Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT85HPZE)

• DOT Name: Very-long-chain (HACD4)
• Synonyms: 3R)-3-hydroxyacyl-CoA dehydratase 4 (EC 4.2.1.134; 3-hydroxyacyl-CoA dehydratase 4; HACD4; Protein-tyrosine phosphatase-like A domain-containing protein 2
• Gene Name: HACD4
• Related Disease:
  Neoplasm
  Arteriosclerosis
  Atherosclerosis
• UniProt ID: HACD4_HUMAN
• EC Number: 4.2.1.134
• Pfam ID: PF04387
• Sequence:
  MGPLALPAWLQPRYRKNAYLFIYYLIQFCGHSWIFTNMTVRFFSFGKDSMVDTFYAIGLV
  MRLCQSVSLLELLHIYVGIESNHLLPRFLQLTERIIILFVVITSQEEVQEKYVVCVLFVF
  WNLLDMVRYTYSMLSVIGISYAVLTWLSQTLWMPIYPLCVLAEAFAIYQSLPYFESFGTY
  STKLPFDLSIYFPYVLKIYLMMLFIGMYFTYSHLYSERRDILGIFPIKKKKM
• Function: Catalyzes the third of the four reactions of the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process, allows the addition of two carbons to the chain of long- and very long-chain fatty acids/VLCFAs per cycle. This enzyme catalyzes the dehydration of the 3-hydroxyacyl-CoA intermediate into trans-2,3-enoyl-CoA, within each cycle of fatty acid elongation. Thereby, it participates in the production of VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators.
• Tissue Specificity: Highly expressed in leukocytes, and low expression in heart, spleen, kidney, and placenta.
• 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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[2]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[2]

11 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 (HACD4).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Very-long-chain (HACD4).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Very-long-chain (HACD4).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Very-long-chain (HACD4).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Very-long-chain (HACD4).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Very-long-chain (HACD4).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Very-long-chain (HACD4).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Very-long-chain (HACD4).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Very-long-chain (HACD4).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Very-long-chain (HACD4).	[12]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Very-long-chain (HACD4).	[13]

References

• [1] PTPLAD2 is a tumor suppressor in esophageal squamous cell carcinogenesis.FEBS Lett. 2014 Mar 18;588(6):981-9. doi: 10.1016/j.febslet.2014.01.058. Epub 2014 Feb 14.
• [2] The HACD4 haplotype as a risk factor for atherosclerosis in males.Gene. 2018 Jan 30;641:35-40. doi: 10.1016/j.gene.2017.10.030. Epub 2017 Oct 12.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [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] 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.
• [7] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] 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.
• [10] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [11] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [12] 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.
• [13] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.