Details of Drug Off-Target (DOT)

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

• DOT Name: Very-long-chain (HACD3)
• Synonyms: 3R)-3-hydroxyacyl-CoA dehydratase 3 (EC 4.2.1.134; 3-hydroxyacyl-CoA dehydratase 3; HACD3; Butyrate-induced protein 1; B-ind1; hB-ind1; Protein-tyrosine phosphatase-like A domain-containing protein 1
• Gene Name: HACD3
• Related Disease:
  Non-insulin dependent diabetes
  Depression
  Major depressive disorder
• UniProt ID: HACD3_HUMAN
• EC Number: 4.2.1.134
• Pfam ID: PF04387
• Sequence:
  MENQVLTPHVYWAQRHRELYLRVELSDVQNPAISITENVLHFKAQGHGAKGDNVYEFHLE
  FLDLVKPEPVYKLTQRQVNITVQKKVSQWWERLTKQEKRPLFLAPDFDRWLDESDAEMEL
  RAKEEERLNKLRLESEGSPETLTNLRKGYLFMYNLVQFLGFSWIFVNLTVRFCILGKESF
  YDTFHTVADMMYFCQMLAVVETINAAIGVTTSPVLPSLIQLLGRNFILFIIFGTMEEMQN
  KAVVFFVFYLWSAIEIFRYSFYMLTCIDMDWKVLTWLRYTLWIPLYPLGCLAEAVSVIQS
  IPIFNETGRFSFTLPYPVKIKVRFSFFLQIYLIMIFLGLYINFRHLYKQRRRRYGQKKKK
  IH
• 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. May be involved in Rac1-signaling pathways leading to the modulation of gene expression. Promotes insulin receptor/INSR autophosphorylation and is involved in INSR internalization.
• Tissue Specificity: Highly expressed in testis, kidney, brain, liver and weakly in skeletal muscle, spleen and heart. No expression detected in leukocytes.
• 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
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[1]
Depression	DIS3XJ69	Strong	Biomarker	[2]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[2]

11 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 Very-long-chain (HACD3).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Very-long-chain (HACD3).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Very-long-chain (HACD3).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Very-long-chain (HACD3).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Very-long-chain (HACD3).	[7]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Very-long-chain (HACD3).	[8]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Very-long-chain (HACD3).	[8]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Very-long-chain (HACD3).	[8]
EMODIN	DMAEDQG	Terminated	EMODIN decreases the expression of Very-long-chain (HACD3).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Very-long-chain (HACD3).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Very-long-chain (HACD3).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Very-long-chain (HACD3).	[12]

References

• [1] A type 2 diabetes disease module with a high collective influence for Cdk2 and PTPLAD1 is localized in endosomes.PLoS One. 2018 Oct 9;13(10):e0205180. doi: 10.1371/journal.pone.0205180. eCollection 2018.
• [2] Hippocampal tail volume as a predictive biomarker of antidepressant treatment outcomes in patients with major depressive disorder: a CAN-BIND report.Neuropsychopharmacology. 2020 Jan;45(2):283-291. doi: 10.1038/s41386-019-0542-1. Epub 2019 Oct 14.
• [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] 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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [9] Gene expression alteration during redox-dependent enhancement of arsenic cytotoxicity by emodin in HeLa cells. Cell Res. 2005 Jul;15(7):511-22.
• [10] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [12] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.