Details of Drug Off-Target (DOT)

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

• DOT Name: TBC1 domain family member 23 (TBC1D23)
• Synonyms: HCV non-structural protein 4A-transactivated protein 1
• Gene Name: TBC1D23
• Related Disease:
  Intellectual disability
  Pontocerebellar hypoplasia
  Pontocerebellar hypoplasia, type 11
  Isolated congenital microcephaly
• UniProt ID: TBC23_HUMAN
• PDB ID: 6JL7; 6JM5
• Pfam ID: PF00566 ; PF00581 ; PF19430
• Sequence:
  MAEGEDVPPLPTSSGDGWEKDLEEALEAGGCDLETLRNIIQGRPLPADLRAKVWKIALNV
  AGKGDSLASWDGILDLPEQNTIHKDCLQFIDQLSVPEEKAAELLLDIESVITFYCKSRNI
  KYSTSLSWIHLLKPLVHLQLPRSDLYNCFYAIMNKYIPRDCSQKGRPFHLFRLLIQYHEP
  ELCSYLDTKKITPDSYALNWLGSLFACYCSTEVTQAIWDGYLQQADPFFIYFLMLIILVN
  AKEVILTQESDSKEEVIKFLENTPSSLNIEDIEDLFSLAQYYCSKTPASFRKDNHHLFGS
  TLLGIKDDDADLSQALCLAISVSEILQANQLQGEGVRFFVVDCRPAEQYNAGHLSTAFHL
  DSDLMLQNPSEFAQSVKSLLEAQKQSIESGSIAGGEHLCFMGSGREEEDMYMNMVLAHFL
  QKNKEYVSIASGGFMALQQHLADINVDGPENGYGHWIASTSGSRSSINSVDGESPNGSSD
  RGMKSLVNKMTVALKTKSVNVREKVISFIENTSTPVDRMSFNLPWPDRSCTERHVSSSDR
  VGKPYRGVKPVFSIGDEEEYDTDEIDSSSMSDDDRKEVVNIQTWINKPDVKHHFPCKEVK
  ESGHMFPSHLLVTATHMYCLREIVSRKGLAYIQSRQALNSVVKITSKKKHPELITFKYGN
  SSASGIEILAIERYLIPNAGDATKAIKQQIMKVLDALES
• Function: Putative Rab GTPase-activating protein which plays a role in vesicular trafficking. Involved in endosome-to-Golgi trafficking. Acts as a bridging protein by binding simultaneously to golgins, including GOLGA1 and GOLGA4, located at the trans-Golgi, and to the WASH complex, located on endosome-derived vesicles. Together with WDR11 complex facilitates the golgin-mediated capture of vesicles generated using AP-1. Plays a role in brain development, including in cortical neuron positioning. May also be important for neurite outgrowth, possibly through its involvement in membrane trafficking and cargo delivery, 2 processes that are essential for axonal and dendritic growth. May act as a general inhibitor of innate immunity signaling, strongly inhibiting multiple TLR and dectin/CLEC7A-signaling pathways. Does not alter initial activation events, but instead affects maintenance of inflammatory gene expression several hours after bacterial lipopolysaccharide (LPS) challenge.
• Tissue Specificity: Isoform 1: Widely expressed, including in fetal adult brain (corpus callosum, pons, cerebellum), spinal cord, heart, skeletal muscle, thymus and bone marrow, and at lower levels in spleen. Hardly detected in liver, kidney, colon and testis. Isoform 2: Expressed at high levels in liver, kidney, colon and testis. Hardly detected in tissues expressing high levels of isoform 1. Expressed at low levels in spleen.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Strong	Biomarker	[1]
Pontocerebellar hypoplasia	DISRICMU	Strong	Genetic Variation	[2]
Pontocerebellar hypoplasia, type 11	DISQC4FD	Strong	Autosomal recessive	[3]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of TBC1 domain family member 23 (TBC1D23).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of TBC1 domain family member 23 (TBC1D23).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of TBC1 domain family member 23 (TBC1D23).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of TBC1 domain family member 23 (TBC1D23).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of TBC1 domain family member 23 (TBC1D23).	[10]

3 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 TBC1 domain family member 23 (TBC1D23).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of TBC1 domain family member 23 (TBC1D23).	[9]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of TBC1 domain family member 23 (TBC1D23).	[9]

References

• [1] Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families. Mol Psychiatry. 2018 Apr;23(4):973-984. doi: 10.1038/mp.2017.60. Epub 2017 Apr 11.
• [2] Structural and functional studies of TBC1D23 C-terminal domain provide a link between endosomal trafficking and PCH.Proc Natl Acad Sci U S A. 2019 Nov 5;116(45):22598-22608. doi: 10.1073/pnas.1909316116. Epub 2019 Oct 17.
• [3] Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development. Am J Hum Genet. 2017 Sep 7;101(3):428-440. doi: 10.1016/j.ajhg.2017.07.010. Epub 2017 Aug 17.
• [4] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [9] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [10] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.