Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAZO9F6)

• DOT Name: Very-long-chain (HACD2)
• Synonyms: 3R)-3-hydroxyacyl-CoA dehydratase 2 (EC 4.2.1.134; 3-hydroxyacyl-CoA dehydratase 2; HACD2; Protein-tyrosine phosphatase-like member B
• Gene Name: HACD2
• UniProt ID: HACD2_HUMAN
• EC Number: 4.2.1.134
• Pfam ID: PF04387
• Sequence:
  MAAVAATAAAKGNGGGGGRAGAGDASGTRKKKGPGPLATAYLVIYNVVMTAGWLVIAVGL
  VRAYLAKGSYHSLYYSIEKPLKFFQTGALLEILHCAIGIVPSSVVLTSFQVMSRVFLIWA
  VTHSVKEVQSEDSVLLFVIAWTITEIIRYSFYTFSLLNHLPYLIKWARYTLFIVLYPMGV
  SGELLTIYAALPFVRQAGLYSISLPNKYNFSFDYYAFLILIMISYIPIFPQLYFHMIHQR
  RKILSHTEEHKKFE
• Function: Catalyzes the third of the very long-chain fatty acids (VLCFA) elongation four-step cycle (condensation, reduction, dehydration, and reduction). This endoplasmic reticulum-elongation process is characterized by the addition of two carbons to the lipid chain through each cycle. This enzyme catalyzes the dehydration of the 3-hydroxyacyl-CoA intermediate into trans-2,3-enoyl-CoA, within each cycle of elongation. Therefore, it participates in the production of various VLCFAs involved in multiple biological processes as precursors of membrane lipids and lipid mediators.
• Tissue Specificity: Highly expressed in testis, spleen, prostate, colon and heart, followed by moderate expression in thymus, ovary, small intestine, peripheral blood leukocytes, liver, skeletal muscle and pancreas. Weakly detected in kidney, placenta, brain and lung.
• KEGG Pathway:
  Fatty acid elongation (hsa00062)
  Biosynthesis of unsaturated fatty acids (hsa01040)
  Metabolic pathways (hsa01100)
  Fatty acid metabolism (hsa01212)
• Reactome Pathway: Synthesis of very long-chain fatty acyl-CoAs (R-HSA-75876)

Molecular Interaction Atlas (MIA) of This DOT

16 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 Very-long-chain (HACD2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Very-long-chain (HACD2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Very-long-chain (HACD2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Very-long-chain (HACD2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Very-long-chain (HACD2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Very-long-chain (HACD2).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Very-long-chain (HACD2).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Very-long-chain (HACD2).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Very-long-chain (HACD2).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Very-long-chain (HACD2).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Very-long-chain (HACD2).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Very-long-chain (HACD2).	[13]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Very-long-chain (HACD2).	[14]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Very-long-chain (HACD2).	[15]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Very-long-chain (HACD2).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Very-long-chain (HACD2).	[18]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Very-long-chain (HACD2).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Very-long-chain (HACD2).	[17]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [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] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.
• [15] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [16] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [17] 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.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.