Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT41D0L3)

DOT Name	Transcobalamin-2 (TCN2)
Synonyms	TC-2; Transcobalamin II; TC II; TCII
Gene Name	TCN2
Related Disease	Advanced cancer ( ) Cerebrovascular disease ( ) Transcobalamin II deficiency ( ) Agammaglobulinemia ( ) Agranulocytosis ( ) Alzheimer disease ( ) Autism ( ) Autism spectrum disorder ( ) Chagas disease ( ) Coeliac disease ( ) Colorectal carcinoma ( ) Crohn disease ( ) Esophageal squamous cell carcinoma ( ) Glioblastoma multiforme ( ) Inborn error of metabolism ( ) Intellectual disability ( ) Isolated cleft lip ( ) leukaemia ( ) Leukemia ( ) Leukoencephalopathy with vanishing white matter ( ) Megaloblastic anemia ( ) Neural tube defect ( ) Obesity ( ) Pancytopenia ( ) Peripheral neuropathy ( ) Prostate cancer ( ) Prostate neoplasm ( ) Rheumatoid arthritis ( ) Severe combined immunodeficiency ( ) Stroke ( ) Thrombocytopenia ( ) Trichohepatoenteric syndrome ( ) Ulcerative colitis ( ) Wilms tumor ( ) Meningioma ( ) Moyamoya disease ( ) Pernicious anemia ( ) Cognitive impairment ( ) Malaria ( ) Adenoma ( ) Colorectal neoplasm ( ) Coronary atherosclerosis ( ) Coronary heart disease ( ) High blood pressure ( ) Mesothelioma ( ) Vitamin B12 deficiency ( )
UniProt ID	TCO2_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	2BB5; 4ZRP; 4ZRQ; 5NO0; 5NP4; 5NRP; 5NSA; 7QBD; 7QBE; 7QBF; 7QBG
Pfam ID	PF01122 ; PF14478
Sequence	MRHLGAFLFLLGVLGALTEMCEIPEMDSHLVEKLGQHLLPWMDRLSLEHLNPSIYVGLRL SSLQAGTKEDLYLHSLKLGYQQCLLGSAFSEDDGDCQGKPSMGQLALYLLALRANCEFVR GHKGDRLVSQLKWFLEDEKRAIGHDHKGHPHTSYYQYGLGILALCLHQKRVHDSVVDKLL YAVEPFHQGHHSVDTAAMAGLAFTCLKRSNFNPGRRQRITMAIRTVREEILKAQTPEGHF GNVYSTPLALQFLMTSPMRGAELGTACLKARVALLASLQDGAFQNALMISQLLPVLNHKT YIDLIFPDCLAPRVMLEPAAETIPQTQEIISVTLQVLSLLPPYRQSISVLAGSTVEDVLK KAHELGGFTYETQASLSGPYLTSVMGKAAGEREFWQLLRDPNTPLLQGIADYRPKDGETI ELRLVSW
Function	Primary vitamin B12-binding and transport protein. Delivers cobalamin to cells.
KEGG Pathway	Vitamin digestion and absorption (hsa04977 ) Cobalamin transport and metabolism (hsa04980 )
Reactome Pathway	Defective CD320 causes MMATC (R-HSA-3359485 ) Transport of RCbl within the body (R-HSA-9758890 ) Defective TCN2 causes TCN2 deficiency (R-HSA-3359454 )

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Cerebrovascular disease	DISAB237	Definitive	Genetic Variation	[2]
Transcobalamin II deficiency	DISRY7ST	Definitive	Autosomal recessive	[3]
Agammaglobulinemia	DISXMS80	Strong	Biomarker	[4]
Agranulocytosis	DISJS4LS	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[6]
Autism	DISV4V1Z	Strong	Biomarker	[7]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[8]
Chagas disease	DIS8KNVF	Strong	Biomarker	[9]
Coeliac disease	DISIY60C	Strong	Genetic Variation	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[11]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[12]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[13]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[14]
Inborn error of metabolism	DISO5FAY	Strong	Genetic Variation	[15]
Intellectual disability	DISMBNXP	Strong	Biomarker	[5]
Isolated cleft lip	DIS2O2JV	Strong	Biomarker	[16]
leukaemia	DISS7D1V	Strong	Altered Expression	[17]
Leukemia	DISNAKFL	Strong	Altered Expression	[17]
Leukoencephalopathy with vanishing white matter	DIS3J8NN	Strong	Biomarker	[18]
Megaloblastic anemia	DISVIZPC	Strong	Biomarker	[19]
Neural tube defect	DIS5J95E	Strong	Biomarker	[20]
Obesity	DIS47Y1K	Strong	Genetic Variation	[21]
Pancytopenia	DISVKEHV	Strong	Biomarker	[4]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[22]
Prostate cancer	DISF190Y	Strong	Biomarker	[23]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[23]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[24]
Severe combined immunodeficiency	DIS6MF4Q	Strong	Biomarker	[5]
Stroke	DISX6UHX	Strong	Genetic Variation	[25]
Thrombocytopenia	DISU61YW	Strong	Biomarker	[4]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[26]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[27]
Wilms tumor	DISB6T16	Strong	Genetic Variation	[28]
Meningioma	DISPT4TG	moderate	Biomarker	[29]
Moyamoya disease	DISO62CA	moderate	Genetic Variation	[30]
Pernicious anemia	DISWV404	moderate	Genetic Variation	[31]
Cognitive impairment	DISH2ERD	Disputed	Biomarker	[32]
Malaria	DISQ9Y50	Disputed	Genetic Variation	[33]
Adenoma	DIS78ZEV	Limited	Biomarker	[34]
Colorectal neoplasm	DISR1UCN	Limited	Biomarker	[34]
Coronary atherosclerosis	DISKNDYU	Limited	Genetic Variation	[35]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[35]
High blood pressure	DISY2OHH	Limited	Genetic Variation	[36]
Mesothelioma	DISKWK9M	Limited	Genetic Variation	[37]
Vitamin B12 deficiency	DIS91UJ1	Limited	Genetic Variation	[12]
------------------------------------------------------------------------------------


⏷ Show the Full List of 46 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Transcobalamin-2 (TCN2) affects the metabolism of Methotrexate.	[18]
------------------------------------------------------------------------------------

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Transcobalamin-2 (TCN2).	[38]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transcobalamin-2 (TCN2).	[39]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transcobalamin-2 (TCN2).	[40]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Transcobalamin-2 (TCN2).	[41]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of Transcobalamin-2 (TCN2).	[42]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Transcobalamin-2 (TCN2).	[44]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Transcobalamin-2 (TCN2).	[45]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Transcobalamin-2 (TCN2).	[46]
------------------------------------------------------------------------------------


⏷ Show the Full List of 8 Drug(s)

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 decreases the methylation of Transcobalamin-2 (TCN2).	[43]
------------------------------------------------------------------------------------

References

1	Proteome Analysis of Hypoxic Glioblastoma Cells Reveals Sequential Metabolic Adaptation of One-Carbon Metabolic Pathways.Mol Cell Proteomics. 2017 Nov;16(11):1906-1921. doi: 10.1074/mcp.RA117.000154. Epub 2017 Sep 5.
2	Association of homocysteine (but not of MTHFR 677 C>T, MTR 2756 A>G, MTRR 66 A>G and TCN2 776 C>G) with ischaemic cerebrovascular disease in Sicily.Thromb Haemost. 2006 Aug;96(2):154-9.
3	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.
4	Human uncoupling protein 2 and 3 genes are associated with obesity in Japanese.Endocrine. 2008 Aug-Dec;34(1-3):87-95. doi: 10.1007/s12020-008-9111-9. Epub 2008 Oct 28.
5	TC II deficiency: avoidance of false-negative molecular genetics by RNA-based investigations.J Hum Genet. 2009 Jun;54(6):331-4. doi: 10.1038/jhg.2009.34. Epub 2009 Apr 17.
6	Association of the transcobalamin II gene 776C ?G polymorphism with Alzheimer's type dementia: dependence on the 5, 10-methylenetetrahydrofolate reductase 1298A ?C polymorphism genotype.Ann Clin Biochem. 2015 Jul;52(Pt 4):448-55. doi: 10.1177/0004563214561770. Epub 2014 Nov 13.
7	Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism.Am J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141B(8):947-56. doi: 10.1002/ajmg.b.30366.
8	Association Study of Polymorphisms in Genes Relevant to Vitamin B12 and Folate Metabolism with Childhood Autism Spectrum Disorder in a Han Chinese Population.Med Sci Monit. 2018 Jan 19;24:370-376. doi: 10.12659/msm.905567.
9	Trypanosoma cruzi discrete typing units in Chagas disease patients from endemic and non-endemic regions of Argentina.Parasitology. 2012 Apr;139(4):516-21. doi: 10.1017/S0031182011002186. Epub 2012 Feb 6.
10	Polymorphic variants of genes involved in homocysteine metabolism in celiac disease.Mol Biol Rep. 2012 Mar;39(3):3123-30. doi: 10.1007/s11033-011-1077-7. Epub 2011 Jun 19.
11	A candidate gene study of one-carbon metabolism pathway genes and colorectal cancer risk.Br J Nutr. 2013 Mar 28;109(6):984-9. doi: 10.1017/S0007114512002796. Epub 2012 Jul 16.
12	An Analysis of Transcobalamin II Gene Polymorphisms and Serum Levels of Homocysteine, Folate and Vitamin B12 in Chinese Patients with Crohn's Disease.Dig Dis. 2017;35(5):463-471. doi: 10.1159/000471848. Epub 2017 May 5.
13	Exome-wide analyses identify low-frequency variant in CYP26B1 and additional coding variants associated with esophageal squamous cell carcinoma. Nat Genet. 2018 Mar;50(3):338-343. doi: 10.1038/s41588-018-0045-8. Epub 2018 Jan 29.
14	The methionine synthase polymorphism c.2756A>G alters susceptibility to glioblastoma multiforme.Cancer Epidemiol Biomarkers Prev. 2006 Nov;15(11):2314-6. doi: 10.1158/1055-9965.EPI-05-0979.
15	Temporary myoclonus with treatment of congenital transcobalamin 2 deficiency.Pediatr Neurol. 2001 Jan;24(1):75-6. doi: 10.1016/s0887-8994(00)00235-6.
16	Study of four genes belonging to the folate pathway: transcobalamin 2 is involved in the onset of non-syndromic cleft lip with or without cleft palate.Hum Mutat. 2006 Mar;27(3):294. doi: 10.1002/humu.9411.
17	Expression of transcobalamin II receptors by human leukemia K562 and HL-60 cells.Blood. 1990 Oct 1;76(7):1380-6.
18	MTX-induced white matter changes are associated with polymorphisms of methionine metabolism. Neurology. 2005 Mar 8;64(5):912-3. doi: 10.1212/01.WNL.0000152840.26156.74.
19	Hereditary partial transcobalamin II deficiency with neurologic, mental and hematologic abnormalities in children and adults.Isr Med Assoc J. 2003 Dec;5(12):868-72.
20	Exome sequencing of cases with neural tube defects identifies candidate genes involved in one-carbon/vitamin B12 metabolisms and Sonic Hedgehog pathway.Hum Genet. 2019 Jul;138(7):703-713. doi: 10.1007/s00439-019-02015-7. Epub 2019 May 28.
21	The TCN2 variant of rs9606756 [Ile23Val] acts as risk loci for obesity-related traits and mediates by interacting with Apo-A1.Obesity (Silver Spring). 2017 Jun;25(6):1098-1108. doi: 10.1002/oby.21826. Epub 2017 Apr 17.
22	Transcobalamin 776CG polymorphism is associated with peripheral neuropathy in elderly individuals with high folate intake.Am J Clin Nutr. 2016 Dec;104(6):1665-1670. doi: 10.3945/ajcn.116.139030. Epub 2016 Oct 12.
23	Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
24	Associations between single-nucleotide polymorphisms of RFC-1, GGH, MTHFR , TYMS, and TCII genes and the efficacy and toxicity of methotrexate treatment in patients with rheumatoid arthritis.Pol Arch Med Wewn. 2015;125(3):152-61. doi: 10.20452/pamw.2707. Epub 2015 Jan 19.
25	A comprehensive association analysis of homocysteine metabolic pathway genes in Singaporean Chinese with ischemic stroke.PLoS One. 2011;6(9):e24757. doi: 10.1371/journal.pone.0024757. Epub 2011 Sep 15.
26	Homozygous AMN mutation in hereditary selective intestinal malabsorption of vitamin B12 in Jordan.Saudi Med J. 2005 Jul;26(7):1061-4.
27	Association of ulcerative colitis with transcobalamin II gene polymorphisms and serum homocysteine, vitamin B(12), and folate levels in Chinese patients.Immunogenetics. 2017 Jul;69(7):421-428. doi: 10.1007/s00251-017-0998-2. Epub 2017 May 19.
28	A genome-wide association study identifies susceptibility loci for Wilms tumor.Nat Genet. 2012 Apr 29;44(6):681-4. doi: 10.1038/ng.2251.
29	Assignment of human transcobalamin II (TC2) to chromosome 22 using somatic cell hybrids and monosomic meningioma cells.Hum Genet. 1986 Dec;74(4):378-81. doi: 10.1007/BF00280489.
30	Novel Susceptibility Loci for Moyamoya Disease Revealed by a Genome-Wide Association Study.Stroke. 2018 Jan;49(1):11-18. doi: 10.1161/STROKEAHA.117.017430.
31	Single nucleotide polymorphisms related to vitamin B12 serum levels in autoimmune gastritis patients with or without pernicious anaemia.Dig Liver Dis. 2015 Apr;47(4):285-90. doi: 10.1016/j.dld.2015.01.147. Epub 2015 Jan 22.
32	B vitamin polymorphisms and behavior: evidence of associations with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline.Neurosci Biobehav Rev. 2014 Nov;47:307-20. doi: 10.1016/j.neubiorev.2014.08.006. Epub 2014 Aug 27.
33	Environmental influence on the worldwide prevalence of a 776C->G variant in the transcobalamin gene (TCN2).J Med Genet. 2007 Jun;44(6):363-7. doi: 10.1136/jmg.2006.048041. Epub 2007 Jan 12.
34	Twenty-four non-synonymous polymorphisms in the one-carbon metabolic pathway and risk of colorectal adenoma in the Nurses' Health Study.Carcinogenesis. 2007 Jul;28(7):1510-9. doi: 10.1093/carcin/bgm062. Epub 2007 Mar 26.
35	Polymorphisms in transcobalamin II gene is associated with coronary artery disease in Indian population.Biomarkers. 2012 Mar;17(2):119-24. doi: 10.3109/1354750X.2011.642408. Epub 2011 Dec 22.
36	Association of single nucleotide polymorphisms of MTHFR, TCN2, RNF213 with susceptibility to hypertension and blood pressure.Biosci Rep. 2019 Dec 20;39(12):BSR20191454. doi: 10.1042/BSR20191454.
37	Survey and biological insights of pemetrexed-related therapeutic improvement in mesothelioma: The Nancy Centre of Biological Resources' Mesothelioma Cohort.J Thorac Oncol. 2009 Oct;4(10):1259-63. doi: 10.1097/JTO.0b013e3181aba6bd.
38	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.
39	Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
40	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.
41	Glucocorticoid regulation of human eosinophil gene expression. J Steroid Biochem Mol Biol. 2003 Mar;84(4):441-52. doi: 10.1016/s0960-0760(03)00065-7.
42	Screening autism-associated environmental factors in differentiating human neural progenitors with fractional factorial design-based transcriptomics. Sci Rep. 2023 Jun 29;13(1):10519. doi: 10.1038/s41598-023-37488-0.
43	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.
44	Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation. Respir Res. 2005 Aug 8;6(1):89. doi: 10.1186/1465-9921-6-89.
45	Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
46	Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
47	MTX-induced white matter changes are associated with polymorphisms of methionine metabolism. Neurology. 2005 Mar 8;64(5):912-3. doi: 10.1212/01.WNL.0000152840.26156.74.