Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3IXYII)

• DOT Name: Protein-cysteine N-palmitoyltransferase HHAT (HHAT)
• Synonyms: EC 2.3.1.-; Hedgehog acyltransferase; Melanoma antigen recognized by T-cells 2; MART-2; Skinny hedgehog protein 1
• Gene Name: HHAT
• Related Disease: Chondrodysplasia-pseudohermaphroditism syndrome
• UniProt ID: HHAT_HUMAN
• PDB ID: 6P64; 6UJO; 6UJQ; 6UK2; 6UK4; 7MHY; 7MHZ; 7Q1U; 7Q6Z; 7URF
• EC Number: 2.3.1.-
• Pfam ID: PF03062
• Sequence:
  MLPRWELALYLLASLGFHFYSFYEVYKVSREHEEELDQEFELETDTLFGGLKKDATDFEW
  SFWMEWGKQWLVWLLLGHMVVSQMATLLARKHRPWILMLYGMWACWCVLGTPGVAMVLLH
  TTISFCVAQFRSQLLTWLCSLLLLSTLRLQGVEEVKRRWYKTENEYYLLQFTLTVRCLYY
  TSFSLELCWQQLPAASTSYSFPWMLAYVFYYPVLHNGPILSFSEFIKQMQQQEHDSLKAS
  LCVLALGLGRLLCWWWLAELMAHLMYMHAIYSSIPLLETVSCWTLGGLALAQVLFFYVKY
  LVLFGVPALLMRLDGLTPPALPRCVSTMFSFTGMWRYFDVGLHNFLIRYVYIPVGGSQHG
  LLGTLFSTAMTFAFVSYWHGGYDYLWCWAALNWLGVTVENGVRRLVETPCIQDSLARYFS
  PQARRRFHAALASCSTSMLILSNLVFLGGNEVGKTYWNRIFIQGWPWVTLSVLGFLYCYS
  HVGIAWAQTYATD
• Function: Palmitoyl acyltransferase that catalyzes N-terminal palmitoylation of SHH; which is required for SHH signaling. It also catalyzes N-terminal palmitoylation of DHH. Promotes the transfer of palmitoyl-CoA from the cytoplasmic to the luminal side of the endoplasmic reticulum membrane, where SHH palmitoylation occurs. It is an essential factor for proper embryonic development and testicular organogenesis.
• Tissue Specificity: Widely expressed. Expressed in fetal ovary and testis, with high levels of expression observed in Sertoli cells .
• KEGG Pathway: Hedgehog sig.ling pathway (hsa04340)
• Reactome Pathway:
  HHAT G278V doesn't palmitoylate Hh-Np (R-HSA-5658034)
  Hedgehog ligand biogenesis (R-HSA-5358346)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chondrodysplasia-pseudohermaphroditism syndrome	DIS3HYGD	Strong	Autosomal recessive	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Protein-cysteine N-palmitoyltransferase HHAT (HHAT) affects the response to substance of Temozolomide.	[11]
DTI-015	DMXZRW0	Approved	Protein-cysteine N-palmitoyltransferase HHAT (HHAT) affects the response to substance of DTI-015.	[11]

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 Protein-cysteine N-palmitoyltransferase HHAT (HHAT).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein-cysteine N-palmitoyltransferase HHAT (HHAT).	[6]

8 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 Protein-cysteine N-palmitoyltransferase HHAT (HHAT).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein-cysteine N-palmitoyltransferase HHAT (HHAT).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein-cysteine N-palmitoyltransferase HHAT (HHAT).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Protein-cysteine N-palmitoyltransferase HHAT (HHAT).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Protein-cysteine N-palmitoyltransferase HHAT (HHAT).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Protein-cysteine N-palmitoyltransferase HHAT (HHAT).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein-cysteine N-palmitoyltransferase HHAT (HHAT).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protein-cysteine N-palmitoyltransferase HHAT (HHAT).	[8]

References

• [1] Unique survival in chrondrodysplasia-hermaphrodism syndrome. Am J Med Genet A. 2005 Jan 30;132A(3):335-7. doi: 10.1002/ajmg.a.30417.
• [2] 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.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] 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.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] 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.
• [10] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [11] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.