Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAWMGP3)

• DOT Name: Adenylate cyclase type 7 (ADCY7)
• Synonyms: EC 4.6.1.1; ATP pyrophosphate-lyase 7; Adenylate cyclase type VII; Adenylyl cyclase 7
• Gene Name: ADCY7
• Related Disease:
  Alcohol dependence
  Autoimmune disease
  Autoimmune disease, susceptibility to, 6
  Depression
  Hypothyroidism
  Inflammatory bowel disease
  Juvenile idiopathic arthritis
  Major depressive disorder
  Mood disorder
  Promyelocytic leukaemia
  Schizophrenia
  STAT3-related early-onset multisystem autoimmune disease
  Acute myelogenous leukaemia
  Ankylosing spondylitis
  Autoimmune thyroid disease
  Coeliac disease
  Common variable immunodeficiency
  Crohn disease
  leukaemia
  Leukemia
  Psoriasis
  Systemic lupus erythematosus
  Type-1 diabetes
  Mental disorder
  Ulcerative colitis
• UniProt ID: ADCY7_HUMAN
• EC Number: 4.6.1.1
• Pfam ID: PF16214 ; PF06327 ; PF00211
• Sequence:
  MPAKGRYFLNEGEEGPDQDALYEKYQLTSQHGPLLLTLLLVAATACVALIIIAFSQGDPS
  RHQAILGMAFLVLAVFAALSVLMYVECLLRRWLRALALLTWACLVALGYVLVFDAWTKAA
  CAWEQVPFFLFIVFVVYTLLPFSMRGAVAVGAVSTASHLLVLGSLMGGFTTPSVRVGLQL
  LANAVIFLCGNLTGAFHKHQMQDASRDLFTYTVKCIQIRRKLRIEKRQQENLLLSVLPAH
  ISMGMKLAIIERLKEHGDRRCMPDNNFHSLYVKRHQNVSILYADIVGFTQLASDCSPKEL
  VVVLNELFGKFDQIAKANECMRIKILGDCYYCVSGLPVSLPTHARNCVKMGLDMCQAIKQ
  VREATGVDINMRVGIHSGNVLCGVIGLRKWQYDVWSHDVSLANRMEAAGVPGRVHITEAT
  LKHLDKAYEVEDGHGQQRDPYLKEMNIRTYLVIDPRSQQPPPPSQHLPRPKGDAALKMRA
  SVRMTRYLESWGAARPFAHLNHRESVSSGETHVPNGRRPKSVPQRHRRTPDRSMSPKGRS
  EDDSYDDEMLSAIEGLSSTRPCCSKSDDFYTFGSIFLEKGFEREYRLAPIPRARHDFACA
  SLIFVCILLVHVLLMPRTAALGVSFGLVACVLGLVLGLCFATKFSRCCPARGTLCTISER
  VETQPLLRLTLAVLTIGSLLTVAIINLPLMPFQVPELPVGNETGLLAASSKTRALCEPLP
  YYTCSCVLGFIACSVFLRMSLEPKVVLLTVALVAYLVLFNLSPCWQWDCCGQGLGNLTKP
  NGTTSGTPSCSWKDLKTMTNFYLVLFYITLLTLSRQIDYYCRLDCLWKKKFKKEHEEFET
  MENVNRLLLENVLPAHVAAHFIGDKLNEDWYHQSYDCVCVMFASVPDFKVFYTECDVNKE
  GLECLRLLNEIIADFDELLLKPKFSGVEKIKTIGSTYMAAAGLSVASGHENQELERQHAH
  IGVMVEFSIALMSKLDGINRHSFNSFRLRVGINHGPVIAGVIGARKPQYDIWGNTVNVAS
  RMESTGELGKIQVTEETCTILQGLGYSCECRGLINVKGKGELRTYFVCTDTAKFQGLGLN
• Function: Catalyzes the formation of cAMP in response to activation of G protein-coupled receptors (Probable). Functions in signaling cascades activated namely by thrombin and sphingosine 1-phosphate and mediates regulation of cAMP synthesis through synergistic action of the stimulatory G alpha protein with GNA13. Also, during inflammation, mediates zymosan-induced increase intracellular cAMP, leading to protein kinase A pathway activation in order to modulate innate immune responses through heterotrimeric G proteins G(12/13). Functions in signaling cascades activated namely by dopamine and C5 alpha chain and mediates regulation of cAMP synthesis through synergistic action of the stimulatory G protein with G beta:gamma complex. Functions, through cAMP response regulation, to keep inflammation under control during bacterial infection by sensing the presence of serum factors, such as the bioactive lysophospholipid (LPA) that regulate LPS-induced TNF-alpha production. However, it is also required for the optimal functions of B and T cells during adaptive immune responses by regulating cAMP synthesis in both B and T cells.
• 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)
  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

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[1]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[2]
Autoimmune disease, susceptibility to, 6	DISHNUXI	Strong	Genetic Variation	[2]
Depression	DIS3XJ69	Strong	Biomarker	[3]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[2]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[4]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Genetic Variation	[5]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[6]
Mood disorder	DISLVMWO	Strong	Biomarker	[6]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[7]
Schizophrenia	DISSRV2N	Strong	Biomarker	[8]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	Strong	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	moderate	Altered Expression	[9]
Ankylosing spondylitis	DISRC6IR	moderate	Genetic Variation	[5]
Autoimmune thyroid disease	DISIHC6A	moderate	Genetic Variation	[5]
Coeliac disease	DISIY60C	moderate	Genetic Variation	[5]
Common variable immunodeficiency	DISHE7JQ	moderate	Genetic Variation	[5]
Crohn disease	DIS2C5Q8	moderate	Genetic Variation	[5]
leukaemia	DISS7D1V	moderate	Biomarker	[10]
Leukemia	DISNAKFL	moderate	Biomarker	[10]
Psoriasis	DIS59VMN	moderate	Genetic Variation	[5]
Systemic lupus erythematosus	DISI1SZ7	moderate	Genetic Variation	[5]
Type-1 diabetes	DIS7HLUB	moderate	Genetic Variation	[5]
Mental disorder	DIS3J5R8	Limited	Genetic Variation	[11]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[12]

1 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 7 (ADCY7).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Adenylate cyclase type 7 (ADCY7).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Adenylate cyclase type 7 (ADCY7).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Adenylate cyclase type 7 (ADCY7).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Adenylate cyclase type 7 (ADCY7).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Adenylate cyclase type 7 (ADCY7).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Adenylate cyclase type 7 (ADCY7).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Adenylate cyclase type 7 (ADCY7).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Adenylate cyclase type 7 (ADCY7).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Adenylate cyclase type 7 (ADCY7).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Adenylate cyclase type 7 (ADCY7).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Adenylate cyclase type 7 (ADCY7).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Adenylate cyclase type 7 (ADCY7).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Adenylate cyclase type 7 (ADCY7).	[26]

References

• [1] Sex-specific role for adenylyl cyclase type 7 in alcohol dependence.Biol Psychiatry. 2011 Jun 1;69(11):1100-8. doi: 10.1016/j.biopsych.2011.01.037. Epub 2011 Apr 8.
• [2] 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.
• [3] Adenylyl cyclase 7 and neuropsychiatric disorders: A new target for depression?.Pharmacol Res. 2019 May;143:106-112. doi: 10.1016/j.phrs.2019.03.015. Epub 2019 Mar 20.
• [4] Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7.Nat Genet. 2017 Feb;49(2):186-192. doi: 10.1038/ng.3761. Epub 2017 Jan 9.
• [5] Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases.Nat Med. 2015 Sep;21(9):1018-27. doi: 10.1038/nm.3933. Epub 2015 Aug 24.
• [6] Adenylate cyclase 7 is implicated in the biology of depression and modulation of affective neural circuitry.Biol Psychiatry. 2012 Apr 1;71(7):627-32. doi: 10.1016/j.biopsych.2011.11.029. Epub 2012 Jan 20.
• [7] Adenylate cyclase 7 regulated by miR-192 promotes ATRA-induced differentiation of acute promyelocytic leukemia cells.Biochem Biophys Res Commun. 2018 Nov 30;506(3):543-547. doi: 10.1016/j.bbrc.2018.10.125. Epub 2018 Oct 23.
• [8] Exome sequencing supports a de novo mutational paradigm for schizophrenia.Nat Genet. 2011 Aug 7;43(9):864-8. doi: 10.1038/ng.902.
• [9] CD300A promotes tumor progression by PECAM1, ADCY7 and AKT pathway in acute myeloid leukemia. Oncotarget. 2018 Jan 11;9(44):27574-27584.
• [10] ADCY7 supports development of acute myeloid leukemia.Biochem Biophys Res Commun. 2015 Sep 11;465(1):47-52. doi: 10.1016/j.bbrc.2015.07.123. Epub 2015 Jul 26.
• [11] A sex-specific role of type VII adenylyl cyclase in depression.J Neurosci. 2006 Nov 29;26(48):12609-19. doi: 10.1523/JNEUROSCI.1040-06.2006.
• [12] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [13] 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.
• [14] 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.
• [15] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [16] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [17] 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.
• [18] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [19] Gene microarray analysis of human renal cell carcinoma: the effects of HDAC inhibition and retinoid treatment. Cancer Biol Ther. 2008 Oct;7(10):1607-18.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [23] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [24] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [25] 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.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.