Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK8PU0T)

• DOT Name: Enamelin (ENAM)
• Gene Name: ENAM
• Related Disease:
  Amelogenesis imperfecta type 1B
  Amelogenesis imperfecta type 1C
  Autoimmune hepatitis
  Hepatitis C virus infection
  Liver cirrhosis
  Amelogenesis imperfecta
  Amelogenesis imperfecta type 1
  Arthritis
  Dental enamel hypoplasia
  Dentin dysplasia
  Dentinogenesis imperfecta
• UniProt ID: ENAM_HUMAN
• Pfam ID: PF15362
• Sequence:
  MLVLRCRLGTSFPKLDNLVPKGKMKILLVFLGLLGNSVAMPMHMPRMPGFSSKSEEMMRY
  NQFNFMNGPHMAHLGPFFGNGLPQQFPQYQMPMWPQPPPNTWHPRKSSAPKRHNKTDQTQ
  ETQKPNQTQSKKPPQKRPLKQPSHNQPQPEEEAQPPQAFPPFGNGLFPYQQPPWQIPQRL
  PPPGYGRPPISNEEGGNPYFGYFGYHGFGGRPPYYSEEMFEQDFEKPKEEDPPKAESPGT
  EPTANSTVTETNSTQPNPKGSQGGNDTSPTGNSTPGLNTGNNPPAQNGIGPLPAVNASGQ
  GGPGSQIPWRPSQPNIRENHPYPNIRNFPSGRQWYFTGTVMGHRQNRPFYRNQQVQRGPR
  WNFFAWERKQVARPGNPVYHKAYPPTSRGNYPNYAGNPANLRRKPQGPNKHPVGTTVAPL
  GPKPGPVVRNEKIQNPKEKPLGPKEQIIVPTKNPTSPWRNSQQYEVNKSNYKLPHSEGYM
  PVPNFNSVDQHENSYYPRGDSRKVPNSDGQTQSQNLPKGIVLGSRRMPYESETNQSELKH
  SSYQPAVYPEEIPSPAKEHFPAGRNTWDHQEISPPFKEDPGRQEEHLPHPSHGSRGSVFY
  PEYNPYDPRENSPYLRGNTWDERDDSPNTMGQKESPLYPINTPDQKEIVPYNEEDPVDPT
  GDEVFPGQNRWGEELSFKGGPTVRHYEGEQYTSNQPKEYLPYSLDNPSKPREDFYYSEFY
  PWSPDENFPSYNTASTMPPPIESRGYYVNNAAGPEESTLFPSRNSWDHRIQAQGQRERRP
  YFNRNIWDQATHLQKAPARPPDQKGNQPYYSNTPAGLQKNPIWHEGENLNYGMQITRMNS
  PEREHSSFPNFIPPSYPSGQKEAHLFHLSQRGSCCAGSSTGPKDNPLALQDYTPSYGLAP
  GENQDTSPLYTDGSHTKQTRDIISPTSILPGQRNSSEKRESQNPFRDDVSTLRRNTPCSI
  KNQLGQKEIMPFPEASSLQSKNTPCLKNDLGGDGNNILEQVFEDNQLNERTVDLTPEQLV
  IGTPDEGSNPEGIQSQVQENESERQQQRPSNILHLPCFGSKLAKHHSSTTGTPSSDGRQS
  PFDGDSITPTENPNTLVELATEEQFKSINVDPLDADEHSPFEFLQRGTNVQDQVQDCLLL
  QA
• Function: Involved in the mineralization and structural organization of enamel. Involved in the extension of enamel during the secretory stage of dental enamel formation.
• Tissue Specificity: Expressed in tooth particularly in odontoblast, ameloblast and cementoblast.
• Reactome Pathway:
  Post-translational protein phosphorylation (R-HSA-8957275)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amelogenesis imperfecta type 1B	DISWPUI8	Strong	Semidominant	[1]
Amelogenesis imperfecta type 1C	DISIN2WF	Strong	Autosomal recessive	[2]
Autoimmune hepatitis	DISOX03Q	Strong	Biomarker	[3]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[4]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[5]
Amelogenesis imperfecta	DISGYR9E	moderate	Genetic Variation	[6]
Amelogenesis imperfecta type 1	DISVEG5A	Supportive	Autosomal dominant	[7]
Arthritis	DIST1YEL	Limited	Biomarker	[8]
Dental enamel hypoplasia	DISN6ZMR	Limited	Genetic Variation	[9]
Dentin dysplasia	DISCGIX8	Limited	Biomarker	[10]
Dentinogenesis imperfecta	DISJLZU4	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Enamelin (ENAM).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Enamelin (ENAM).	[12]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Diagnostic criteria for non-traumatic osteonecrosis of the femoral head. A multicentre study. J Bone Joint Surg Br. 1999 Jul;81(4):590-5. doi: 10.1302/0301-620x.81b4.9393.
• [3] Diagnosis and Management of Pediatric Autoimmune Liver Disease: ESPGHAN Hepatology Committee Position Statement.J Pediatr Gastroenterol Nutr. 2018 Feb;66(2):345-360. doi: 10.1097/MPG.0000000000001801.
• [4] Overlapping but distinct specificities of anti-liver-kidney microsome antibodies in autoimmune hepatitis type II and hepatitis C revealed by recombinant native CYP2D6 and novel peptide epitopes.Clin Exp Immunol. 1999 Nov;118(2):290-7. doi: 10.1046/j.1365-2249.1999.01027.x.
• [5] Autoimmune hepatitis.J Hepatol. 2000;32(1 Suppl):181-97. doi: 10.1016/s0168-8278(00)80425-0.
• [6] Canine models of human amelogenesis imperfecta: identification of novel recessive ENAM and ACP4 variants.Hum Genet. 2019 May;138(5):525-533. doi: 10.1007/s00439-019-01997-8. Epub 2019 Mar 15.
• [7] A nonsense mutation in the enamelin gene causes local hypoplastic autosomal dominant amelogenesis imperfecta (AIH2). Hum Mol Genet. 2002 May 1;11(9):1069-74. doi: 10.1093/hmg/11.9.1069.
• [8] Frequency of concurrent autoimmune disorders in patients with autoimmune hepatitis: effect of age, gender, and genetic background.J Clin Gastroenterol. 2008 Mar;42(3):300-5. doi: 10.1097/MCG.0b013e31802dbdfc.
• [9] Enamelin Directs Crystallite Organization at the Enamel-Dentine Junction.J Dent Res. 2016 May;95(5):580-7. doi: 10.1177/0022034516632745. Epub 2016 Feb 24.
• [10] Enamelin is critical for ameloblast integrity and enamel ultrastructure formation.PLoS One. 2014 Mar 6;9(3):e89303. doi: 10.1371/journal.pone.0089303. eCollection 2014.
• [11] 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.
• [12] 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.