Details of Drug Off-Target (DOT)

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

• DOT Name: Fatty acyl-CoA reductase 1 (FAR1)
• Synonyms: EC 1.2.1.84; Male sterility domain-containing protein 2
• Gene Name: FAR1
• Related Disease:
  Atopic dermatitis
  Fatty acyl-CoA reductase 1 deficiency
  Hereditary spastic paraplegia
  Rhizomelic chondrodysplasia punctata
  Spastic paraparesis-cataracts-speech delay syndrome
  Cataract
  Fatty acyl-CoA reductase 1 upregulation
  Methicillin-resistant staphylococci infection
  Hereditary spastic paraplegia 9A
• UniProt ID: FACR1_HUMAN
• EC Number: 1.2.1.84
• Pfam ID: PF07993 ; PF03015
• Sequence:
  MVSIPEYYEGKNVLLTGATGFLGKVLLEKLLRSCPKVNSVYVLVRQKAGQTPQERVEEVL
  SGKLFDRLRDENPDFREKIIAINSELTQPKLALSEEDKEVIIDSTNIIFHCAATVRFNEN
  LRDAVQLNVIATRQLILLAQQMKNLEVFMHVSTAYAYCNRKHIDEVVYPPPVDPKKLIDS
  LEWMDDGLVNDITPKLIGDRPNTYIYTKALAEYVVQQEGAKLNVAIVRPSIVGASWKEPF
  PGWIDNFNGPSGLFIAAGKGILRTIRASNNALADLVPVDVVVNMSLAAAWYSGVNRPRNI
  MVYNCTTGSTNPFHWGEVEYHVISTFKRNPLEQAFRRPNVNLTSNHLLYHYWIAVSHKAP
  AFLYDIYLRMTGRSPRMMKTITRLHKAMVFLEYFTSNSWVWNTENVNMLMNQLNPEDKKT
  FNIDVRQLHWAEYIENYCLGTKKYVLNEEMSGLPAARKHLNKLRNIRYGFNTILVILIWR
  IFIARSQMARNIWYFVVSLCYKFLSYFRASSTMRY
• Function: Catalyzes the reduction of saturated and unsaturated C16 or C18 fatty acyl-CoA to fatty alcohols. It plays an essential role in the production of ether lipids/plasmalogens which synthesis requires fatty alcohols. In parallel, it is also required for wax monoesters production since fatty alcohols also constitute a substrate for their synthesis.
• KEGG Pathway: Peroxisome (hsa04146)
• Reactome Pathway: Wax biosynthesis (R-HSA-9640463)
• BioCyc Pathway: MetaCyc:HS16231-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atopic dermatitis	DISTCP41	Strong	Genetic Variation	[1]
Fatty acyl-CoA reductase 1 deficiency	DISZ4COL	Strong	Autosomal recessive	[2]
Hereditary spastic paraplegia	DISGZQV1	Strong	Biomarker	[3]
Rhizomelic chondrodysplasia punctata	DISF3YE7	Strong	Biomarker	[4]
Spastic paraparesis-cataracts-speech delay syndrome	DISSK7MJ	Strong	Autosomal dominant	[5]
Cataract	DISUD7SL	moderate	Biomarker	[2]
Fatty acyl-CoA reductase 1 upregulation	DIS1GWH1	Moderate	Autosomal dominant	[6]
Methicillin-resistant staphylococci infection	DIS6DRDZ	moderate	Biomarker	[7]
Hereditary spastic paraplegia 9A	DISQHJ22	Supportive	Autosomal dominant	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Fatty acyl-CoA reductase 1 (FAR1).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Fatty acyl-CoA reductase 1 (FAR1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Fatty acyl-CoA reductase 1 (FAR1).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of Fatty acyl-CoA reductase 1 (FAR1).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Fatty acyl-CoA reductase 1 (FAR1).	[12]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Fatty acyl-CoA reductase 1 (FAR1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Fatty acyl-CoA reductase 1 (FAR1).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Fatty acyl-CoA reductase 1 (FAR1).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Fatty acyl-CoA reductase 1 (FAR1).	[17]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Fatty acyl-CoA reductase 1 (FAR1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Fatty acyl-CoA reductase 1 (FAR1).	[16]

References

• [1] Supplemental feeding of phospholipid-enriched alkyl phospholipid from krill relieves spontaneous atopic dermatitis and strengthens skin intercellular lipid barriers in NC/Nga mice.Biosci Biotechnol Biochem. 2019 Apr;83(4):717-727. doi: 10.1080/09168451.2018.1559024. Epub 2018 Dec 20.
• [2] A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency. Am J Hum Genet. 2014 Nov 6;95(5):602-10. doi: 10.1016/j.ajhg.2014.10.003. Epub 2014 Oct 30.
• [3] Going Too Far Is the Same as Falling Short(?: Kinesin-3 Family Members in Hereditary Spastic Paraplegia.Front Cell Neurosci. 2019 Sep 26;13:419. doi: 10.3389/fncel.2019.00419. eCollection 2019.
• [4] Growth charts for individuals with rhizomelic chondrodysplasia punctata.Am J Med Genet A. 2017 Jan;173(1):108-113. doi: 10.1002/ajmg.a.37961. Epub 2016 Sep 12.
• [5] An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids. Genet Med. 2021 Apr;23(4):740-750. doi: 10.1038/s41436-020-01027-3. Epub 2020 Nov 26.
• [6] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [7] Staphylococcus aureus in dermatology outpatients with special emphasis on community-associated methicillin-resistant strains.J Invest Dermatol. 2008 Nov;128(11):2655-2664. doi: 10.1038/jid.2008.133. Epub 2008 Jul 3.
• [8] 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.
• [9] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [10] 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.
• [11] 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.
• [12] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [13] 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.
• [14] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] 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.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.