Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHBLJA7)

• DOT Name: Adenylate cyclase type 4 (ADCY4)
• Synonyms: EC 4.6.1.1; ATP pyrophosphate-lyase 4; Adenylate cyclase type IV; Adenylyl cyclase 4
• Gene Name: ADCY4
• Related Disease:
  Osteoarthritis
  Breast cancer
  Breast carcinoma
• UniProt ID: ADCY4_HUMAN
• EC Number: 4.6.1.1
• Pfam ID: PF16214 ; PF06327 ; PF00211
• Sequence:
  MARLFSPRPPPSEDLFYETYYSLSQQYPLLLLLLGIVLCALAALLAVAWASGRELTSDPS
  FLTTVLCALGGFSLLLGLASREQRLQRWTRPLSGLVWVALLALGHAFLFTGGVVSAWDQV
  SYFLFVIFTAYAMLPLGMRDAAVAGLASSLSHLLVLGLYLGPQPDSRPALLPQLAANAVL
  FLCGNVAGVYHKALMERALRATFREALSSLHSRRRLDTEKKHQEHLLLSILPAYLAREMK
  AEIMARLQAGQGSRPESTNNFHSLYVKRHQGVSVLYADIVGFTRLASECSPKELVLMLNE
  LFGKFDQIAKEHECMRIKILGDCYYCVSGLPLSLPDHAINCVRMGLDMCRAIRKLRAATG
  VDINMRVGVHSGSVLCGVIGLQKWQYDVWSHDVTLANHMEAGGVPGRVHITGATLALLAG
  AYAVEDAGMEHRDPYLRELGEPTYLVIDPRAEEEDEKGTAGGLLSSLEGLKMRPSLLMTR
  YLESWGAAKPFAHLSHGDSPVSTSTPLPEKTLASFSTQWSLDRSRTPRGLDDELDTGDAK
  FFQVIEQLNSQKQWKQSKDFNPLTLYFREKEMEKEYRLSAIPAFKYYEACTFLVFLSNFI
  IQMLVTNRPPALAITYSITFLLFLLILFVCFSEDLMRCVLKGPKMLHWLPALSGLVATRP
  GLRIALGTATILLVFAMAITSLFFFPTSSDCPFQAPNVSSMISNLSWELPGSLPLISVPY
  SMHCCTLGFLSCSLFLHMSFELKLLLLLLWLAASCSLFLHSHAWLSECLIVRLYLGPLDS
  RPGVLKEPKLMGAISFFIFFFTLLVLARQNEYYCRLDFLWKKKLRQEREETETMENLTRL
  LLENVLPAHVAPQFIGQNRRNEDLYHQSYECVCVLFASVPDFKEFYSESNINHEGLECLR
  LLNEIIADFDELLSKPKFSGVEKIKTIGSTYMAATGLNATSGQDAQQDAERSCSHLGTMV
  EFAVALGSKLDVINKHSFNNFRLRVGLNHGPVVAGVIGAQKPQYDIWGNTVNVASRMEST
  GVLGKIQVTEETAWALQSLGYTCYSRGVIKVKGKGQLCTYFLNTDLTRTGPPSATLG
• Function: Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling.
• Tissue Specificity: Detected in the zona glomerulosa and the zona fasciculata in the adrenal gland (at protein level).
• 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)
  Taste transduction (hsa04742)
  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)
  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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	moderate	Biomarker	[2]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Adenylate cyclase type 4 (ADCY4).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Adenylate cyclase type 4 (ADCY4).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Adenylate cyclase type 4 (ADCY4).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Adenylate cyclase type 4 (ADCY4).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Adenylate cyclase type 4 (ADCY4).	[5]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Adenylate cyclase type 4 (ADCY4).	[6]

References

• [1] Candidate methylated genes in osteoarthritis explored by bioinformatics analysis.Knee. 2016 Dec;23(6):1035-1043. doi: 10.1016/j.knee.2016.09.020. Epub 2016 Oct 31.
• [2] Epigenetic identification of ADCY4 as a biomarker for breast cancer: an integrated analysis of adenylate cyclases.Epigenomics. 2019 Nov;11(14):1561-1579. doi: 10.2217/epi-2019-0207. Epub 2019 Oct 4.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [7] 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.
• [8] 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.