Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT76J52A)

• DOT Name: Hydroperoxide isomerase ALOXE3 (ALOXE3)
• Synonyms: Epidermis-type lipoxygenase 3; Epidermal LOX-3; e-LOX-3; eLOX-3; Hydroperoxy dehydratase ALOXE3; Hydroperoxy icosatetraenoate dehydratase; EC 4.2.1.152; Hydroperoxy icosatetraenoate isomerase; EC 5.4.4.7
• Gene Name: ALOXE3
• Related Disease:
  Autosomal recessive congenital ichthyosis 1
  Autosomal recessive congenital ichthyosis 3
  Congenital ichthyosiform erythroderma
  Epidermolytic ichthyosis
  Fatty liver disease
  Metabolic disorder
  Obesity
  Prostate carcinoma
  Prostate neoplasm
  Lamellar ichthyosis
  Self-healing collodion baby
  Prostate cancer
• UniProt ID: LOXE3_HUMAN
• PDB ID: 6VB2
• EC Number: 4.2.1.152; 5.4.4.7
• Pfam ID: PF00305 ; PF01477
• Sequence:
  MAVYRLCVTTGPYLRAGTLDNISVTLVGTCGESPKQRLDRMGRDFAPGSVQKYKVRCTAE
  LGELLLLRVHKERYAFFRKDSWYCSRICVTEPDGSVSHFPCYQWIEGYCTVELRPGTART
  ICQDSLPLLLDHRTRELRARQECYRWKIYAPGFPCMVDVNSFQEMESDKKFALTKTTTCV
  DQGDSSGNRYLPGFPMKIDIPSLMYMEPNVRYSATKTISLLFNAIPASLGMKLRGLLDRK
  GSWKKLDDMQNIFWCHKTFTTKYVTEHWCEDHFFGYQYLNGVNPVMLHCISSLPSKLPVT
  NDMVAPLLGQDTCLQTELERGNIFLADYWILAEAPTHCLNGRQQYVAAPLCLLWLSPQGA
  LVPLAIQLSQTPGPDSPIFLPTDSEWDWLLAKTWVRNSEFLVHENNTHFLCTHLLCEAFA
  MATLRQLPLCHPIYKLLLPHTRYTLQVNTIARATLLNPEGLVDQVTSIGRQGLIYLMSTG
  LAHFTYTNFCLPDSLRARGVLAIPNYHYRDDGLKIWAAIESFVSEIVGYYYPSDASVQQD
  SELQAWTGEIFAQAFLGRESSGFPSRLCTPGEMVKFLTAIIFNCSAQHAAVNSGQHDFGA
  WMPNAPSSMRQPPPQTKGTTTLKTYLDTLPEVNISCNNLLLFWLVSQEPKDQRPLGTYPD
  EHFTEEAPRRSIAAFQSRLAQISRDIQERNQGLALPYTYLDPPLIENSVSI
• Function: Non-heme iron-containing lipoxygenase which is atypical in that it displays a prominent hydroperoxide isomerase activity and a reduced lipoxygenases activity. The hydroperoxide isomerase activity catalyzes the isomerization of hydroperoxides, derived from arachidonic and linoleic acid by ALOX12B, into hepoxilin-type epoxyalcohols and ketones. In presence of oxygen, oxygenates polyunsaturated fatty acids, including arachidonic acid, to produce fatty acid hydroperoxides. In the skin, acts downstream of ALOX12B on the linoleate moiety of esterified omega-hydroxyacyl-sphingosine (EOS) ceramides to produce an epoxy-ketone derivative, a crucial step in the conjugation of omega-hydroxyceramide to membrane proteins. Therefore plays a crucial role in the synthesis of corneocytes lipid envelope and the establishment of the skin barrier to water loss. In parallel, it may have a signaling function in barrier formation through the production of hepoxilins metabolites. Also plays a role in adipocyte differentiation through hepoxilin A3 and hepoxilin B3 production which in turn activate PPARG. Through the production of hepoxilins in the spinal cord, it may regulate inflammatory tactile allodynia.
• Tissue Specificity: Predominantly expressed in skin.
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Synthesis of 12-eicosatetraenoic acid derivatives (R-HSA-2142712)
• BioCyc Pathway: MetaCyc:ENSG00000179148-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive congenital ichthyosis 1	DISWMIO6	Strong	Biomarker	[1]
Autosomal recessive congenital ichthyosis 3	DISDBKJ4	Strong	Autosomal recessive	[2]
Congenital ichthyosiform erythroderma	DISV8HQX	Strong	Autosomal recessive	[2]
Epidermolytic ichthyosis	DISJPEP3	Strong	Genetic Variation	[3]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[4]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[4]
Obesity	DIS47Y1K	Strong	Altered Expression	[4]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[6]
Lamellar ichthyosis	DIS714UN	Supportive	Autosomal recessive	[7]
Self-healing collodion baby	DIS1EEFN	Supportive	Autosomal recessive	[8]
Prostate cancer	DISF190Y	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Hydroperoxide isomerase ALOXE3 (ALOXE3).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Hydroperoxide isomerase ALOXE3 (ALOXE3).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Hydroperoxide isomerase ALOXE3 (ALOXE3).	[11]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Hydroperoxide isomerase ALOXE3 (ALOXE3).	[12]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Hydroperoxide isomerase ALOXE3 (ALOXE3).	[13]
Ibuprofen	DM8VCBE	Approved	Ibuprofen affects the expression of Hydroperoxide isomerase ALOXE3 (ALOXE3).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Hydroperoxide isomerase ALOXE3 (ALOXE3).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Hydroperoxide isomerase ALOXE3 (ALOXE3).	[17]

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 Hydroperoxide isomerase ALOXE3 (ALOXE3).	[15]

References

• [1] Discovery of potent and selective inhibitors of human platelet-type 12- lipoxygenase.J Med Chem. 2011 Aug 11;54(15):5485-97. doi: 10.1021/jm2005089. Epub 2011 Jul 8.
• [2] 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.
• [3] Identification and association of recurrent ALOXE3 mutation with non-bullous congenital ichthyosiform erythroderma in two ethnically distinct Pakistani families.Congenit Anom (Kyoto). 2019 May;59(3):93-98. doi: 10.1111/cga.12303. Epub 2018 Jul 18.
• [4] Hepatocyte ALOXE3 is induced during adaptive fasting and enhances insulin sensitivity by activating hepatic PPAR.JCI Insight. 2018 Aug 23;3(16):e120794. doi: 10.1172/jci.insight.120794. eCollection 2018 Aug 23.
• [5] The associations of DNA methylation alterations in oxidative stress-related genes with cancer incidence and mortality outcomes: a population-based cohort study.Clin Epigenetics. 2019 Jan 24;11(1):14. doi: 10.1186/s13148-018-0604-y.
• [6] The Interaction between Pesticide Use and Genetic Variants Involved in Lipid Metabolism on Prostate Cancer Risk.J Cancer Epidemiol. 2012;2012:358076. doi: 10.1155/2012/358076. Epub 2012 Aug 2.
• [7] Lamellar ichthyosis caused by a previously unreported homozygous ALOXE3 mutation in East Asia. Acta Derm Venereol. 2015 Sep;95(7):858-9. doi: 10.2340/00015555-2022.
• [8] Genotypic and clinical spectrum of self-improving collodion ichthyosis: ALOX12B, ALOXE3, and TGM1 mutations in Scandinavian patients. J Invest Dermatol. 2010 Feb;130(2):438-43. doi: 10.1038/jid.2009.346. Epub 2009 Nov 5.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [11] 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.
• [12] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [13] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [14] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [15] 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.
• [16] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.