Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1IZT5K)

• DOT Name: Adenylate cyclase type 9 (ADCY9)
• Synonyms: EC 4.6.1.1; ATP pyrophosphate-lyase 9; Adenylate cyclase type IX; ACIX; Adenylyl cyclase 9; AC9
• Gene Name: ADCY9
• Related Disease:
  Acute coronary syndrome
  Adult respiratory distress syndrome
  Arteriosclerosis
  Atherosclerosis
  Atrichia with papular lesions
  Bipolar disorder
  Breast carcinoma
  Cardiovascular disease
  Colon cancer
  Colon carcinoma
  Congenital alveolar dysplasia
  Focal epilepsy
  Glucocorticoid resistance
  Helminth infection
  Mood disorder
  Obesity
  Promyelocytic leukaemia
  Vascular disease
  Alcohol dependence
  Alpha thalassemia
  Asthma
  Sickle-cell anaemia
  Stroke
• UniProt ID: ADCY9_HUMAN
• EC Number: 4.6.1.1
• Pfam ID: PF00211
• Sequence:
  MASPPHQQLLHHHSTEVSCDSSGDSNSVRVKINPKQLSSNSHPKHCKYSISSSCSSSGDS
  GGVPRRVGGGGRLRRQKKLPQLFERASSRWWDPKFDSVNLEEACLERCFPQTQRRFRYAL
  FYIGFACLLWSIYFAVHMRSRLIVMVAPALCFLLVCVGFFLFTFTKLYARHYAWTSLALT
  LLVFALTLAAQFQVLTPVSGRGDSSNLTATARPTDTCLSQVGSFSMCIEVLFLLYTVMHL
  PLYLSLCLGVAYSVLFETFGYHFRDEACFPSPGAGALHWELLSRGLLHGCIHAIGVHLFV
  MSQVRSRSTFLKVGQSIMHGKDLEVEKALKERMIHSVMPRIIADDLMKQGDEESENSVKR
  HATSSPKNRKKKSSIQKAPIAFRPFKMQQIEEVSILFADIVGFTKMSANKSAHALVGLLN
  DLFGRFDRLCEETKCEKISTLGDCYYCVAGCPEPRADHAYCCIEMGLGMIKAIEQFCQEK
  KEMVNMRVGVHTGTVLCGILGMRRFKFDVWSNDVNLANLMEQLGVAGKVHISEATAKYLD
  DRYEMEDGKVIERLGQSVVADQLKGLKTYLISGQRAKESRCSCAEALLSGFEVIDGSQVS
  SGPRGQGTASSGNVSDLAQTVKTFDNLKTCPSCGITFAPKSEAGAEGGAPQNGCQDEHKN
  STKASGGPNPKTQNGLLSPPQEEKLTNSQTSLCEILQEKGRWAGVSLDQSALLPLRFKNI
  REKTDAHFVDVIKEDSLMKDYFFKPPINQFSLNFLDQELERSYRTSYQEEVIKNSPVKTF
  ASPTFSSLLDVFLSTTVFLTLSTTCFLKYEAATVPPPPAALAVFSAALLLEVLSLAVSIR
  MVFFLEDVMACTKRLLEWIAGWLPRHCIGAILVSLPALAVYSHVTSEYETNIHFPVFTGS
  AALIAVVHYCNFCQLSSWMRSSLATVVGAGPLLLLYVSLCPDSSVLTSPLDAVQNFSSER
  NPCNSSVPRDLRRPASLIGQEVVLVFFLLLLLVWFLNREFEVSYRLHYHGDVEADLHRTK
  IQSMRDQADWLLRNIIPYHVAEQLKVSQTYSKNHDSGGVIFASIVNFSEFYEENYEGGKE
  CYRVLNELIGDFDELLSKPDYSSIEKIKTIGATYMAASGLNTAQAQDGSHPQEHLQILFE
  FAKEMMRVVDDFNNNMLWFNFKLRVGFNHGPLTAGVIGTTKLLYDIWGDTVNIASRMDTT
  GVECRIQVSEESYRVLSKMGYDFDYRGTVNVKGKGQMKTYLYPKCTDHRVIPQHQLSISP
  DIRVQVDGSIGRSPTDEIANLVPSVQYVDKTSLGSDSSTQAKDAHLSPKRPWKEPVKAEE
  RGRFGKAIEKDDCDETGIEEANELTKLNVSKSV
• Function: Adenylyl cyclase that catalyzes the formation of the signaling molecule cAMP in response to activation of G protein-coupled receptors. Contributes to signaling cascades activated by CRH (corticotropin-releasing factor), corticosteroids and beta-adrenergic receptors.
• Tissue Specificity: Detected in skeletal muscle, pancreas, lung, heart, kidney, liver, brain and placenta . Expressed in multiple cells of the lung, with expression highest in airway smooth muscle .
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  Endocrine resistance (hsa01522)
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Chemokine sig.ling pathway (hsa04062)
  Phospholipase D sig.ling pathway (hsa04072)
  Oocyte meiosis (hsa04114)
  Longevity regulating pathway (hsa04211)
  Longevity regulating pathway - multiple species (hsa04213)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Vascular smooth muscle contraction (hsa04270)
  Apelin sig.ling pathway (hsa04371)
  Gap junction (hsa04540)
  Platelet activation (hsa04611)
  Circadian entrainment (hsa04713)
  Thermogenesis (hsa04714)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Glutamatergic sy.pse (hsa04724)
  Cholinergic sy.pse (hsa04725)
  GABAergic sy.pse (hsa04727)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Insulin secretion (hsa04911)
  GnRH sig.ling pathway (hsa04912)
  Ovarian steroidogenesis (hsa04913)
  Progesterone-mediated oocyte maturation (hsa04914)
  Estrogen sig.ling pathway (hsa04915)
  Melanogenesis (hsa04916)
  Thyroid hormone synthesis (hsa04918)
  Oxytocin sig.ling pathway (hsa04921)
  Regulation of lipolysis in adipocytes (hsa04923)
  Aldosterone synthesis and secretion (hsa04925)
  Relaxin sig.ling pathway (hsa04926)
  Cortisol synthesis and secretion (hsa04927)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Cushing syndrome (hsa04934)
  Growth hormone synthesis, secretion and action (hsa04935)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Vasopressin-regulated water reabsorption (hsa04962)
  Salivary secretion (hsa04970)
  Gastric acid secretion (hsa04971)
  Pancreatic secretion (hsa04972)
  Bile secretion (hsa04976)
  Morphine addiction (hsa05032)
  Vibrio cholerae infection (hsa05110)
  Human cytomegalovirus infection (hsa05163)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Pathways in cancer (hsa05200)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway:
  PKA activation (R-HSA-163615)
  PKA activation in glucagon signalling (R-HSA-164378)
  Adenylate cyclase activating pathway (R-HSA-170660)
  Adenylate cyclase inhibitory pathway (R-HSA-170670)
  G alpha (s) signalling events (R-HSA-418555)
  G alpha (i) signalling events (R-HSA-418594)
  G alpha (z) signalling events (R-HSA-418597)
  Vasopressin regulates renal water homeostasis via Aquaporins (R-HSA-432040)
  Hedgehog 'off' state (R-HSA-5610787)
  GPER1 signaling (R-HSA-9634597)
  ADORA2B mediated anti-inflammatory cytokines production (R-HSA-9660821)
  FCGR3A-mediated IL10 synthesis (R-HSA-9664323)
  Glucagon signaling in metabolic regulation (R-HSA-163359)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute coronary syndrome	DIS7DYEW	Strong	Genetic Variation	[1]
Adult respiratory distress syndrome	DISIJV47	Strong	Genetic Variation	[2]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[3]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[3]
Atrichia with papular lesions	DIS80CUB	Strong	Altered Expression	[4]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[6]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[7]
Colon cancer	DISVC52G	Strong	Altered Expression	[8]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[8]
Congenital alveolar dysplasia	DIS1IYUN	Strong	Genetic Variation	[2]
Focal epilepsy	DIS4LY5L	Strong	Genetic Variation	[9]
Glucocorticoid resistance	DIS3HNXT	Strong	Genetic Variation	[2]
Helminth infection	DIS7CGKY	Strong	Genetic Variation	[10]
Mood disorder	DISLVMWO	Strong	Biomarker	[11]
Obesity	DIS47Y1K	Strong	Genetic Variation	[12]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[4]
Vascular disease	DISVS67S	Strong	Genetic Variation	[13]
Alcohol dependence	DIS4ZSCO	moderate	Genetic Variation	[14]
Alpha thalassemia	DIS5XGK0	Limited	Genetic Variation	[15]
Asthma	DISW9QNS	Limited	Biomarker	[16]
Sickle-cell anaemia	DIS5YNZB	Limited	Genetic Variation	[17]
Stroke	DISX6UHX	Limited	Genetic Variation	[15]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Adenylate cyclase type 9 (ADCY9) increases the Cardiovascular disorder ADR of Chlorothiazide.	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Adenylate cyclase type 9 (ADCY9).	[18]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Adenylate cyclase type 9 (ADCY9).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Adenylate cyclase type 9 (ADCY9).	[20]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Adenylate cyclase type 9 (ADCY9).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Adenylate cyclase type 9 (ADCY9).	[23]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Adenylate cyclase type 9 (ADCY9).	[24]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Adenylate cyclase type 9 (ADCY9).	[25]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Adenylate cyclase type 9 (ADCY9).	[26]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Adenylate cyclase type 9 (ADCY9).	[25]
Clotrimazole	DMMFCIH	Approved	Clotrimazole decreases the activity of Adenylate cyclase type 9 (ADCY9).	[27]
Miconazole	DMPMYE8	Approved	Miconazole increases the activity of Adenylate cyclase type 9 (ADCY9).	[27]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Adenylate cyclase type 9 (ADCY9).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Adenylate cyclase type 9 (ADCY9).	[29]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Adenylate cyclase type 9 (ADCY9).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Adenylate cyclase type 9 (ADCY9).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Adenylate cyclase type 9 (ADCY9).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Adenylate cyclase type 9 (ADCY9).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Adenylate cyclase type 9 (ADCY9).	[32]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Adenylate cyclase type 9 (ADCY9).	[31]

References

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• [3] ADCY9 (Adenylate Cyclase Type 9) Inactivation Protects From Atherosclerosis Only in the Absence of CETP (Cholesteryl Ester Transfer Protein).Circulation. 2018 Oct 16;138(16):1677-1692. doi: 10.1161/CIRCULATIONAHA.117.031134.
• [4] MicroRNA-181a-mediated downregulation of AC9 protein decreases intracellular cAMP level and inhibits ATRA-induced APL cell differentiation.Cell Death Dis. 2014 Apr 10;5(4):e1161. doi: 10.1038/cddis.2014.130.
• [5] Association analysis of adenylate cyclase type 9 gene using pedigree disequilibrium test in bipolar disorder.Mol Psychiatry. 2002;7(5):450-2. doi: 10.1038/sj.mp.4000992.
• [6] Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.Nat Genet. 2017 Dec;49(12):1767-1778. doi: 10.1038/ng.3785. Epub 2017 Oct 23.
• [7] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [8] Elevated Adenylyl Cyclase 9 Expression Is a Potential Prognostic Biomarker for Patients with Colon Cancer.Med Sci Monit. 2018 Jan 2;24:19-25. doi: 10.12659/msm.906002.
• [9] Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study.Brain. 2010 Jul;133(Pt 7):2136-47. doi: 10.1093/brain/awq130. Epub 2010 Jun 3.
• [10] Adenylyl cyclase type 9 gene polymorphisms are associated with asthma and allergy in Brazilian children.Mol Immunol. 2017 Feb;82:137-145. doi: 10.1016/j.molimm.2017.01.001. Epub 2017 Jan 8.
• [11] Molecular analysis, mutation screening, and association study of adenylate cyclase type 9 gene (ADCY9) in mood disorders.Am J Med Genet. 2002 Jan 8;114(1):84-92. doi: 10.1002/ajmg.10117.
• [12] Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.Nat Genet. 2013 May;45(5):501-12. doi: 10.1038/ng.2606. Epub 2013 Apr 7.
• [13] ADCY9 Genetic Variants and Cardiovascular Outcomes With Evacetrapib in Patients With High-Risk Vascular Disease: A Nested Case-Control Study.JAMA Cardiol. 2018 May 1;3(5):401-408. doi: 10.1001/jamacardio.2018.0569.
• [14] Integrative epigenetic profiling analysis identifies DNA methylation changes associated with chronic alcohol consumption.Comput Biol Med. 2015 Sep;64:299-306. doi: 10.1016/j.compbiomed.2014.12.003. Epub 2014 Dec 11.
• [15] Genetic predictors for stroke in children with sickle cell anemia.Blood. 2011 Jun 16;117(24):6681-4. doi: 10.1182/blood-2011-01-332205. Epub 2011 Apr 22.
• [16] Pharmacogenetic Factors Affecting Asthma Treatment Response. Potential Implications for Drug Therapy.Front Pharmacol. 2019 May 21;10:520. doi: 10.3389/fphar.2019.00520. eCollection 2019.
• [17] Potential Signal Transduction Regulation by HDL of the 2-Adrenergic Receptor Pathway. Implications in Selected Pathological Situations.Arch Med Res. 2015 Jul;46(5):361-71. doi: 10.1016/j.arcmed.2015.05.008. Epub 2015 May 23.
• [18] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [19] 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.
• [20] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [21] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [22] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [23] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [24] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [25] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [26] Expression profiling of nucleotide metabolism-related genes in human breast cancer cells after treatment with 5-fluorouracil. Cancer Invest. 2009 Jun;27(5):561-7.
• [27] Direct stimulation of adenylyl cyclase 9 by the fungicide imidazole miconazole. Naunyn Schmiedebergs Arch Pharmacol. 2019 Apr;392(4):497-504. doi: 10.1007/s00210-018-01610-1. Epub 2019 Jan 3.
• [28] Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin. Mol Cancer Ther. 2005 Feb;4(2):233-41.
• [29] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [30] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [31] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [32] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [33] 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.
• [34] Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib. Circ Cardiovasc Genet. 2015 Apr;8(2):372-82. doi: 10.1161/CIRCGENETICS.114.000663. Epub 2015 Jan 11.