Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK9NM7G)

• DOT Name: Tolloid-like protein 1 (TLL1)
• Synonyms: EC 3.4.24.-
• Gene Name: TLL1
• Related Disease:
  Chronic renal failure
  Atrial septal defect
  Autism
  Autism spectrum disorder
  Non-alcoholic fatty liver disease
  Periodontitis
  Post-traumatic stress disorder
  Cryohydrocytosis
  Atrial septal defect 6
  Coronary heart disease
  Non-insulin dependent diabetes
  Osteogenesis imperfecta
• UniProt ID: TLL1_HUMAN
• PDB ID: 3EDI
• EC Number: 3.4.24.-
• Pfam ID: PF01400 ; PF00431 ; PF14670
• Sequence:
  MGLGTLSPRMLVWLVASGIVFYGELWVCAGLDYDYTFDGNEEDKTETIDYKDPCKAAVFW
  GDIALDDEDLNIFQIDRTIDLTQNPFGNLGHTTGGLGDHAMSKKRGALYQLIDRIRRIGF
  GLEQNNTVKGKVPLQFSGQNEKNRVPRAATSRTERIWPGGVIPYVIGGNFTGSQRAMFKQ
  AMRHWEKHTCVTFIERSDEESYIVFTYRPCGCCSYVGRRGNGPQAISIGKNCDKFGIVVH
  ELGHVIGFWHEHTRPDRDNHVTIIRENIQPGQEYNFLKMEPGEVNSLGERYDFDSIMHYA
  RNTFSRGMFLDTILPSRDDNGIRPAIGQRTRLSKGDIAQARKLYRCPACGETLQESNGNL
  SSPGFPNGYPSYTHCIWRVSVTPGEKIVLNFTTMDLYKSSLCWYDYIEVRDGYWRKSPLL
  GRFCGDKLPEVLTSTDSRMWIEFRSSSNWVGKGFAAVYEAICGGEIRKNEGQIQSPNYPD
  DYRPMKECVWKITVSESYHVGLTFQSFEIERHDNCAYDYLEVRDGTSENSPLIGRFCGYD
  KPEDIRSTSNTLWMKFVSDGTVNKAGFAANFFKEEDECAKPDRGGCEQRCLNTLGSYQCA
  CEPGYELGPDRRSCEAACGGLLTKLNGTITTPGWPKEYPPNKNCVWQVVAPTQYRISVKF
  EFFELEGNEVCKYDYVEIWSGLSSESKLHGKFCGAEVPEVITSQFNNMRIEFKSDNTVSK
  KGFKAHFFSDKDECSKDNGGCQHECVNTMGSYMCQCRNGFVLHDNKHDCKEAECEQKIHS
  PSGLITSPNWPDKYPSRKECTWEISATPGHRIKLAFSEFEIEQHQECAYDHLEVFDGETE
  KSPILGRLCGNKIPDPLVATGNKMFVRFVSDASVQRKGFQATHSTECGGRLKAESKPRDL
  YSHAQFGDNNYPGQVDCEWLLVSERGSRLELSFQTFEVEEEADCGYDYVELFDGLDSTAV
  GLGRFCGSGPPEEIYSIGDSVLIHFHTDDTINKKGFHIRYKSIRYPDTTHTKK
• Function: Protease which processes procollagen C-propeptides, such as chordin, pro-biglycan and pro-lysyl oxidase. Required for the embryonic development. Predominant protease, which in the development, influences dorsal-ventral patterning and skeletogenesis.
• Reactome Pathway:
  Collagen biosynthesis and modifying enzymes (R-HSA-1650814)
  Anchoring fibril formation (R-HSA-2214320)
  Crosslinking of collagen fibrils (R-HSA-2243919)
  Degradation of the extracellular matrix (R-HSA-1474228)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[1]
Atrial septal defect	DISJT76B	Strong	Biomarker	[2]
Autism	DISV4V1Z	Strong	Biomarker	[3]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[2]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[4]
Periodontitis	DISI9JOI	Strong	Biomarker	[5]
Post-traumatic stress disorder	DISHL1EY	Strong	Genetic Variation	[6]
Cryohydrocytosis	DISMQHL3	moderate	Genetic Variation	[7]
Atrial septal defect 6	DISW4351	Limited	Autosomal dominant	[8]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[9]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[9]
Osteogenesis imperfecta	DIS7XQSD	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Tolloid-like protein 1 (TLL1).	[10]

6 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 Tolloid-like protein 1 (TLL1).	[11]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Tolloid-like protein 1 (TLL1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tolloid-like protein 1 (TLL1).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Tolloid-like protein 1 (TLL1).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Tolloid-like protein 1 (TLL1).	[14]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Tolloid-like protein 1 (TLL1).	[15]

References

• [1] Genetic loci associated with renal function measures and chronic kidney disease in children: the Pediatric Investigation for Genetic Factors Linked with Renal Progression Consortium.Nephrol Dial Transplant. 2016 Feb;31(2):262-9. doi: 10.1093/ndt/gfv342. Epub 2015 Sep 28.
• [2] A de novo splicing variant supports the candidacy of TLL1 in ASD pathogenesis.Eur J Hum Genet. 2020 Apr;28(4):525-528. doi: 10.1038/s41431-019-0524-0. Epub 2019 Sep 30.
• [3] Extreme male developmental trajectories of homotopic brain connectivity in autism.Hum Brain Mapp. 2019 Feb 15;40(3):987-1000. doi: 10.1002/hbm.24427. Epub 2018 Oct 11.
• [4] Combination of PNPLA3 and TLL1 polymorphism can predict advanced fibrosis in Japanese patients with nonalcoholic fatty liver disease.J Gastroenterol. 2018 Mar;53(3):438-448. doi: 10.1007/s00535-017-1372-8. Epub 2017 Jul 25.
• [5] BMP1 and TLL1 Are Required for Maintaining Periodontal Homeostasis.J Dent Res. 2017 May;96(5):578-585. doi: 10.1177/0022034516686558. Epub 2017 Jan 9.
• [6] Genome-wide association study identifies new susceptibility loci for posttraumatic stress disorder.Biol Psychiatry. 2013 Nov 1;74(9):656-63. doi: 10.1016/j.biopsych.2013.04.013. Epub 2013 May 28.
• [7] TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus by interferon-free therapy.J Gastroenterol. 2019 Apr;54(4):339-346. doi: 10.1007/s00535-018-1526-3. Epub 2018 Oct 31.
• [8] 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.
• [9] Peroxisome proliferator-activated receptor pathway gene polymorphism associated with extent of coronary artery disease in patients with type 2 diabetes in the bypass angioplasty revascularization investigation 2 diabetes trial.Circulation. 2011 Sep 27;124(13):1426-34. doi: 10.1161/CIRCULATIONAHA.111.029173. Epub 2011 Sep 12.
• [10] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [11] Effect of benzo[a]pyrene on proliferation and metastasis of oral squamous cell carcinoma cells: A transcriptome analysis based on RNA-seq. Environ Toxicol. 2022 Nov;37(11):2589-2604. doi: 10.1002/tox.23621. Epub 2022 Jul 23.
• [12] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [13] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [14] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [15] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.