Details of Drug Off-Target (DOT)

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

• DOT Name: Alpha-tocopherol transfer protein
• Synonyms: Alpha-TTP
• Gene Name: TTPA
• Related Disease: Familial isolated deficiency of vitamin E
• UniProt ID: TTPA_HUMAN
• PDB ID: 1OIP; 1OIZ; 1R5L; 5MUE; 5MUG; 6ZPD
• Pfam ID: PF00650 ; PF03765
• Sequence:
  MAEARSQPSAGPQLNALPDHSPLLQPGLAALRRRAREAGVPLAPLPLTDSFLLRFLRARD
  FDLDLAWRLLKNYYKWRAECPEISADLHPRSIIGLLKAGYHGVLRSRDPTGSKVLIYRIA
  HWDPKVFTAYDVFRVSLITSELIVQEVETQRNGIKAIFDLEGWQFSHAFQITPSVAKKIA
  AVLTDSFPLKVRGIHLINEPVIFHAVFSMIKPFLTEKIKERIHMHGNNYKQSLLQHFPDI
  LPLEYGGEEFSMEDICQEWTNFIMKSEDYLSSISESIQ
• Function: Binds alpha-tocopherol, enhances its transfer between separate membranes, and stimulates its release from liver cells. Binds both phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 4,5-bisphosphate; the resulting conformation change is important for the release of the bound alpha-tocopherol.
• Reactome Pathway: Vitamin E (R-HSA-8877627)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial isolated deficiency of vitamin E	DIS53306	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tocopherol	DMBIJZ6	Phase 2	Alpha-tocopherol transfer protein decreases the abundance of Tocopherol.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Alpha-tocopherol transfer protein.	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Alpha-tocopherol transfer protein.	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Alpha-tocopherol transfer protein.	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Alpha-tocopherol transfer protein.	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Alpha-tocopherol transfer protein.	[3]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Alpha-tocopherol transfer protein.	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Alpha-tocopherol transfer protein.	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Alpha-tocopherol transfer protein.	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Alpha-tocopherol transfer protein.	[9]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Alpha-tocopherol transfer protein.	[10]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Alpha-tocopherol transfer protein.	[11]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] 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.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [6] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [9] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [10] 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.
• [11] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [12] Ataxia with isolated vitamin E deficiency: neurological phenotype, clinical follow-up and novel mutations in TTPA gene in Italian families. Neurol Sci. 2004 Jul;25(3):130-7. doi: 10.1007/s10072-004-0246-z.