Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXTQ59R)

• DOT Name: 40-kDa huntingtin-associated protein (F8A1)
• Synonyms: HAP40; CpG island protein; Factor VIII intron 22 protein
• Gene Name: F8A1
• Related Disease:
  Huntington disease
  Severe hemophilia A
  Type-1 diabetes
• UniProt ID: HAP40_HUMAN
• PDB ID: 6EZ8; 6X9O; 7DXJ; 7DXK; 8SAH
• Sequence:
  MAAAAAGLGGGGAGPGPEAGDFLARYRLVSNKLKKRFLRKPNVAEAGEQFGQLGRELRAQ
  ECLPYAAWCQLAVARCQQALFHGPGEALALTEAARLFLRQERDARQRLVCPAAYGEPLQA
  AASALGAAVRLHLELGQPAAAAALCLELAAALRDLGQPAAAAGHFQRAAQLQLPQLPLAA
  LQALGEAASCQLLARDYTGALAVFTRMQRLAREHGSHPVQSLPPPPPPAPQPGPGATPAL
  PAALLPPNSGSAAPSPAALGAFSDVLVRCEVSRVLLLLLLQPPPAKLLPEHAQTLEKYSW
  EAFDSHGQESSGQLPEELFLLLQSLVMATHEKDTEAIKSLQVEMWPLLTAEQNHLLHLVL
  QETISPSGQGV
• Function: RAB5A effector molecule that is involved in vesicular trafficking of early endosomes. Mediates the recruitment of HTT by RAB5A onto early endosomes. The HTT-F8A1/F8A2/F8A3-RAB5A complex stimulates early endosomal interaction with actin filaments and inhibits interaction with microtubules, leading to the reduction of endosome motility.
• Tissue Specificity: Produced abundantly in a wide variety of cell types.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Huntington disease	DISQPLA4	Strong	Biomarker	[1]
Severe hemophilia A	DISXUFDW	Strong	Genetic Variation	[2]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	40-kDa huntingtin-associated protein (F8A1) affects the response to substance of Cisplatin.	[12]

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 40-kDa huntingtin-associated protein (F8A1).	[4]

7 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 40-kDa huntingtin-associated protein (F8A1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 40-kDa huntingtin-associated protein (F8A1).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of 40-kDa huntingtin-associated protein (F8A1).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of 40-kDa huntingtin-associated protein (F8A1).	[8]
Menadione	DMSJDTY	Approved	Menadione affects the expression of 40-kDa huntingtin-associated protein (F8A1).	[9]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of 40-kDa huntingtin-associated protein (F8A1).	[10]
Capecitabine	DMTS85L	Approved	Capecitabine decreases the expression of 40-kDa huntingtin-associated protein (F8A1).	[11]

References

• [1] Design and characterization of mutant and wildtype huntingtin proteins produced from a toolkit of scalable eukaryotic expression systems.J Biol Chem. 2019 Apr 26;294(17):6986-7001. doi: 10.1074/jbc.RA118.007204. Epub 2019 Mar 6.
• [2] Inversion mutation as a major cause of severe hemophilia A in Italian patients.Haematologica. 1997 Jan-Feb;82(1):75-6.
• [3] Multivariate eQTL mapping uncovers functional variation on the X-chromosome associated with complex disease traits.Hum Genet. 2016 Jul;135(7):827-39. doi: 10.1007/s00439-016-1674-6. Epub 2016 May 7.
• [4] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [11] Gene expression responses reflecting 5-FU-induced toxicity: Comparison between patient colon tissue and 3D human colon organoids. Toxicol Lett. 2022 Dec 1;371:17-24. doi: 10.1016/j.toxlet.2022.09.013. Epub 2022 Sep 29.
• [12] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.