Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6RXLXS)

• DOT Name: Cytochrome P450 2U1 (CYP2U1)
• Synonyms: Long-chain fatty acid omega-monooxygenase; EC 1.14.14.80
• Gene Name: CYP2U1
• Related Disease:
  Corpus callosum, agenesis of
  GM1 gangliosidosis
  Hereditary spastic paraplegia
  Hereditary spastic paraplegia 56
  Peripheral neuropathy
  Dystonia
  Vascular purpura
  Advanced cancer
  Breast cancer
  Breast carcinoma
• UniProt ID: CP2U1_HUMAN
• EC Number: 1.14.14.80
• Pfam ID: PF00067
• Sequence:
  MSSPGPSQPPAEDPPWPARLLRAPLGLLRLDPSGGALLLCGLVALLGWSWLRRRRARGIP
  PGPTPWPLVGNFGHVLLPPFLRRRSWLSSRTRAAGIDPSVIGPQVLLAHLARVYGSIFSF
  FIGHYLVVVLSDFHSVREALVQQAEVFSDRPRVPLISIVTKEKGVVFAHYGPVWRQQRKF
  SHSTLRHFGLGKLSLEPKIIEEFKYVKAEMQKHGEDPFCPFSIISNAVSNIICSLCFGQR
  FDYTNSEFKKMLGFMSRGLEICLNSQVLLVNICPWLYYLPFGPFKELRQIEKDITSFLKK
  IIKDHQESLDRENPQDFIDMYLLHMEEERKNNSNSSFDEEYLFYIIGDLFIAGTDTTTNS
  LLWCLLYMSLNPDVQEKVHEEIERVIGANRAPSLTDKAQMPYTEATIMEVQRLTVVVPLA
  IPHMTSENTVLQGYTIPKGTLILPNLWSVHRDPAIWEKPEDFYPNRFLDDQGQLIKKETF
  IPFGIGKRVCMGEQLAKMELFLMFVSLMQSFAFALPEDSKKPLLTGRFGLTLAPHPFNIT
  ISRR
• Function: A cytochrome P450 monooxygenase involved in the metabolism of arachidonic acid and its conjugates. 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). Acts as an omega and omega-1 hydroxylase for arachidonic acid and possibly for other long chain fatty acids. May modulate the arachidonic acid signaling pathway and play a role in other fatty acid signaling processes. May down-regulate the biological activities of N-arachidonoyl-serotonin, an endocannabinoid that has anti-nociceptive effects through inhibition of fatty acid amide hydrolase FAAH, TRPV1 receptor and T-type calcium channels. Catalyzes C-2 oxidation of the indole ring of N-arachidonoyl-serotonin forming a less active product 2-oxo-N-arachidonoyl-serotonin.
• Tissue Specificity: Widely expressed with stronger expression in thymus, heart and cerebellum.
• KEGG Pathway:
  Fatty acid degradation (hsa00071)
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE) (R-HSA-2142816)
  Defective CYP2U1 causes SPG56 (R-HSA-5579011)
  Miscellaneous substrates (R-HSA-211958)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Corpus callosum, agenesis of	DISO9P40	Definitive	Biomarker	[1]
GM1 gangliosidosis	DISN3L2M	Definitive	Genetic Variation	[2]
Hereditary spastic paraplegia	DISGZQV1	Definitive	Autosomal recessive	[3]
Hereditary spastic paraplegia 56	DISJLW1T	Definitive	Autosomal recessive	[4]
Peripheral neuropathy	DIS7KN5G	Definitive	Biomarker	[1]
Dystonia	DISJLFGW	Strong	Genetic Variation	[5]
Vascular purpura	DIS6ZZMF	Strong	Genetic Variation	[6]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[7]
Breast cancer	DIS7DPX1	moderate	Biomarker	[7]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[7]

14 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 Cytochrome P450 2U1 (CYP2U1).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cytochrome P450 2U1 (CYP2U1).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytochrome P450 2U1 (CYP2U1).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cytochrome P450 2U1 (CYP2U1).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytochrome P450 2U1 (CYP2U1).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cytochrome P450 2U1 (CYP2U1).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Cytochrome P450 2U1 (CYP2U1).	[14]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Cytochrome P450 2U1 (CYP2U1).	[15]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Cytochrome P450 2U1 (CYP2U1).	[16]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Cytochrome P450 2U1 (CYP2U1).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Cytochrome P450 2U1 (CYP2U1).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cytochrome P450 2U1 (CYP2U1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cytochrome P450 2U1 (CYP2U1).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Cytochrome P450 2U1 (CYP2U1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of Cytochrome P450 2U1 (CYP2U1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cytochrome P450 2U1 (CYP2U1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cytochrome P450 2U1 (CYP2U1).	[21]

References

• [1] ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease. Brain. 2016 Jan;139(Pt 1):73-85. doi: 10.1093/brain/awv320. Epub 2015 Nov 10.
• [2] Defining the genetic basis of early onset hereditary spastic paraplegia using whole genome sequencing.Neurogenetics. 2016 Oct;17(4):265-270. doi: 10.1007/s10048-016-0495-z. Epub 2016 Sep 28.
• [3] 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.
• [4] Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. Am J Hum Genet. 2012 Dec 7;91(6):1051-64. doi: 10.1016/j.ajhg.2012.11.001. Epub 2012 Nov 21.
• [5] CYP2U1 mutations in two Iranian patients with activity induced dystonia, motor regression and spastic paraplegia.Eur J Paediatr Neurol. 2016 Sep;20(5):782-7. doi: 10.1016/j.ejpn.2016.05.013. Epub 2016 Jun 2.
• [6] Whole exome sequencing identifies novel variant underlying hereditary spastic paraplegia in consanguineous Pakistani families.J Clin Neurosci. 2019 Sep;67:19-23. doi: 10.1016/j.jocn.2019.06.039. Epub 2019 Jul 4.
• [7] Anti-breast Cancer Activity of SPG-56 from Sweet Potato in MCF-7 Bearing Mice in Situ through Promoting Apoptosis and Inhibiting Metastasis.Sci Rep. 2019 Jan 16;9(1):146. doi: 10.1038/s41598-018-29099-x.
• [8] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [9] 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.
• [10] Differentiation-specific factors modulate epidermal CYP1-4 gene expression in human skin in response to retinoic acid and classic aryl hydrocarbon receptor ligands. J Pharmacol Exp Ther. 2006 Dec;319(3):1162-71.
• [11] 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.
• [12] 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.
• [13] Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women. Arch Toxicol. 2017 May;91(5):2067-2078. doi: 10.1007/s00204-016-1879-4. Epub 2016 Nov 12.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [16] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [17] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [18] 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.
• [19] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [20] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [21] 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.
• [22] 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.
• [23] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.