Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUG4BWA)

• DOT Name: Phytanoyl-CoA dioxygenase, peroxisomal (PHYH)
• Synonyms: EC 1.14.11.18; Phytanic acid oxidase; Phytanoyl-CoA alpha-hydroxylase; PhyH
• Gene Name: PHYH
• Related Disease:
  Adult Refsum disease
  Phytanoyl-CoA hydroxylase deficiency
  Congenital nervous system disorder
  Retinitis pigmentosa
  Lupus nephritis
• UniProt ID: PAHX_HUMAN
• PDB ID: 2A1X
• EC Number: 1.14.11.18
• Pfam ID: PF05721
• Sequence:
  MEQLRAAARLQIVLGHLGRPSAGAVVAHPTSGTISSASFHPQQFQYTLDNNVLTLEQRKF
  YEENGFLVIKNLVPDADIQRFRNEFEKICRKEVKPLGLTVMRDVTISKSEYAPSEKMITK
  VQDFQEDKELFRYCTLPEILKYVECFTGPNIMAMHTMLINKPPDSGKKTSRHPLHQDLHY
  FPFRPSDLIVCAWTAMEHISRNNGCLVVLPGTHKGSLKPHDYPKWEGGVNKMFHGIQDYE
  ENKARVHLVMEKGDTVFFHPLLIHGSGQNKTQGFRKAISCHFASADCHYIDVKGTSQENI
  EKEVVGIAHKFFGAENSVNLKDIWMFRARLVKGERTNL
• Function: Catalyzes the 2-hydroxylation of not only racemic phytanoyl-CoA and the isomers of 3-methylhexadecanoyl-CoA, but also a variety of other mono-branched 3-methylacyl-CoA esters (with a chain length of at least seven carbon atoms) and straight-chain acyl-CoA esters (with a chain length longer than four carbon atoms). Does not hydroxylate long and very long straight chain acyl-CoAs or 2-methyl- and 4-methyl-branched acyl-CoAs.
• Tissue Specificity: Expressed in liver, kidney, and T-cells, but not in spleen, brain, heart, lung and skeletal muscle.
• KEGG Pathway: Peroxisome (hsa04146)
• Reactome Pathway:
  Peroxisomal protein import (R-HSA-9033241)
  TYSND1 cleaves peroxisomal proteins (R-HSA-9033500)
  Alpha-oxidation of phytanate (R-HSA-389599)
• BioCyc Pathway: MetaCyc:HS03003-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
Adult Refsum disease	DISU2BLL	Definitive	Autosomal recessive	[1]
Phytanoyl-CoA hydroxylase deficiency	DISDT292	Definitive	Autosomal recessive	[2]
Congenital nervous system disorder	DIS2BIP8	Strong	Genetic Variation	[3]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[4]
Lupus nephritis	DISCVGPZ	Limited	Altered Expression	[5]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Phytanoyl-CoA dioxygenase, peroxisomal (PHYH) affects the response to substance of Fluorouracil.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[14]

19 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 Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[16]
Sertraline	DM0FB1J	Approved	Sertraline increases the expression of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[9]
Thioridazine	DM35M8J	Approved	Thioridazine increases the expression of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[9]
Clomipramine	DMINRKW	Approved	Clomipramine increases the expression of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[9]
Ofloxacin	DM0VQN3	Approved	Ofloxacin decreases the expression of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[9]
Clarithromycin	DM4M1SG	Approved	Clarithromycin decreases the expression of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[9]
Sulfamethoxazole	DMB08GE	Approved	Sulfamethoxazole decreases the expression of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[9]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine increases the expression of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[18]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Phytanoyl-CoA dioxygenase, peroxisomal (PHYH).	[19]

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] 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.
• [3] Non-manifesting Refsum heterozygotes carrying the c.135-2A>G PAHX gene transition.Neurol Sci. 2008 Jun;29(3):173-5. doi: 10.1007/s10072-008-0931-4. Epub 2008 Jul 9.
• [4] Molecular basis of Refsum disease: sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7).Hum Mutat. 2004 Mar;23(3):209-18. doi: 10.1002/humu.10315.
• [5] Immunophilins, Refsum disease, and lupus nephritis: the peroxisomal enzyme phytanoyl-COA alpha-hydroxylase is a new FKBP-associated protein.Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2104-9. doi: 10.1073/pnas.96.5.2104.
• [6] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [7] 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.
• [8] 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.
• [9] A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci. 2005 Feb;83(2):282-92.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] 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.
• [14] 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.
• [15] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [16] 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.
• [17] 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.
• [18] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [19] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.
• [20] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.