Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOX7946)

• DOT Name: Threonine aspartase 1 (TASP1)
• Synonyms: Taspase-1; EC 3.4.25.-
• Gene Name: TASP1
• Related Disease:
  Hepatocellular carcinoma
  Suleiman-El-Hattab syndrome
  Isolated congenital microcephaly
  Wiedemann-Steiner syndrome
• UniProt ID: TASP1_HUMAN
• PDB ID: 2A8I; 2A8J; 2A8L; 2A8M; 6UGK; 6VIN
• EC Number: 3.4.25.-
• Pfam ID: PF01112
• Sequence:
  MTMEKGMSSGEGLPSRSSQVSAGKITAKELETKQSYKEKRGGFVLVHAGAGYHSESKAKE
  YKHVCKRACQKAIEKLQAGALATDAVTAALVELEDSPFTNAGMGSNLNLLGEIECDASIM
  DGKSLNFGAVGALSGIKNPVSVANRLLCEGQKGKLSAGRIPPCFLVGEGAYRWAVDHGIP
  SCPPNIMTTRFSLAAFKRNKRKLELAERVDTDFMQLKKRRQSSEKENDSGTLDTVGAVVV
  DHEGNVAAAVSSGGLALKHPGRVGQAALYGCGCWAENTGAHNPYSTAVSTSGCGEHLVRT
  ILARECSHALQAEDAHQALLETMQNKFISSPFLASEDGVLGGVIVLRSCRCSAEPDSSQN
  KQTLLVEFLWSHTTESMCVGYMSAQDGKAKTHISRLPPGAVAGQSVAIEGGVCRLESPVN
• Function: Protease responsible for KMT2A/MLL1 processing and activation. It also activates KMT2D/MLL2. Through substrate activation, it controls the expression of HOXA genes, and the expression of key cell cycle regulators including CCNA1, CCNB1, CCNE1 and CDKN2A.
• Reactome Pathway: Formation of WDR5-containing histone-modifying complexes (R-HSA-9772755)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[1]
Suleiman-El-Hattab syndrome	DISHJUXH	Strong	Autosomal recessive	[2]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[3]
Wiedemann-Steiner syndrome	DIS67KX5	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Threonine aspartase 1 (TASP1).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Threonine aspartase 1 (TASP1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Threonine aspartase 1 (TASP1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Threonine aspartase 1 (TASP1).	[8]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Threonine aspartase 1 (TASP1).	[9]

References

• [1] EPS15R, TASP1, and PRPF3 are novel disease candidate genes targeted by HNF4alpha splice variants in hepatocellular carcinomas.Gastroenterology. 2008 Apr;134(4):1191-202. doi: 10.1053/j.gastro.2008.01.027. Epub 2008 Jan 17.
• [2] Proteolysis of MLL family proteins is essential for taspase1-orchestrated cell cycle progression. Genes Dev. 2006 Sep 1;20(17):2397-409. doi: 10.1101/gad.1449406.
• [3] Homozygous loss-of-function variants of TASP1, a gene encoding an activator of the histone methyltransferases KMT2A and KMT2D, cause a syndrome of developmental delay, happy demeanor, distinctive facial features, and congenital anomalies.Hum Mutat. 2019 Nov;40(11):1985-1992. doi: 10.1002/humu.23844. Epub 2019 Jul 22.
• [4] TASP1 is deleted in an infant with developmental delay, microcephaly, distinctive facial features, and multiple congenital anomalies.Clin Genet. 2018 Jul;94(1):170-173. doi: 10.1111/cge.13258. Epub 2018 May 10.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [7] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [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] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.