Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR1WCZX)

• DOT Name: Adenylate cyclase type 8 (ADCY8)
• Synonyms: EC 4.6.1.1; ATP pyrophosphate-lyase 8; Adenylate cyclase type VIII; Adenylyl cyclase 8; AC8; Ca(2+)/calmodulin-activated adenylyl cyclase
• Gene Name: ADCY8
• Related Disease:
  Bipolar disorder
  Chronic renal failure
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Breast carcinoma
  Depression
  Diabetic kidney disease
  Duchenne muscular dystrophy
  Mood disorder
  Neoplasm
  Obesity
  Substance withdrawal syndrome
  Glioma
  Neurofibromatosis type 1
  Type-1/2 diabetes
  Post-traumatic stress disorder
• UniProt ID: ADCY8_HUMAN
• EC Number: 4.6.1.1
• Pfam ID: PF16214 ; PF06327 ; PF00211
• Sequence:
  MELSDVRCLTGSEELYTIHPTPPAGDGRSASRPQRLLWQTAVRHITEQRFIHGHRGGSGS
  GSGGSGKASDPAGGGPNHHAPQLSGDSALPLYSLGPGERAHSTCGTKVFPERSGSGSASG
  SGGGGDLGFLHLDCAPSNSDFFLNGGYSYRGVIFPTLRNSFKSRDLERLYQRYFLGQRRK
  SEVVMNVLDVLTKLTLLVLHLSLASAPMDPLKGILLGFFTGIEVVICALVVVRKDTTSHT
  YLQYSGVVTWVAMTTQILAAGLGYGLLGDGIGYVLFTLFATYSMLPLPLTWAILAGLGTS
  LLQVILQVVIPRLAVISINQVVAQAVLFMCMNTAGIFISYLSDRAQRQAFLETRRCVEAR
  LRLETENQRQERLVLSVLPRFVVLEMINDMTNVEDEHLQHQFHRIYIHRYENVSILFADV
  KGFTNLSTTLSAQELVRMLNELFARFDRLAHEHHCLRIKILGDCYYCVSGLPEPRQDHAH
  CCVEMGLSMIKTIRYVRSRTKHDVDMRIGIHSGSVLCGVLGLRKWQFDVWSWDVDIANKL
  ESGGIPGRIHISKATLDCLNGDYNVEEGHGKERNEFLRKHNIETYLIKQPEDSLLSLPED
  IVKESVSSSDRRNSGATFTEGSWSPELPFDNIVGKQNTLAALTRNSINLLPNHLAQALHV
  QSGPEEINKRIEHTIDLRSGDKLRREHIKPFSLMFKDSSLEHKYSQMRDEVFKSNLVCAF
  IVLLFITAIQSLLPSSRVMPMTIQFSILIMLHSALVLITTAEDYKCLPLILRKTCCWINE
  TYLARNVIIFASILINFLGAILNILWCDFDKSIPLKNLTFNSSAVFTDICSYPEYFVFTG
  VLAMVTCAVFLRLNSVLKLAVLLIMIAIYALLTETVYAGLFLRYDNLNHSGEDFLGTKEV
  SLLLMAMFLLAVFYHGQQLEYTARLDFLWRVQAKEEINEMKELREHNENMLRNILPSHVA
  RHFLEKDRDNEELYSQSYDAVGVMFASIPGFADFYSQTEMNNQGVECLRLLNEIIADFDE
  LLGEDRFQDIEKIKTIGSTYMAVSGLSPEKQQCEDKWGHLCALADFSLALTESIQEINKH
  SFNNFELRIGISHGSVVAGVIGAKKPQYDIWGKTVNLASRMDSTGVSGRIQVPEETYLIL
  KDQGFAFDYRGEIYVKGISEQEGKIKTYFLLGRVQPNPFILPPRRLPGQYSLAAVVLGLV
  QSLNRQRQKQLLNENNNTGIIKGHYNRRTLLSPSGTEPGAQAEGTDKSDLP
• Function: Catalyzes the formation of cAMP in response to calcium entry leadings to cAMP signaling activation that affect processes suche as synaptic plasticity and insulin secretion. Plays a role in many brain functions, such as learning, memory, drug addiction, and anxiety modulation through regulation of synaptic plasticity by modulating long-term memory and long-term potentiation (LTP) through CREB transcription factor activity modulation. Plays a central role in insulin secretion by controlling glucose homeostasis through glucagon-like peptide 1 and glucose signaling pathway and maintains insulin secretion through calcium-dependent PKA activation leading to vesicle pool replenishment. Also, allows PTGER3 to induce potentiation of PTGER4-mediated PLA2 secretion by switching from a negative to a positive regulation, during the IL1B induced-dedifferentiation of smooth muscle cells.
• Tissue Specificity: Detected in brain cortex . Expressed in islet .
• 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)
  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)
  Glucagon-like Peptide-1 (GLP1) regulates insulin secretion (R-HSA-381676)
  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

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bipolar disorder	DISAM7J2	Definitive	Biomarker	[1]
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[4]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Depression	DIS3XJ69	Strong	Biomarker	[6]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[7]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Genetic Variation	[8]
Mood disorder	DISLVMWO	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Obesity	DIS47Y1K	Strong	Biomarker	[10]
Substance withdrawal syndrome	DISTT24U	Strong	Biomarker	[11]
Glioma	DIS5RPEH	moderate	Biomarker	[12]
Neurofibromatosis type 1	DIS53JH9	moderate	Biomarker	[12]
Type-1/2 diabetes	DISIUHAP	moderate	Altered Expression	[10]
Post-traumatic stress disorder	DISHL1EY	Limited	Genetic Variation	[13]

2 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 8 (ADCY8).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Adenylate cyclase type 8 (ADCY8).	[18]

4 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 Adenylate cyclase type 8 (ADCY8).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Adenylate cyclase type 8 (ADCY8).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Adenylate cyclase type 8 (ADCY8).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Adenylate cyclase type 8 (ADCY8).	[19]

References

• [1] Interspecies trait genetics reveals association of Adcy8 with mouse avoidance behavior and a human mood disorder.Biol Psychiatry. 2009 Dec 15;66(12):1123-30. doi: 10.1016/j.biopsych.2009.06.016. Epub 2009 Aug 19.
• [2] Genetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE Study.Front Genet. 2019 May 24;10:494. doi: 10.3389/fgene.2019.00494. eCollection 2019.
• [3] Profiling of transcripts and proteins modulated by K-ras oncogene in the lung tissues of K-ras transgenic mice by omics approaches.Int J Oncol. 2009 Jan;34(1):161-72.
• [4] The Notch pathway attenuates interleukin 1 (IL1)-mediated induction of adenylyl cyclase 8 (AC8) expression during vascular smooth muscle cell (VSMC) trans-differentiation.J Biol Chem. 2012 Jul 20;287(30):24978-89. doi: 10.1074/jbc.M111.292516. Epub 2012 May 21.
• [5] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [6] Genetic markers of comorbid depression and alcoholism in women.Alcohol Clin Exp Res. 2013 Jun;37(6):896-904. doi: 10.1111/acer.12060. Epub 2012 Dec 27.
• [7] MicroRNAs in the Progress of Diabetic Nephropathy: A Systematic Review and Meta-Analysis.Evid Based Complement Alternat Med. 2019 Mar 7;2019:3513179. doi: 10.1155/2019/3513179. eCollection 2019.
• [8] Long-range genomic regulators of THBS1 and LTBP4 modify disease severity in duchenne muscular dystrophy.Ann Neurol. 2018 Aug;84(2):234-245. doi: 10.1002/ana.25283. Epub 2018 Aug 25.
• [9] Mutation profiles in early-stage lung squamous cell carcinoma with clinical follow-up and correlation with markers of immune function.Ann Oncol. 2017 Jan 1;28(1):83-89. doi: 10.1093/annonc/mdw437.
• [10] Association between serum magnesium and blood count: influence of type 2 diabetes and central obesity.Br J Nutr. 2019 Jun;121(11):1287-1293. doi: 10.1017/S0007114519000862. Epub 2019 Apr 29.
• [11] Calmodulin-stimulated adenylyl cyclase gene deletion affects morphine responses.Mol Pharmacol. 2006 Nov;70(5):1742-9. doi: 10.1124/mol.106.025783. Epub 2006 Aug 16.
• [12] The cyclic AMP pathway is a sex-specific modifier of glioma risk in type I neurofibromatosis patients.Cancer Res. 2015 Jan 1;75(1):16-21. doi: 10.1158/0008-5472.CAN-14-1891. Epub 2014 Nov 7.
• [13] A genome-wide association study of clinical symptoms of dissociation in a trauma-exposed sample.Depress Anxiety. 2014 Apr;31(4):352-60. doi: 10.1002/da.22260. Epub 2014 Mar 27.
• [14] Nuclear and Mitochondrial DNA Methylation Patterns Induced by Valproic Acid in Human Hepatocytes. Chem Res Toxicol. 2017 Oct 16;30(10):1847-1854. doi: 10.1021/acs.chemrestox.7b00171. Epub 2017 Sep 13.
• [15] 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.
• [16] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [17] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [18] 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.
• [19] 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.