Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQDYH8E)

• DOT Name: Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A)
• Synonyms: 2',3'-cGAMP phosphodiesterase SMPDL3A; EC 3.1.4.-; Acid sphingomyelinase-like phosphodiesterase 3a; ASM-like phosphodiesterase 3a; EC 3.6.1.15
• Gene Name: SMPDL3A
• UniProt ID: ASM3A_HUMAN
• PDB ID: 5EBB; 5EBE
• EC Number: 3.1.4.-; 3.6.1.15
• Pfam ID: PF19272 ; PF00149
• Sequence:
  MALVRALVCCLLTAWHCRSGLGLPVAPAGGRNPPPAIGQFWHVTDLHLDPTYHITDDHTK
  VCASSKGANASNPGPFGDVLCDSPYQLILSAFDFIKNSGQEASFMIWTGDSPPHVPVPEL
  STDTVINVITNMTTTIQSLFPNLQVFPALGNHDYWPQDQLPVVTSKVYNAVANLWKPWLD
  EEAISTLRKGGFYSQKVTTNPNLRIISLNTNLYYGPNIMTLNKTDPANQFEWLESTLNNS
  QQNKEKVYIIAHVPVGYLPSSQNITAMREYYNEKLIDIFQKYSDVIAGQFYGHTHRDSIM
  VLSDKKGSPVNSLFVAPAVTPVKSVLEKQTNNPGIRLFQYDPRDYKLLDMLQYYLNLTEA
  NLKGESIWKLEYILTQTYDIEDLQPESLYGLAKQFTILDSKQFIKYYNYFFVSYDSSVTC
  DKTCKAFQICAIMNLDNISYADCLKQLYIKHNY
• Function: Cyclic-nucleotide phosphodiesterase that acts as a negative regulator of innate immunity by mediating degradation of 2',3'-cGAMP, thereby inhibiting the cGAS-STING signaling. Specifically linearizes 2',3'-cGAMP into 2'5'-bond pGpA and further hydrolyzes pGpA to produce GpA. Also has in vitro nucleotide phosphodiesterase activity with nucleoside triphosphates, such as ATP. Has in vitro activity with p-nitrophenyl-TMP. Has lower activity with nucleoside diphosphates, and no activity with nucleoside monophosphates. Has in vitro activity with CDP-choline, giving rise to CMP and phosphocholine. Has in vitro activity with CDP-ethanolamine. Does not have sphingomyelin phosphodiesterase activity.
• Tissue Specificity: Detected in blood serum. Detected in macrophages (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A) affects the response to substance of Etoposide.	[17]
Mitomycin	DMH0ZJE	Approved	Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A) affects the response to substance of Mitomycin.	[17]
Theophylline	DMRJFN9	Approved	Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A) increases the Therapeutic agent toxicity ADR of Theophylline.	[18]
Enprofylline	DMFYZKN	Approved	Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A) increases the Therapeutic agent toxicity ADR of Enprofylline.	[18]
isobutylmethylxanthine	DM46F5X	Investigative	Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A) increases the Therapeutic agent toxicity ADR of isobutylmethylxanthine.	[18]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A).	[6]

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A).	[7]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A).	[8]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A).	[9]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A).	[10]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cyclic GMP-AMP phosphodiesterase SMPDL3A (SMPDL3A).	[16]

References

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• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [6] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [11] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [12] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [18] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.