP1 was confirmed using recombinant protein and was depleted in tissue extracts and plasma from Enpp1(-/-) mice. We synthesized a hydrolysis-resistant bisphosphothioate analog of 2'3'-cGAMP (2'3'-cG(s)A(s)MP) that has similar affinity for hSTING in vitro and is ten times more potent at inducing IFN-β secretion from human THP1 monocytes. Studies in mouse Enpp1(-/-) lung fibroblasts indicate that resistance to hydrolysis contributes substantially to its higher potency. 2'3'-cG(s)A(s)MP is therefore improved over natural 2'3'-cGAMP as a model agonist and has potential as a vaccine adjuvant and cancer therapeutic. << Less
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Structural insights into cGAMP degradation by Ecto-nucleotide pyrophosphatase phosphodiesterase 1.
Kato K., Nishimasu H., Oikawa D., Hirano S., Hirano H., Kasuya G., Ishitani R., Tokunaga F., Nureki O.
ENPP1 (Ecto-nucleotide pyrophosphatase phosphodiesterase 1), a type II transmembrane glycoprotein, hydrolyzes ATP to produce AMP and diphosphate, thereby inhibiting bone mineralization. A recent study showed that ENPP1 also preferentially hydrolyzes 2'3'-cGAMP (cyclic GMP-AMP) but not its linkage ... >> More
ENPP1 (Ecto-nucleotide pyrophosphatase phosphodiesterase 1), a type II transmembrane glycoprotein, hydrolyzes ATP to produce AMP and diphosphate, thereby inhibiting bone mineralization. A recent study showed that ENPP1 also preferentially hydrolyzes 2'3'-cGAMP (cyclic GMP-AMP) but not its linkage isomer 3'3'-cGAMP, and negatively regulates the cGAS-STING pathway in the innate immune system. Here, we present the high-resolution crystal structures of ENPP1 in complex with 3'3'-cGAMP and the reaction intermediate pA(3',5')pG. The structures revealed that the adenine and guanine bases of the dinucleotides are recognized by nucleotide- and guanine-pockets, respectively. Furthermore, the structures indicate that 2'3'-cGAMP, but not 3'3'-cGAMP, binds to the active site in a conformation suitable for catalysis, thereby explaining the specific degradation of 2'3'-cGAMP by ENPP1. Our findings provide insights into how ENPP1 hydrolyzes both ATP and cGAMP to participate in the two distinct biological processes. << Less