Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW6A49Y)

• DOT Name: Transcobalamin-1 (TCN1)
• Synonyms: TC-1; Haptocorrin; HC; Protein R; Transcobalamin I; TC I; TCI
• Gene Name: TCN1
• Related Disease:
  Adenocarcinoma
  Advanced cancer
  Atopic dermatitis
  Breast cancer
  Breast carcinoma
  Chronic kidney disease
  Depression
  Gastric cancer
  Hepatocellular carcinoma
  Hypopharyngeal squamous cell carcinoma
  Liposarcoma
  Lung cancer
  Lung carcinoma
  Megaloblastic anemia
  Neoplasm
  Non-hodgkin lymphoma
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
  Rectal carcinoma
  Stomach cancer
  Transcobalamin II deficiency
  Vitamin B12 deficiency
  Anxiety disorder
  Neural tube defect
• UniProt ID: TCO1_HUMAN
• PDB ID: 4KKI; 4KKJ
• Pfam ID: PF01122 ; PF14478
• Sequence:
  MRQSHQLPLVGLLLFSFIPSQLCEICEVSEENYIRLKPLLNTMIQSNYNRGTSAVNVVLS
  LKLVGIQIQTLMQKMIQQIKYNVKSRLSDVSSGELALIILALGVCRNAEENLIYDYHLID
  KLENKFQAEIENMEAHNGTPLTNYYQLSLDVLALCLFNGNYSTAEVVNHFTPENKNYYFG
  SQFSVDTGAMAVLALTCVKKSLINGQIKADEGSLKNISIYTKSLVEKILSEKKENGLIGN
  TFSTGEAMQALFVSSDYYNENDWNCQQTLNTVLTEISQGAFSNPNAAAQVLPALMGKTFL
  DINKDSSCVSASGNFNISADEPITVTPPDSQSYISVNYSVRINETYFTNVTVLNGSVFLS
  VMEKAQKMNDTIFGFTMEERSWGPYITCIQGLCANNNDRTYWELLSGGEPLSQGAGSYVV
  RNGENLEVRWSKY
• Function: Binds vitamin B12 with femtomolar affinity and protects it from the acidic environment of the stomach.
• Tissue Specificity: Produced by the salivary glands of the oral cavity, in response to ingestion of food. Major constituent of secondary granules in neutrophils.
• KEGG Pathway: Cobalamin transport and metabolism (hsa04980)
• Reactome Pathway:
  Uptake of dietary cobalamins into enterocytes (R-HSA-9758881)
  Transport of RCbl within the body (R-HSA-9758890)
  Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Atopic dermatitis	DISTCP41	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Chronic kidney disease	DISW82R7	Strong	Genetic Variation	[4]
Depression	DIS3XJ69	Strong	Genetic Variation	[5]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Hypopharyngeal squamous cell carcinoma	DISDDD65	Strong	Biomarker	[7]
Liposarcoma	DIS8IZVM	Strong	Altered Expression	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[1]
Lung carcinoma	DISTR26C	Strong	Biomarker	[1]
Megaloblastic anemia	DISVIZPC	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Biomarker	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[1]
Prostate cancer	DISF190Y	Strong	Biomarker	[12]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[12]
Rectal carcinoma	DIS8FRR7	Strong	Genetic Variation	[3]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[6]
Transcobalamin II deficiency	DISRY7ST	Strong	Altered Expression	[13]
Vitamin B12 deficiency	DIS91UJ1	Strong	Altered Expression	[14]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[15]
Neural tube defect	DIS5J95E	Limited	Altered Expression	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Transcobalamin-1 (TCN1).	[17]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Transcobalamin-1 (TCN1).	[18]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Transcobalamin-1 (TCN1).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Transcobalamin-1 (TCN1).	[21]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Transcobalamin-1 (TCN1).	[22]

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 Transcobalamin-1 (TCN1).	[20]

References

• [1] Vitamin B12 and its binding proteins in patients with non-small cell lung cancer referred to fast-track diagnostic work-up for lung cancer.Scand J Clin Lab Invest. 2020 Feb;80(1):14-19. doi: 10.1080/00365513.2019.1692232. Epub 2019 Nov 18.
• [2] The effects of season and weather on healthcare utilization among patients with atopic dermatitis.J Eur Acad Dermatol Venereol. 2018 Oct;32(10):1745-1753. doi: 10.1111/jdv.15023. Epub 2018 May 31.
• [3] Overexpression of Transcobalamin 1 is an Independent Negative Prognosticator in Rectal Cancers Receiving Concurrent Chemoradiotherapy.J Cancer. 2017 May 12;8(8):1330-1337. doi: 10.7150/jca.18274. eCollection 2017.
• [4] Clinical Indices Can Standardize and Monitor Pediatric Care: A Novel Mechanism to Improve Quality and Safety.J Pediatr. 2018 Feb;193:190-195.e1. doi: 10.1016/j.jpeds.2017.09.073. Epub 2017 Dec 6.
• [5] Psychopathological constellation in patients with PNES: A new hypothesis.Epilepsy Behav. 2018 Jan;78:297-301. doi: 10.1016/j.yebeh.2017.09.025. Epub 2017 Oct 29.
• [6] Association study between genome-wide significant variants of vitamin B12 metabolism and gastric cancer in a han Chinese population.IUBMB Life. 2016 Apr;68(4):303-10. doi: 10.1002/iub.1485. Epub 2016 Mar 9.
• [7] Transcobalamin I: a novel prognostic biomarker of neoadjuvant chemotherapy in locally advanced hypopharyngeal squamous cell cancers.Onco Targets Ther. 2018 Jul 24;11:4253-4261. doi: 10.2147/OTT.S166514. eCollection 2018.
• [8] Expression of human papillomavirus type 16 E7 oncoprotein alters keratinocytes expression profile in response to tumor necrosis factor-alpha.Carcinogenesis. 2010 Mar;31(3):521-31. doi: 10.1093/carcin/bgp333. Epub 2009 Dec 30.
• [9] Megaloblastic anemia after anticonvulsive therapy.N Engl J Med. 1972 Nov 9;287(19):990. doi: 10.1056/NEJM197211092871925.
• [10] Combined immunotherapy: CTLA-4 blockade potentiates anti-tumor response induced by transcutaneous immunization.J Dermatol Sci. 2017 Sep;87(3):300-306. doi: 10.1016/j.jdermsci.2017.06.013. Epub 2017 Jun 16.
• [11] Genetic polymorphisms in the one-carbon metabolism pathway genes and susceptibility to non-Hodgkin lymphoma.Tumour Biol. 2015 Mar;36(3):1819-34. doi: 10.1007/s13277-014-2785-0. Epub 2014 Nov 11.
• [12] Associations of folate, vitamin B12, homocysteine, and folate-pathway polymorphisms with prostate-specific antigen velocity in men with localized prostate cancer.Cancer Epidemiol Biomarkers Prev. 2010 Nov;19(11):2833-8. doi: 10.1158/1055-9965.EPI-10-0582. Epub 2010 Sep 17.
• [13] Transcobalamin II and its cell surface receptor.Vitam Horm. 2000;59:337-66. doi: 10.1016/s0083-6729(00)59012-8.
• [14] Three family members with elevated plasma cobalamin, transcobalamin and soluble transcobalamin receptor (sCD320).Clin Chem Lab Med. 2013 Mar 1;51(3):677-82. doi: 10.1515/cclm-2012-0554.
• [15] Temperament clusters associate with anxiety disorder comorbidity in depression.J Affect Disord. 2018 Aug 15;236:252-258. doi: 10.1016/j.jad.2018.04.084. Epub 2018 Apr 23.
• [16] Increased levels of apo-transcobalamins I and II in amniotic fluid from pregnant women with previous neural tube defect offspring.Clin Genet. 1986 Sep;30(3):167-72. doi: 10.1111/j.1399-0004.1986.tb00590.x.
• [17] 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.
• [18] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [19] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [20] 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.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.