Details of Drug Off-Target (DOT)

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

• DOT Name: Ultra-long-chain fatty acid omega-hydroxylase (CYP4F22)
• Synonyms: EC 1.14.14.177; Cytochrome P450 4F22
• Gene Name: CYP4F22
• Related Disease:
  Autosomal recessive congenital ichthyosis 5
  Self-healing collodion baby
  Lamellar ichthyosis
  Congenital ichthyosiform erythroderma
  Non-syndromic ichthyosis
• UniProt ID: CP4FN_HUMAN
• EC Number: 1.14.14.177
• Pfam ID: PF00067
• Sequence:
  MLPITDRLLHLLGLEKTAFRIYAVSTLLLFLLFFLFRLLLRFLRLCRSFYITCRRLRCFP
  QPPRRNWLLGHLGMYLPNEAGLQDEKKVLDNMHHVLLVWMGPVLPLLVLVHPDYIKPLLG
  ASAAIAPKDDLFYGFLKPWLGDGLLLSKGDKWSRHRRLLTPAFHFDILKPYMKIFNQSAD
  IMHAKWRHLAEGSAVSLDMFEHISLMTLDSLQKCVFSYNSNCQEKMSDYISAIIELSALS
  VRRQYRLHHYLDFIYYRSADGRRFRQACDMVHHFTTEVIQERRRALRQQGAEAWLKAKQG
  KTLDFIDVLLLARDEDGKELSDEDIRAEADTFMFEGHDTTSSGISWMLFNLAKYPEYQEK
  CREEIQEVMKGRELEELEWDDLTQLPFTTMCIKESLRQYPPVTLVSRQCTEDIKLPDGRI
  IPKGIICLVSIYGTHHNPTVWPDSKVYNPYRFDPDNPQQRSPLAYVPFSAGPRNCIGQSF
  AMAELRVVVALTLLRFRLSVDRTRKVRRKPELILRTENGLWLKVEPLPPRA
• Function: A cytochrome P450 monooxygenase involved in epidermal ceramide biosynthesis. Hydroxylates the terminal carbon (omega-hydroxylation) of ultra-long-chain fatty acyls (C28-C36) prior to ceramide synthesis. Contributes to the synthesis of three classes of omega-hydroxy-ultra-long chain fatty acylceramides having sphingosine, 6-hydroxysphingosine and phytosphingosine bases, all major lipid components that underlie the permeability barrier of the stratum corneum. Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase).
• Reactome Pathway:
  Miscellaneous substrates (R-HSA-211958)
  Eicosanoids (R-HSA-211979)
  Synthesis of Leukotrienes (LT) and Eoxins (EX) (R-HSA-2142691)
  Defective CYP4F22 causes ARCI5 (R-HSA-5579005)
  Fatty acids (R-HSA-211935)
• BioCyc Pathway: MetaCyc:ENSG00000171954-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive congenital ichthyosis 5	DISXNNPN	Strong	Autosomal recessive	[1]
Self-healing collodion baby	DIS1EEFN	Strong	Genetic Variation	[2]
Lamellar ichthyosis	DIS714UN	Supportive	Autosomal recessive	[3]
Congenital ichthyosiform erythroderma	DISV8HQX	Limited	Genetic Variation	[4]
Non-syndromic ichthyosis	DISZ9QBQ	Limited	Biomarker	[4]

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 Ultra-long-chain fatty acid omega-hydroxylase (CYP4F22).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ultra-long-chain fatty acid omega-hydroxylase (CYP4F22).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Ultra-long-chain fatty acid omega-hydroxylase (CYP4F22).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ultra-long-chain fatty acid omega-hydroxylase (CYP4F22).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Ultra-long-chain fatty acid omega-hydroxylase (CYP4F22).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Ultra-long-chain fatty acid omega-hydroxylase (CYP4F22).	[7]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Ultra-long-chain fatty acid omega-hydroxylase (CYP4F22).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ultra-long-chain fatty acid omega-hydroxylase (CYP4F22).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ultra-long-chain fatty acid omega-hydroxylase (CYP4F22).	[11]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Two Cases of Autosomal Recessive Congenital Ichthyosis due to CYP4F22 Mutations: Expanding the Genotype of Self-Healing Collodion Baby.Pediatr Dermatol. 2016 Mar-Apr;33(2):e48-51. doi: 10.1111/pde.12740. Epub 2015 Dec 9.
• [3] Inherited ichthyoses/generalized Mendelian disorders of cornification. Eur J Hum Genet. 2013 Feb;21(2):123-33. doi: 10.1038/ejhg.2012.121. Epub 2012 Jun 27.
• [4] Severe Skin Permeability Barrier Dysfunction inKnockout Mice Deficient in a Fatty Acid -Hydroxylase Crucial to Acylceramide Production.J Invest Dermatol. 2020 Feb;140(2):319-326.e4. doi: 10.1016/j.jid.2019.07.689. Epub 2019 Jul 26.
• [5] 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.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [8] 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.
• [9] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [10] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [11] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.