Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYSTB0R)

• DOT Name: Adenylate cyclase type 10 (ADCY10)
• Synonyms: EC 4.6.1.1; AH-related protein; Adenylate cyclase homolog; Germ cell soluble adenylyl cyclase; hsAC; sAC; Testicular soluble adenylyl cyclase
• Gene Name: ADCY10
• Related Disease:
  Asthma
  Glioma
  Infantile malignant osteopetrosis
  Abdominal aortic aneurysm
  Adenocarcinoma
  Advanced cancer
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Carcinoma
  Cardiac failure
  Congestive heart failure
  Hypercalciuria, absorptive, 2
  Metabolic bone disease
  Metastatic malignant neoplasm
  Neoplasm
  Obesity
  Autosomal recessive osteopetrosis 3
  Diabetic retinopathy
  Retinopathy
  Obsolete idiopathic inherited hypercalciuria
  Arrhythmia
  Glaucoma/ocular hypertension
  Leiomyoma
  Small lymphocytic lymphoma
  Type-1 diabetes
  Uterine fibroids
• UniProt ID: ADCYA_HUMAN
• PDB ID: 4CLF ; 4CLK ; 4CLL ; 4CLP ; 4CLS ; 4CLT ; 4CLU ; 4CLW ; 4CLY ; 4CLZ ; 4CM0 ; 4CM2 ; 4OYA ; 4OYB ; 4OYI ; 4OYM ; 4OYO ; 4OYP ; 4OYW ; 4OYX ; 4OYZ ; 4OZ2 ; 4OZ3 ; 4UST ; 4USU ; 4USV ; 4USW ; 5D0R ; 5IV3 ; 5IV4 ; 7OVD ; 8B75 ; 8CNH ; 8COJ ; 8COT ; 8IL7
• EC Number: 4.6.1.1
• Pfam ID: PF00211
• Sequence:
  MNTPKEEFQDWPIVRIAAHLPDLIVYGHFSPERPFMDYFDGVLMFVDISGFTAMTEKFSS
  AMYMDRGAEQLVEILNYHISAIVEKVLIFGGDILKFAGDALLALWRVERKQLKNIITVVI
  KCSLEIHGLFETQEWEEGLDIRVKIGLAAGHISMLVFGDETHSHFLVIGQAVDDVRLAQN
  MAQMNDVILSPNCWQLCDRSMIEIESVPDQRAVKVNFLKPPPNFNFDEFFTKCTTFMHYY
  PSGEHKNLLRLACTLKPDPELEMSLQKYVMESILKQIDNKQLQGYLSELRPVTIVFVNLM
  FEDQDKAEEIGPAIQDAYMHITSVLKIFQGQINKVFMFDKGCSFLCVFGFPGEKVPDELT
  HALECAMDIFDFCSQVHKIQTVSIGVASGIVFCGIVGHTVRHEYTVIGQKVNLAARMMMY
  YPGIVTCDSVTYNGSNLPAYFFKELPKKVMKGVADSGPLYQYWGRTEKVMFGMACLICNR
  KEDYPLLGRNKEINYFMYTMKKFLISNSSQVLMYEGLPGYGKSQILMKIEYLAQGKNHRI
  IAISLNKISFHQTFYTIQMFMANVLGLDTCKHYKERQTNLRNKVMTLLDEKFYCLLNDIF
  HVQFPISREISRMSTLKKQKQLEILFMKILKLIVKEERIIFIIDEAQFVDSTSWRFMEKL
  IRTLPIFIIMSLCPFVNIPCAAARAVIKNRNTTYIVIGAVQPNDISNKICLDLNVSCISK
  ELDSYLGEGSCGIPFYCEELLKNLEHHEVLVFQQTESEEKTNRTWNNLFKYSIKLTEKLN
  MVTLHSDKESEEVCHLTSGVRLKNLSPPTSLKEISLIQLDSMRLSHQMLVRCAAIIGLTF
  TTELLFEILPCWNMKMMIKTLATLVESNIFYCFRNGKELQKALKQNDPSFEVHYRSLSLK
  PSEGMDHGEEEQLRELENEVIECHRIRFCNPMMQKTAYELWLKDQRKAMHLKCARFLEED
  AHRCDHCRGRDFIPYHHFTVNIRLNALDMDAIKKMAMSHGFKTEEKLILSNSEIPETSAF
  FPENRSPEEIREKILNFFDHVLTKMKTSDEDIIPLESCQCEEILEIVILPLAHHFLALGE
  NDKALYYFLEIASAYLIFCDNYMAYMYLNEGQKLLKTLKKDKSWSQTFESATFYSLKGEV
  CFNMGQIVLAKKMLRKALKLLNRIFPYNLISLFLHIHVEKNRHFHYVNRQAQESPPPGKK
  RLAQLYRQTVCLSLLWRIYSYSYLFHCKYYAHLAVMMQMNTALETQNCFQIIKAYLDYSL
  YHHLAGYKGVWFKYEVMAMEHIFNLPLKGEGIEIVAYVAETLVFNKLIMGHLDLAIELGS
  RALQMWALLQNPNRHYQSLCRLSRCLLLNSRYPQLIQVLGRLWELSVTQEHIFSKAFFYF
  VCLDILLYSGFVYRTFEECLEFIHQYENNRILKFHSGLLLGLYSSVAIWYARLQEWDNFY
  KFSNRAKNLLPRRTMTLTYYDGISRYMEGQVLHLQKQIKEQSENAQASGEELLKNLENLV
  AQNTTGPVFCPRLYHLMAYVCILMGDGQKCGLFLNTALRLSETQGNILEKCWLNMNKESW
  YSTSELKEDQWLQTILSLPSWEKIVAGRVNIQDLQKNKFLMRANTVDNHF
• Function: Catalyzes the formation of the signaling molecule cAMP. May function as sensor that mediates responses to changes in cellular bicarbonate and CO(2) levels. Has a critical role in mammalian spermatogenesis by producing the cAMP which regulates cAMP-responsive nuclear factors indispensable for sperm maturation in the epididymis. Induces capacitation, the maturational process that sperm undergo prior to fertilization. Involved in ciliary beat regulation.
• Tissue Specificity: Detected in airway epithelial cells and testis (at protein level) . Weakly expressed in multiple tissues. Expressed in brain, heart, kidney, liver, lung, pancreas, peripheral blood leukocytes, placenta, skeletal muscle, stomach, thymus, airway epithelial cells, duodenum, jejunum and ileum. Very low level of expression in bone.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  cAMP sig.ling pathway (hsa04024)
  Apelin sig.ling pathway (hsa04371)
  Circadian entrainment (hsa04713)
  Thermogenesis (hsa04714)
  Growth hormone synthesis, secretion and action (hsa04935)
• Reactome Pathway: Hedgehog 'off' state (R-HSA-5610787)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asthma	DISW9QNS	Definitive	Biomarker	[1]
Glioma	DIS5RPEH	Definitive	Biomarker	[2]
Infantile malignant osteopetrosis	DIS8C3LZ	Definitive	Biomarker	[3]
Abdominal aortic aneurysm	DISD06OF	Strong	Genetic Variation	[4]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[5]
Alzheimer disease	DISF8S70	Strong	Biomarker	[6]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[7]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[7]
Carcinoma	DISH9F1N	Strong	Altered Expression	[8]
Cardiac failure	DISDC067	Strong	Biomarker	[9]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[9]
Hypercalciuria, absorptive, 2	DISHHLZR	Strong	Autosomal dominant	[10]
Metabolic bone disease	DISO7RI8	Strong	Genetic Variation	[11]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[12]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[13]
Obesity	DIS47Y1K	Strong	Biomarker	[7]
Autosomal recessive osteopetrosis 3	DISWBB4P	moderate	Genetic Variation	[11]
Diabetic retinopathy	DISHGUJM	moderate	Biomarker	[14]
Retinopathy	DISB4B0F	moderate	Biomarker	[14]
Obsolete idiopathic inherited hypercalciuria	DIS30UZ5	Supportive	Autosomal dominant	[10]
Arrhythmia	DISFF2NI	Limited	Altered Expression	[15]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Biomarker	[16]
Leiomyoma	DISLDDFN	Limited	Altered Expression	[12]
Small lymphocytic lymphoma	DIS30POX	Limited	Biomarker	[17]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[18]
Uterine fibroids	DISBZRMJ	Limited	Altered Expression	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Adenylate cyclase type 10 (ADCY10).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Adenylate cyclase type 10 (ADCY10).	[20]
Bicarbonate	DMT5E36	Investigative	Bicarbonate increases the expression of Adenylate cyclase type 10 (ADCY10).	[21]

References

• [1] Exploring factors associated with health disparities in asthma and poorly controlled asthma among school-aged children in the U.S.J Asthma. 2020 Mar;57(3):271-285. doi: 10.1080/02770903.2019.1571080. Epub 2019 Feb 7.
• [2] The accuracy of survival time prediction for patients with glioma is improved by measuring mitotic spindle checkpoint gene expression.PLoS One. 2011;6(10):e25631. doi: 10.1371/journal.pone.0025631. Epub 2011 Oct 12.
• [3] The determination of osteopetrotic phenotypes by selective inactivation of red cell carbonic anhydrase isoenzymes.Clin Chim Acta. 1985 Nov 15;152(3):347-54. doi: 10.1016/0009-8981(85)90110-x.
• [4] The potential role of DNA methylation in abdominal aortic aneurysms.Int J Mol Sci. 2015 May 18;16(5):11259-75. doi: 10.3390/ijms160511259.
• [5] Airborne particulate matter induces mitotic slippage and chromosomal missegregation through disruption of the spindle assembly checkpoint (SAC).Chemosphere. 2019 Nov;235:794-804. doi: 10.1016/j.chemosphere.2019.06.232. Epub 2019 Jul 1.
• [6] Novel sulfamate derivatives of menthol: Synthesis, characterization, and cholinesterases and carbonic anhydrase enzymes inhibition properties.Arch Pharm (Weinheim). 2018 Nov;351(11):e1800209. doi: 10.1002/ardp.201800209. Epub 2018 Sep 26.
• [7] Hydroxycarboxylic Acid Receptor Ligands Modulate Proinflammatory Cytokine Expression in Human Macrophages and Adipocytes without Affecting Adipose Differentiation.Biol Pharm Bull. 2018;41(10):1574-1580. doi: 10.1248/bpb.b18-00301.
• [8] Deregulation of HMGA1 expression induces chromosome instability through regulation of spindle assembly checkpoint genes.Oncotarget. 2015 Jul 10;6(19):17342-53. doi: 10.18632/oncotarget.3944.
• [9] Lower Hospitalization and Healthcare Costs With Sacubitril/Valsartan Versus Angiotensin-Converting Enzyme Inhibitor or Angiotensin-Receptor Blocker in a Retrospective Analysis of Patients With Heart Failure.J Am Heart Assoc. 2019 May 7;8(9):e011089. doi: 10.1161/JAHA.118.011089.
• [10] Identification and characterization of a gene with base substitutions associated with the absorptive hypercalciuria phenotype and low spinal bone density. J Clin Endocrinol Metab. 2002 Apr;87(4):1476-85. doi: 10.1210/jcem.87.4.8300.
• [11] Small-molecule suppression of misfolding of mutated human carbonic anhydrase II linked to marble brain disease.Biochemistry. 2009 Jun 16;48(23):5358-64. doi: 10.1021/bi900128e.
• [12] Increased infiltration of M2-macrophages, T-cells and PD-L1 expression in high grade leiomyosarcomas supports immunotherapeutic strategies.Oncoimmunology. 2017 Oct 26;7(2):e1386828. doi: 10.1080/2162402X.2017.1386828. eCollection 2018.
• [13] Aneuploidy: Cancer strength or vulnerability?.Int J Cancer. 2019 Jan 1;144(1):8-25. doi: 10.1002/ijc.31718. Epub 2018 Oct 31.
• [14] Constitutive expression of HCA(2) in human retina and primary human retinal pigment epithelial cells.Curr Eye Res. 2014 May;39(5):487-92. doi: 10.3109/02713683.2013.848900. Epub 2013 Nov 11.
• [15] Effects of bepridil on stretch-activated BKca channels and stretch-induced extrasystoles in isolated chick hearts.Physiol Res. 2017 Jul 18;66(3):459-465. doi: 10.33549/physiolres.933315. Epub 2017 Feb 28.
• [16] Continued exploration and tail approach synthesis of benzenesulfonamides containing triazole and dual triazole moieties as carbonic anhydrase I, II, IV and IX inhibitors.Eur J Med Chem. 2019 Dec 1;183:111698. doi: 10.1016/j.ejmech.2019.111698. Epub 2019 Sep 12.
• [17] Mitotic slippage: an old tale with a new twist.Cell Cycle. 2019 Jan;18(1):7-15. doi: 10.1080/15384101.2018.1559557. Epub 2019 Jan 2.
• [18] Apolipoprotein C-III protein concentrations and gene polymorphisms in Type 1 diabetes: associations with microvascular disease complications in the DCCT/EDIC cohort.J Diabetes Complications. 2005 Jan-Feb;19(1):18-25. doi: 10.1016/j.jdiacomp.2004.04.005.
• [19] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [20] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [21] [HCO3-]-regulated expression and activity of soluble adenylyl cyclase in corneal endothelial and Calu-3 cells. BMC Physiol. 2004 Apr 29;4:8. doi: 10.1186/1472-6793-4-8.