Details of Drug Off-Target (DOT)

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

• DOT Name: Adenylate cyclase type 1 (ADCY1)
• Synonyms: EC 4.6.1.1; ATP pyrophosphate-lyase 1; Adenylate cyclase type I; Adenylyl cyclase 1; Ca(2+)/calmodulin-activated adenylyl cyclase
• Gene Name: ADCY1
• Related Disease:
  Hearing loss, autosomal recessive
  Autosomal recessive nonsyndromic hearing loss 44
• UniProt ID: ADCY1_HUMAN
• EC Number: 4.6.1.1
• Pfam ID: PF16214 ; PF00211
• Sequence:
  MAGAPRGGGGGGGGAGEPGGAERAAGTSRRRGLRACDEEFACPELEALFRGYTLRLEQAA
  TLKALAVLSLLAGALALAELLGAPGPAPGLAKGSHPVHCVLFLALLVVTNVRSLQVPQLQ
  QVGQLALLFSLTFALLCCPFALGGPARGSAGAAGGPATAEQGVWQLLLVTFVSYALLPVR
  SLLAIGFGLVVAASHLLVTATLVPAKRPRLWRTLGANALLFVGVNMYGVFVRILTERSQR
  KAFLQARSCIEDRLRLEDENEKQERLLMSLLPRNVAMEMKEDFLKPPERIFHKIYIQRHD
  NVSILFADIVGFTGLASQCTAQELVKLLNELFGKFDELATENHCRRIKILGDCYYCVSGL
  TQPKTDHAHCCVEMGLDMIDTITSVAEATEVDLNMRVGLHTGRVLCGVLGLRKWQYDVWS
  NDVTLANVMEAAGLPGKVHITKTTLACLNGDYEVEPGYGHERNSFLKTHNIETFFIVPSH
  RRKIFPGLILSDIKPAKRMKFKTVCYLLVQLMHCRKMFKAEIPFSNVMTCEDDDKRRALR
  TASEKLRNRSSFSTNVVYTTPGTRVNRYISRLLEARQTELEMADLNFFTLKYKHVEREQK
  YHQLQDEYFTSAVVLTLILAALFGLVYLLIFPQSVVVLLLLVFCICFLVACVLYLHITRV
  QCFPGCLTIQIRTVLCIFIVVLIYSVAQGCVVGCLPWAWSSKPNSSLVVLSSGGQRTALP
  TLPCESTHHALLCCLVGTLPLAIFFRVSSLPKMILLSGLTTSYILVLELSGYTRTGGGAV
  SGRSYEPIVAILLFSCALALHARQVDIRLRLDYLWAAQAEEEREDMEKVKLDNRRILFNL
  LPAHVAQHFLMSNPRNMDLYYQSYSQVGVMFASIPNFNDFYIELDGNNMGVECLRLLNEI
  IADFDELMEKDFYKDIEKIKTIGSTYMAAVGLAPTSGTKAKKSISSHLSTLADFAIEMFD
  VLDEINYQSYNDFVLRVGINVGPVVAGVIGARRPQYDIWGNTVNVASRMDSTGVQGRIQV
  TEEVHRLLRRCPYHFVCRGKVSVKGKGEMLTYFLEGRTDGNGSQIRSLGLDRKMCPFGRA
  GLQGRRPPVCPMPGVSVRAGLPPHSPGQYLPSAAAGKEA
• Function: Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling. Mediates responses to increased cellular Ca(2+)/calmodulin levels. May be involved in regulatory processes in the central nervous system. May play a role in memory and learning. Plays a role in the regulation of the circadian rhythm of daytime contrast sensitivity probably by modulating the rhythmic synthesis of cyclic AMP in the retina.
• Tissue Specificity: Detected in zona glomerulosa and zona fasciculata in the adrenal gland (at protein level) . Brain, retina and adrenal medulla.
• 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)
  Long-term potentiation (hsa04720)
  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)
  Salivary secretion (hsa04970)
  Gastric acid secretion (hsa04971)
  Pancreatic secretion (hsa04972)
  Bile secretion (hsa04976)
  Morphine addiction (hsa05032)
  Chagas disease (hsa05142)
  Amoebiasis (hsa05146)
  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)
  CREB1 phosphorylation through the activation of Adenylate Cyclase (R-HSA-442720)
  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

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[1]
Autosomal recessive nonsyndromic hearing loss 44	DISIZYPW	Limited	Autosomal recessive	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Reserpine	DM6VM38	Approved	Adenylate cyclase type 1 (ADCY1) increases the Flushing ADR of Reserpine.	[17]
Fentanyl	DM8WAHT	Approved	Adenylate cyclase type 1 (ADCY1) increases the Drug tolerance increased ADR of Fentanyl.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Adenylate cyclase type 1 (ADCY1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Adenylate cyclase type 1 (ADCY1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Adenylate cyclase type 1 (ADCY1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Adenylate cyclase type 1 (ADCY1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Adenylate cyclase type 1 (ADCY1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Adenylate cyclase type 1 (ADCY1).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Adenylate cyclase type 1 (ADCY1).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Adenylate cyclase type 1 (ADCY1).	[9]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Adenylate cyclase type 1 (ADCY1).	[10]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Adenylate cyclase type 1 (ADCY1).	[11]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Adenylate cyclase type 1 (ADCY1).	[3]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Adenylate cyclase type 1 (ADCY1).	[12]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Adenylate cyclase type 1 (ADCY1).	[3]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the expression of Adenylate cyclase type 1 (ADCY1).	[3]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Adenylate cyclase type 1 (ADCY1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Adenylate cyclase type 1 (ADCY1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Adenylate cyclase type 1 (ADCY1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Adenylate cyclase type 1 (ADCY1).	[15]

References

• [1] Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish. Hum Mol Genet. 2014 Jun 15;23(12):3289-98. doi: 10.1093/hmg/ddu042. Epub 2014 Jan 29.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [11] Analysis of gene expression induced by diethylstilbestrol (DES) in human primitive Mullerian duct cells using microarray. Cancer Lett. 2005 Apr 8;220(2):197-210.
• [12] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [13] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.