Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO8X1UF)

• DOT Name: Kelch repeat and BTB domain-containing protein 8 (KBTBD8)
• Synonyms: T-cell activation kelch repeat protein; TA-KRP
• Gene Name: KBTBD8
• Related Disease:
  Treacher-Collins syndrome
  Tourette syndrome
• UniProt ID: KBTB8_HUMAN
• Pfam ID: PF07707 ; PF00651 ; PF01344
• Sequence:
  MAASADLSKSSPTPNGIPSSDPASDAMDPFHACSILKQLKTMYDEGQLTDIVVEVDHGKT
  FSCHRNVLAAISPYFRSMFTSGLTESTQKEVRIVGVEAESMDLVLNYAYTSRVILTEANV
  QALFTAASIFQIPSIQDQCAKYMISHLDPQNSIGVFIFADHYGHQELGDRSKEYIRKKFL
  CVTKEQEFLQLTKDQLISILDSDDLNVDREEHVYESIIRWFEHEQNEREVHLPEIFAKCI
  RFPLMEDTFIEKIPPQFAQAIAKSCVEKGPSNTNGCTQRLGMTASEMIICFDAAHKHSGK
  KQTVPCLDIVTGRVFKLCKPPNDLREVGILVSPDNDIYIAGGYRPSSSEVSIDHKAENDF
  WMYDHSTNRWLSKPSLLRARIGCKLVYCCGKMYAIGGRVYEGDGRNSLKSVECYDSRENC
  WTTVCAMPVAMEFHNAVEYKEKIYVLQGEFFLFYEPQKDYWGFLTPMTVPRIQGLAAVYK
  DSIYYIAGTCGNHQRMFTVEAYDIELNKWTRKKDFPCDQSINPYLKLVLFQNKLHLFVRA
  TQVTVEEHVFRTSRKNSLYQYDDIADQWMKVYETPDRLWDLGRHFECAVAKLYPQCLQKV
  L
• Function: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of neural crest specification. The BCR(KBTBD8) complex acts by mediating monoubiquitination of NOLC1 and TCOF1: monoubiquitination promotes the formation of a NOLC1-TCOF1 complex that acts as a platform to connect RNA polymerase I with enzymes responsible for ribosomal processing and modification, leading to remodel the translational program of differentiating cells in favor of neural crest specification.
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Treacher-Collins syndrome	DIS2GXZ1	moderate	Genetic Variation	[1]
Tourette syndrome	DISX9D54	No Known	Unknown	[2]

2 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 Kelch repeat and BTB domain-containing protein 8 (KBTBD8).	[3]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Kelch repeat and BTB domain-containing protein 8 (KBTBD8).	[12]

16 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 Kelch repeat and BTB domain-containing protein 8 (KBTBD8).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Kelch repeat and BTB domain-containing protein 8 (KBTBD8).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Kelch repeat and BTB domain-containing protein 8 (KBTBD8).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Kelch repeat and BTB domain-containing protein 8 (KBTBD8).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Kelch repeat and BTB domain-containing protein 8 (KBTBD8).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Kelch repeat and BTB domain-containing protein 8 (KBTBD8).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Kelch repeat and BTB domain-containing protein 8 (KBTBD8).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Kelch repeat and BTB domain-containing protein 8 (KBTBD8).	[11]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Kelch repeat and BTB domain-containing protein 8 (KBTBD8).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Kelch repeat and BTB domain-containing protein 8 (KBTBD8).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Kelch repeat and BTB domain-containing protein 8 (KBTBD8).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Kelch repeat and BTB domain-containing protein 8 (KBTBD8).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Kelch repeat and BTB domain-containing protein 8 (KBTBD8).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Kelch repeat and BTB domain-containing protein 8 (KBTBD8).	[18]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Kelch repeat and BTB domain-containing protein 8 (KBTBD8).	[19]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Kelch repeat and BTB domain-containing protein 8 (KBTBD8).	[16]

References

• [1] Cell-fate determination by ubiquitin-dependent regulation of translation.Nature. 2015 Sep 24;525(7570):523-7. doi: 10.1038/nature14978.
• [2] De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Neuron. 2017 May 3;94(3):486-499.e9. doi: 10.1016/j.neuron.2017.04.024.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [16] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [17] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.