Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZDQ29F)

• DOT Name: Mitochondrial import receptor subunit TOM40 homolog (TOMM40)
• Synonyms: Protein Haymaker; Translocase of outer membrane 40 kDa subunit homolog; p38.5
• Gene Name: TOMM40
• Related Disease:
  B-cell neoplasm
  Chronic kidney disease
  Acute myocardial infarction
  Aural atresia, congenital
  Autosomal dominant optic atrophy, classic form
  Behavioral variant of frontotemporal dementia
  Carotid artery disease
  Coronary heart disease
  Dementia
  Depression
  Familial Alzheimer disease
  Frontotemporal dementia
  Hepatitis C virus infection
  Huntington disease
  Late-onset Parkinson disease
  Lung adenocarcinoma
  Major depressive disorder
  Nervous system disease
  Obesity
  Parkinson disease
  Parkinsonian disorder
  Pick disease
  Primary progressive aphasia
  Prion disease
  Progressive non-fluent aphasia
  Squamous cell carcinoma
  Cerebral palsy
  Epilepsy
  Lewy body dementia
  Non-insulin dependent diabetes
  Type-1/2 diabetes
• UniProt ID: TOM40_HUMAN
• PDB ID: 7CK6; 7CP9; 7VBY; 7VC4; 7VD2; 7VDD
• Pfam ID: PF01459
• Sequence:
  MGNVLAASSPPAGPPPPPAPALVGLPPPPPSPPGFTLPPLGGSLGAGTSTSRSSERTPGA
  ATASASGAAEDGACGCLPNPGTFEECHRKCKELFPIQMEGVKLTVNKGLSNHFQVNHTVA
  LSTIGESNYHFGVTYVGTKQLSPTEAFPVLVGDMDNSGSLNAQVIHQLGPGLRSKMAIQT
  QQSKFVNWQVDGEYRGSDFTAAVTLGNPDVLVGSGILVAHYLQSITPCLALGGELVYHRR
  PGEEGTVMSLAGKYTLNNWLATVTLGQAGMHATYYHKASDQLQVGVEFEASTRMQDTSVS
  FGYQLDLPKANLLFKGSVDSNWIVGATLEKKLPPLPLTLALGAFLNHRKNKFQCGFGLTI
  G
• Function: Channel-forming protein essential for import of protein precursors into mitochondria. Plays a role in the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) by forming a complex with BCAP31 and mediating the translocation of Complex I components from the cytosol to the mitochondria.
• KEGG Pathway:
  Mitophagy - animal (hsa04137)
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  PINK1-PRKN Mediated Mitophagy (R-HSA-5205685)
  Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Definitive	Genetic Variation	[1]
Chronic kidney disease	DISW82R7	Definitive	Genetic Variation	[2]
Acute myocardial infarction	DISE3HTG	Strong	Altered Expression	[3]
Aural atresia, congenital	DISCP7UV	Strong	Genetic Variation	[4]
Autosomal dominant optic atrophy, classic form	DISXUAV9	Strong	Genetic Variation	[5]
Behavioral variant of frontotemporal dementia	DISQHX2V	Strong	Genetic Variation	[6]
Carotid artery disease	DISLRVLT	Strong	Genetic Variation	[7]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[8]
Dementia	DISXL1WY	Strong	Genetic Variation	[9]
Depression	DIS3XJ69	Strong	Genetic Variation	[10]
Familial Alzheimer disease	DISE75U4	Strong	Biomarker	[11]
Frontotemporal dementia	DISKYHXL	Strong	Genetic Variation	[12]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[13]
Huntington disease	DISQPLA4	Strong	Biomarker	[14]
Late-onset Parkinson disease	DIS9IOUI	Strong	Genetic Variation	[9]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[15]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[10]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[16]
Obesity	DIS47Y1K	Strong	Genetic Variation	[17]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[18]
Parkinsonian disorder	DISHGY45	Strong	Biomarker	[19]
Pick disease	DISP6X50	Strong	Genetic Variation	[12]
Primary progressive aphasia	DISLRYFE	Strong	Genetic Variation	[6]
Prion disease	DISOUMB0	Strong	Genetic Variation	[20]
Progressive non-fluent aphasia	DIS9HZET	Strong	Genetic Variation	[12]
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[21]
Cerebral palsy	DIS82ODL	Limited	Genetic Variation	[22]
Epilepsy	DISBB28L	Limited	Genetic Variation	[22]
Lewy body dementia	DISAE66J	Limited	Genetic Variation	[23]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[24]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Mitochondrial import receptor subunit TOM40 homolog (TOMM40).	[26]

12 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 Mitochondrial import receptor subunit TOM40 homolog (TOMM40).	[27]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mitochondrial import receptor subunit TOM40 homolog (TOMM40).	[28]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitochondrial import receptor subunit TOM40 homolog (TOMM40).	[29]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitochondrial import receptor subunit TOM40 homolog (TOMM40).	[30]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Mitochondrial import receptor subunit TOM40 homolog (TOMM40).	[31]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Mitochondrial import receptor subunit TOM40 homolog (TOMM40).	[32]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Mitochondrial import receptor subunit TOM40 homolog (TOMM40).	[33]
Fenretinide	DMRD5SP	Phase 3	Fenretinide affects the expression of Mitochondrial import receptor subunit TOM40 homolog (TOMM40).	[34]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Mitochondrial import receptor subunit TOM40 homolog (TOMM40).	[35]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Mitochondrial import receptor subunit TOM40 homolog (TOMM40).	[37]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Mitochondrial import receptor subunit TOM40 homolog (TOMM40).	[38]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Mitochondrial import receptor subunit TOM40 homolog (TOMM40).	[39]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Mitochondrial import receptor subunit TOM40 homolog (TOMM40).	[36]

References

• [1] Gene signature in Alzheimer's disease and environmental factors: the virus chronicle.J Alzheimers Dis. 2011;27(4):809-17. doi: 10.3233/JAD-2011-110755.
• [2] Polymorphisms of genes involved in lipid metabolism and risk of chronic kidney disease in Japanese - cross-sectional data from the J-MICC study.Lipids Health Dis. 2014 Oct 14;13:162. doi: 10.1186/1476-511X-13-162.
• [3] Early Aerobic Exercise Combined with Hydrogen-Rich Saline as Preconditioning Protects Myocardial Injury Induced by Acute Myocardial Infarction in Rats.Appl Biochem Biotechnol. 2019 Mar;187(3):663-676. doi: 10.1007/s12010-018-2841-0. Epub 2018 Jul 23.
• [4] Genetics of cerebral amyloid angiopathy: systematic review and meta-analysis.J Neurol Neurosurg Psychiatry. 2013 Aug;84(8):901-8. doi: 10.1136/jnnp-2012-303898. Epub 2013 Mar 2.
• [5] Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage.Hum Mol Genet. 2011 Jul 1;20(13):2495-509. doi: 10.1093/hmg/ddr139. Epub 2011 Mar 31.
• [6] TOMM40, APOE, and APOC1 in primary progressive aphasia and frontotemporal dementia.J Alzheimers Dis. 2012;31(4):731-40. doi: 10.3233/JAD-2012-120403.
• [7] Analysis of recently identified dyslipidemia alleles reveals two loci that contribute to risk for carotid artery disease.Lipids Health Dis. 2009 Dec 1;8:52. doi: 10.1186/1476-511X-8-52.
• [8] Coronary artery disease-associated genetic variants and biomarkers of inflammation.PLoS One. 2017 Jul 7;12(7):e0180365. doi: 10.1371/journal.pone.0180365. eCollection 2017.
• [9] A candidate gene study of risk for dementia in older, postmenopausal women: Results from the Women's Health Initiative Memory Study.Int J Geriatr Psychiatry. 2019 May;34(5):692-699. doi: 10.1002/gps.5068. Epub 2019 Mar 7.
• [10] TOMM40 rs2075650 may represent a new candidate gene for vulnerability to major depressive disorder.Neuropsychopharmacology. 2014 Jun;39(7):1743-53. doi: 10.1038/npp.2014.22. Epub 2014 Jan 29.
• [11] Hidden heterogeneity in Alzheimer's disease: Insights from genetic association studies and other analyses.Exp Gerontol. 2018 Jul 1;107:148-160. doi: 10.1016/j.exger.2017.10.020. Epub 2017 Oct 26.
• [12] Gene-based association studies report genetic links for clinical subtypes of frontotemporal dementia.Brain. 2017 May 1;140(5):1437-1446. doi: 10.1093/brain/awx066.
• [13] Pleiotropy and allelic heterogeneity in the TOMM40-APOE genomic region related to clinical and metabolic features of hepatitis C infection.Hum Genet. 2012 Dec;131(12):1911-20. doi: 10.1007/s00439-012-1220-0. Epub 2012 Aug 17.
• [14] VCP cooperates with UBXD1 to degrade mitochondrial outer membrane protein MCL1 in model of Huntington's disease.Biochim Biophys Acta Mol Basis Dis. 2017 Feb;1863(2):552-559. doi: 10.1016/j.bbadis.2016.11.026. Epub 2016 Nov 29.
• [15] c-Myc targeted regulators of cell metabolism in a transgenic mouse model of papillary lung adenocarcinoma.Oncotarget. 2016 Oct 4;7(40):65514-65539. doi: 10.18632/oncotarget.11804.
• [16] Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity.PLoS Genet. 2015 Dec 17;11(12):e1005728. doi: 10.1371/journal.pgen.1005728. eCollection 2015 Dec.
• [17] Genetic variation at the CELF1 (CUGBP, elav-like family member 1 gene) locus is genome-wide associated with Alzheimer's disease and obesity.Am J Med Genet B Neuropsychiatr Genet. 2014 Jun;165B(4):283-93. doi: 10.1002/ajmg.b.32234. Epub 2014 May 1.
• [18] Wild-type and mutant (G2019S) leucine-rich repeat kinase 2 (LRRK2) associate with subunits of the translocase of outer mitochondrial membrane (TOM) complex.Exp Cell Res. 2019 Feb 15;375(2):72-79. doi: 10.1016/j.yexcr.2018.12.022. Epub 2018 Dec 28.
• [19] Associations between TOMM40 Poly-T Repeat Variants and Dementia in Cases with Parkinsonism.J Parkinsons Dis. 2016;6(1):99-108. doi: 10.3233/JPD-150693.
• [20] Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP.Hum Mol Genet. 2012 Apr 15;21(8):1897-906. doi: 10.1093/hmg/ddr607. Epub 2011 Dec 30.
• [21] Genetic variants at 6p21.1 and 7p15.3 are associated with risk of multiple cancers in Han Chinese.Am J Hum Genet. 2012 Nov 2;91(5):928-34. doi: 10.1016/j.ajhg.2012.09.009. Epub 2012 Oct 25.
• [22] Genes determining the severity of cerebral palsy: the role of single nucleotide polymorphisms on the amount and structure of apolipoprotein E.Acta Paediatr. 2015 Jul;104(7):701-6. doi: 10.1111/apa.12983. Epub 2015 Mar 27.
• [23] Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE-4/TOMM40 long poly-T repeat allele variants.Alzheimers Dement (N Y). 2019 Nov 20;5:814-824. doi: 10.1016/j.trci.2019.08.005. eCollection 2019.
• [24] Linking Alzheimer's disease and type 2 diabetes: Novel shared susceptibility genes detected by cFDR approach.J Neurol Sci. 2017 Sep 15;380:262-272. doi: 10.1016/j.jns.2017.07.044. Epub 2017 Aug 1.
• [25] The TOMM40 poly-T rs10524523 variant is associated with cognitive performance among non-demented elderly with type 2 diabetes.Eur Neuropsychopharmacol. 2014 Sep;24(9):1492-9. doi: 10.1016/j.euroneuro.2014.06.002. Epub 2014 Jun 13.
• [26] 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.
• [27] 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.
• [28] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [29] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [30] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [31] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [32] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [33] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [34] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [35] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [36] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [37] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [38] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [39] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.