Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFOY4WW)

• DOT Name: Adenylate cyclase type 6 (ADCY6)
• Synonyms: EC 4.6.1.1; ATP pyrophosphate-lyase 6; Adenylate cyclase type VI; Adenylyl cyclase 6; Ca(2+)-inhibitable adenylyl cyclase
• Gene Name: ADCY6
• Related Disease:
  Sickle-cell anaemia
  Arrhythmia
  Autosomal dominant polycystic kidney disease
  Cardiac failure
  Congestive heart failure
  Lethal congenital contracture syndrome 8
  Nephrogenic diabetes insipidus
  Osteoarthritis
  Osteoporosis
  Vibrio cholerae infection
  Arthrogryposis
  Obsolete hypomyelination neuropathy-arthrogryposis syndrome
  Cardiac arrest
• UniProt ID: ADCY6_HUMAN
• EC Number: 4.6.1.1
• Pfam ID: PF16214 ; PF06327 ; PF00211
• Sequence:
  MSWFSGLLVPKVDERKTAWGERNGQKRSRRRGTRAGGFCTPRYMSCLRDAEPPSPTPAGP
  PRCPWQDDAFIRRGGPGKGKELGLRAVALGFEDTEVTTTAGGTAEVAPDAVPRSGRSCWR
  RLVQVFQSKQFRSAKLERLYQRYFFQMNQSSLTLLMAVLVLLTAVLLAFHAAPARPQPAY
  VALLACAAALFVGLMVVCNRHSFRQDSMWVVSYVVLGILAAVQVGGALAADPRSPSAGLW
  CPVFFVYIAYTLLPIRMRAAVLSGLGLSTLHLILAWQLNRGDAFLWKQLGANVLLFLCTN
  VIGICTHYPAEVSQRQAFQETRGYIQARLHLQHENRQQERLLLSVLPQHVAMEMKEDINT
  KKEDMMFHKIYIQKHDNVSILFADIEGFTSLASQCTAQELVMTLNELFARFDKLAAENHC
  LRIKILGDCYYCVSGLPEARADHAHCCVEMGVDMIEAISLVREVTGVNVNMRVGIHSGRV
  HCGVLGLRKWQFDVWSNDVTLANHMEAGGRAGRIHITRATLQYLNGDYEVEPGRGGERNA
  YLKEQHIETFLILGASQKRKEEKAMLAKLQRTRANSMEGLMPRWVPDRAFSRTKDSKAFR
  QMGIDDSSKDNRGTQDALNPEDEVDEFLSRAIDARSIDQLRKDHVRRFLLTFQREDLEKK
  YSRKVDPRFGAYVACALLVFCFICFIQLLIFPHSTLMLGIYASIFLLLLITVLICAVYSC
  GSLFPKALQRLSRSIVRSRAHSTAVGIFSVLLVFTSAIANMFTCNHTPIRSCAARMLNLT
  PADITACHLQQLNYSLGLDAPLCEGTMPTCSFPEYFIGNMLLSLLASSVFLHISSIGKLA
  MIFVLGLIYLVLLLLGPPATIFDNYDLLLGVHGLASSNETFDGLDCPAAGRVALKYMTPV
  ILLVFALALYLHAQQVESTARLDFLWKLQATGEKEEMEELQAYNRRLLHNILPKDVAAHF
  LARERRNDELYYQSCECVAVMFASIANFSEFYVELEANNEGVECLRLLNEIIADFDEIIS
  EERFRQLEKIKTIGSTYMAASGLNASTYDQVGRSHITALADYAMRLMEQMKHINEHSFNN
  FQMKIGLNMGPVVAGVIGARKPQYDIWGNTVNVSSRMDSTGVPDRIQVTTDLYQVLAAKG
  YQLECRGVVKVKGKGEMTTYFLNGGPSS
• Function: Catalyzes the formation of the signaling molecule cAMP downstream of G protein-coupled receptors. Functions in signaling cascades downstream of beta-adrenergic receptors in the heart and in vascular smooth muscle cells. Functions in signaling cascades downstream of the vasopressin receptor in the kidney and has a role in renal water reabsorption. Functions in signaling cascades downstream of PTH1R and plays a role in regulating renal phosphate excretion. Functions in signaling cascades downstream of the VIP and SCT receptors in pancreas and contributes to the regulation of pancreatic amylase and fluid secretion. Signaling mediates cAMP-dependent activation of protein kinase PKA. This promotes increased phosphorylation of various proteins, including AKT. Plays a role in regulating cardiac sarcoplasmic reticulum Ca(2+) uptake and storage, and is required for normal heart ventricular contractibility. May contribute to normal heart function. Mediates vasodilatation after activation of beta-adrenergic receptors by isoproterenol. Contributes to bone cell responses to mechanical stimuli.
• Tissue Specificity: Detected in peripheral blood mononuclear leukocytes (at protein level) . Detected in thyroid .
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  Endocrine resistance (hsa01522)
  Rap1 sig.ling pathway (hsa04015)
  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)
  Renin secretion (hsa04924)
  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)
  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)
  Adrenaline,noradrenaline inhibits insulin secretion (R-HSA-400042)
  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

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Sickle-cell anaemia	DIS5YNZB	Definitive	Genetic Variation	[1]
Arrhythmia	DISFF2NI	Strong	Biomarker	[2]
Autosomal dominant polycystic kidney disease	DISBHWUI	Strong	Biomarker	[3]
Cardiac failure	DISDC067	Strong	Biomarker	[2]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[2]
Lethal congenital contracture syndrome 8	DISEUXXH	Strong	Autosomal recessive	[4]
Nephrogenic diabetes insipidus	DISKNSJK	Strong	Biomarker	[5]
Osteoarthritis	DIS05URM	Strong	Biomarker	[6]
Osteoporosis	DISF2JE0	Strong	Biomarker	[7]
Vibrio cholerae infection	DISW7E3U	Strong	Biomarker	[8]
Arthrogryposis	DISC81CM	moderate	Genetic Variation	[4]
Obsolete hypomyelination neuropathy-arthrogryposis syndrome	DISO9PZY	Supportive	Autosomal recessive	[4]
Cardiac arrest	DIS9DIA4	Limited	Genetic Variation	[1]

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 6 (ADCY6).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Adenylate cyclase type 6 (ADCY6).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Adenylate cyclase type 6 (ADCY6).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Adenylate cyclase type 6 (ADCY6).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Adenylate cyclase type 6 (ADCY6).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Adenylate cyclase type 6 (ADCY6).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Adenylate cyclase type 6 (ADCY6).	[14]
Selenium	DM25CGV	Approved	Selenium increases the expression of Adenylate cyclase type 6 (ADCY6).	[15]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Adenylate cyclase type 6 (ADCY6).	[16]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Adenylate cyclase type 6 (ADCY6).	[14]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Adenylate cyclase type 6 (ADCY6).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Adenylate cyclase type 6 (ADCY6).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Adenylate cyclase type 6 (ADCY6).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Adenylate cyclase type 6 (ADCY6).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Adenylate cyclase type 6 (ADCY6).	[21]

References

• [1] Association of adenylyl cyclase 6 rs3730070 polymorphism and hemolytic level in patients with sickle cell anemia.Blood Cells Mol Dis. 2016 May;58:21-5. doi: 10.1016/j.bcmd.2016.02.006. Epub 2016 Feb 18.
• [2] Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure: A Randomized Clinical Trial.JAMA Cardiol. 2016 May 1;1(2):163-71. doi: 10.1001/jamacardio.2016.0008.
• [3] Tolvaptan plus pasireotide shows enhanced efficacy in a PKD1 model.J Am Soc Nephrol. 2015 Jan;26(1):39-47. doi: 10.1681/ASN.2013121312. Epub 2014 Jul 3.
• [4] Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects. Hum Mol Genet. 2014 May 1;23(9):2279-89. doi: 10.1093/hmg/ddt618. Epub 2013 Dec 6.
• [5] Role of adenylyl cyclase 6 in the development of lithium-induced nephrogenic diabetes insipidus.JCI Insight. 2017 Apr 6;2(7):e91042. doi: 10.1172/jci.insight.91042.
• [6] 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.
• [7] Decreased microRNA-182-5p helps alendronate promote osteoblast proliferation and differentiation in osteoporosis via the Rap1/MAPK pathway.Biosci Rep. 2018 Dec 21;38(6):BSR20180696. doi: 10.1042/BSR20180696. Print 2018 Dec 21.
• [8] AC6 is the major adenylate cyclase forming a diarrheagenic protein complex with cystic fibrosis transmembrane conductance regulator in cholera.J Biol Chem. 2018 Aug 17;293(33):12949-12959. doi: 10.1074/jbc.RA118.003378. Epub 2018 Jun 14.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [16] Effects of paclitaxel on proliferation and apoptosis in human acute myeloid leukemia HL-60 cells. Acta Pharmacol Sin. 2004 Mar;25(3):378-84.
• [17] Ascorbic acid inhibits PMP22 expression by reducing cAMP levels. Neuromuscul Disord. 2007 Mar;17(3):248-53. doi: 10.1016/j.nmd.2006.12.008. Epub 2007 Feb 15.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] 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.
• [21] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.