Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGTN8TJ)

• DOT Name: F-box only protein 7 (FBXO7)
• Gene Name: FBXO7
• Related Disease:
  Alzheimer disease
  Autosomal recessive juvenile Parkinson disease 2
  Dystonia
  Epithelial neoplasm
  Hereditary spastic paraplegia 11
  Juvenile-onset Parkinson disease
  Neurodegeneration with brain iron accumulation
  Neurodegeneration with brain iron accumulation 5
  Non-small-cell lung cancer
  Parkinsonian disorder
  Parkinsonian-pyramidal syndrome
  Peripheral neuropathy
  T-cell leukaemia
  T-cell lymphoma
  Young-onset Parkinson disease
  Choreatic disease
  Popliteal pterygium syndrome
  DiGeorge syndrome
  Advanced cancer
  Anxiety
  Anxiety disorder
• UniProt ID: FBX7_HUMAN
• PDB ID: 4L9C; 4L9H
• Pfam ID: PF12937 ; PF11566
• Sequence:
  MRLRVRLLKRTWPLEVPETEPTLGHLRSHLRQSLLCTWGYSSNTRFTITLNYKDPLTGDE
  ETLASYGIVSGDLICLILQDDIPAPNIPSSTDSEHSSLQNNEQPSLATSSNQTSMQDEQP
  SDSFQGQAAQSGVWNDDSMLGPSQNFEAESIQDNAHMAEGTGFYPSEPMLCSESVEGQVP
  HSLETLYQSADCSDANDALIVLIHLLMLESGYIPQGTEAKALSMPEKWKLSGVYKLQYMH
  PLCEGSSATLTCVPLGNLIVVNATLKINNEIRSVKRLQLLPESFICKEKLGENVANIYKD
  LQKLSRLFKDQLVYPLLAFTRQALNLPDVFGLVVLPLELKLRIFRLLDVRSVLSLSAVCR
  DLFTASNDPLLWRFLYLRDFRDNTVRVQDTDWKELYRKRHIQRKESPKGRFVMLLPSSTH
  TIPFYPNPLHPRPFPSSRLPPGIIGGEYDQRPTLPYVGDPISSLIPGPGETPSQFPPLRP
  RFDPVGPLPGPNPILPGRGGPNDRFPFRPSRGRPTDGRLSFM
• Function: Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins and plays a role in several biological processes such as cell cycle, cell proliferation, or maintenance of chromosome stability. Recognizes and ubiquitinates BIRC2 and the cell cycle regulator DLGAP5. Plays a role downstream of PINK1 in the clearance of damaged mitochondria via selective autophagy (mitophagy) by targeting PRKN to dysfunctional depolarized mitochondria. Promotes MFN1 ubiquitination. Mediates the ubiquitination and proteasomal degradation of UXT isoform 2, thereby impairing the NF-kappa-B signaling pathway. Inhibits NF-kappa-B pathway also by promoting the ubiquitination of TRAF2. Affects the assembly state and activity of the proteasome in the cells including neurons by ubiquitinating the proteasomal subunit PSMA2 via 'Lys-63'-linked polyubiquitin chains. Promotes 'Lys-48'-linked polyubiquitination SIRT7, leading to the hydrogen peroxide-induced cell death.
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Autosomal recessive juvenile Parkinson disease 2	DISNSTD1	Strong	Genetic Variation	[2]
Dystonia	DISJLFGW	Strong	Genetic Variation	[3]
Epithelial neoplasm	DIS0T594	Strong	Altered Expression	[4]
Hereditary spastic paraplegia 11	DIS8K8V4	Strong	Genetic Variation	[3]
Juvenile-onset Parkinson disease	DISNT5BI	Strong	Genetic Variation	[5]
Neurodegeneration with brain iron accumulation	DISRK4DZ	Strong	Genetic Variation	[6]
Neurodegeneration with brain iron accumulation 5	DISW9SFJ	Strong	Biomarker	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[7]
Parkinsonian disorder	DISHGY45	Strong	Genetic Variation	[8]
Parkinsonian-pyramidal syndrome	DISHIIPA	Strong	Autosomal recessive	[9]
Peripheral neuropathy	DIS7KN5G	Strong	Biomarker	[10]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[11]
T-cell lymphoma	DISSXRTQ	Strong	Altered Expression	[12]
Young-onset Parkinson disease	DIS05LFS	Strong	Biomarker	[13]
Choreatic disease	DISH8K3M	moderate	Genetic Variation	[14]
Popliteal pterygium syndrome	DISRS4H8	moderate	Biomarker	[2]
DiGeorge syndrome	DIST1RKO	Disputed	Altered Expression	[15]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[16]
Anxiety	DISIJDBA	Limited	Genetic Variation	[17]
Anxiety disorder	DISBI2BT	Limited	Genetic Variation	[17]

6 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 F-box only protein 7 (FBXO7).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of F-box only protein 7 (FBXO7).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of F-box only protein 7 (FBXO7).	[20]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of F-box only protein 7 (FBXO7).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of F-box only protein 7 (FBXO7).	[22]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of F-box only protein 7 (FBXO7).	[23]

References

• [1] F-box protein 7 mutations promote protein aggregation in mitochondria and inhibit mitophagy.Hum Mol Genet. 2015 Nov 15;24(22):6314-30. doi: 10.1093/hmg/ddv340. Epub 2015 Aug 26.
• [2] Pathophysiological mechanisms linking F-box only protein 7 (FBXO7) and Parkinson's disease (PD).Mutat Res Rev Mutat Res. 2018 Oct-Dec;778:72-78. doi: 10.1016/j.mrrev.2018.10.001. Epub 2018 Oct 17.
• [3] Rare causes of dystonia parkinsonism.Curr Neurol Neurosci Rep. 2010 Nov;10(6):431-9. doi: 10.1007/s11910-010-0136-0.
• [4] Transforming activity of Fbxo7 is mediated specifically through regulation of cyclin D/cdk6.EMBO J. 2005 Sep 7;24(17):3104-16. doi: 10.1038/sj.emboj.7600775. Epub 2005 Aug 11.
• [5] A new Turkish family with homozygous FBXO7 truncating mutation and juvenile atypical parkinsonism.Parkinsonism Relat Disord. 2014 Nov;20(11):1248-52. doi: 10.1016/j.parkreldis.2014.06.024. Epub 2014 Jul 22.
• [6] Neuroimaging studies and whole exome sequencing of PLA2G6-associated neurodegeneration in a family with intrafamilial phenotypic heterogeneity.Parkinsonism Relat Disord. 2015 Apr;21(4):402-6. doi: 10.1016/j.parkreldis.2015.01.010. Epub 2015 Jan 17.
• [7] Status of the Parkinson's disease gene family expression in non-small-cell lung cancer.World J Surg Oncol. 2015 Aug 7;13:238. doi: 10.1186/s12957-015-0646-y.
• [8] Loss of FBXO7 results in a Parkinson's-like dopaminergic degeneration via an RPL23-MDM2-TP53 pathway.J Pathol. 2019 Oct;249(2):241-254. doi: 10.1002/path.5312. Epub 2019 Aug 6.
• [9] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [10] Myelinating Glia-Specific Deletion of Fbxo7 in Mice Triggers Axonal Degeneration in the Central Nervous System Together with Peripheral Neuropathy.J Neurosci. 2019 Jul 10;39(28):5606-5626. doi: 10.1523/JNEUROSCI.3094-18.2019. Epub 2019 May 13.
• [11] Gene expression profile of empirically delineated classes of unexplained chronic fatigue.Pharmacogenomics. 2006 Apr;7(3):375-86. doi: 10.2217/14622416.7.3.375.
• [12] Expression of Fbxo7 in haematopoietic progenitor cells cooperates with p53 loss to promote lymphomagenesis.PLoS One. 2011;6(6):e21165. doi: 10.1371/journal.pone.0021165. Epub 2011 Jun 17.
• [13] Genetic analysis of ATP13A2, PLA2G6 and FBXO7 in a cohort of Chinese patients with early-onset Parkinson's disease.Sci Rep. 2018 Sep 19;8(1):14028. doi: 10.1038/s41598-018-32217-4.
• [14] FBXO7-R498X mutation: phenotypic variability from chorea to early onset parkinsonism within a family.Parkinsonism Relat Disord. 2014 Nov;20(11):1253-6. doi: 10.1016/j.parkreldis.2014.07.016. Epub 2014 Aug 14.
• [15] Opposing effects on the cell cycle of T lymphocytes by Fbxo7 via Cdk6 and p27.Cell Mol Life Sci. 2017 Apr;74(8):1553-1566. doi: 10.1007/s00018-016-2427-3. Epub 2016 Dec 3.
• [16] Gsk3 and Tomm20 are substrates of the SCFFbxo7/PARK15 ubiquitin ligase associated with Parkinson's disease.Biochem J. 2016 Oct 15;473(20):3563-3580. doi: 10.1042/BCJ20160387. Epub 2016 Aug 8.
• [17] A new F-box protein 7 gene mutation causing typical Parkinson's disease.Mov Disord. 2015 Jul;30(8):1130-3. doi: 10.1002/mds.26266. Epub 2015 May 23.
• [18] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [19] 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.
• [20] 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.
• [21] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [22] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [23] 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.