Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ0BYK6)

• DOT Name: Arachidonate 12-lipoxygenase, 12R-type (ALOX12B)
• Synonyms: 12R-LOX; 12R-lipoxygenase; EC 1.13.11.-; Epidermis-type lipoxygenase 12
• Gene Name: ALOX12B
• Related Disease:
  Autosomal recessive congenital ichthyosis 2
  Congenital ichthyosiform erythroderma
  Lamellar ichthyosis
  Self-healing collodion baby
• UniProt ID: LX12B_HUMAN
• EC Number: 1.13.11.-
• Pfam ID: PF00305 ; PF01477
• Sequence:
  MATYKVRVATGTDLLSGTRDSISLTIVGTQGESHKQLLNHFGRDFATGAVGQYTVQCPQD
  LGELIIIRLHKERYAFFPKDPWYCNYVQICAPNGRIYHFPAYQWMDGYETLALREATGKT
  TADDSLPVLLEHRKEEIRAKQDFYHWRVFLPGLPSYVHIPSYRPPVRRHRNPNRPEWNGY
  IPGFPILINFKATKFLNLNLRYSFLKTASFFVRLGPMALAFKVRGLLDCKHSWKRLKDIR
  KIFPGKKSVVSEYVAEHWAEDTFFGYQYLNGVNPGLIRRCTRIPDKFPVTDDMVAPFLGE
  GTCLQAELEKGNIYLADYRIMEGIPTVELSGRKQHHCAPLCLLHFGPEGKMMPIAIQLSQ
  TPGPDCPIFLPSDSEWDWLLAKTWVRYAEFYSHEAIAHLLETHLIAEAFCLALLRNLPMC
  HPLYKLLIPHTRYTVQINSIGRAVLLNEGGLSAKGMSLGVEGFAGVMVRALSELTYDSLY
  LPNDFVERGVQDLPGYYYRDDSLAVWNALEKYVTEIITYYYPSDAAVEGDPELQSWVQEI
  FKECLLGRESSGFPRCLRTVPELIRYVTIVIYTCSAKHAAVNTGQMEFTAWMPNFPASMR
  NPPIQTKGLTTLETFMDTLPDVKTTCITLLVLWTLSREPDDRRPLGHFPDIHFVEEAPRR
  SIEAFRQRLNQISHDIRQRNKCLPIPYYYLDPVLIENSISI
• Function: Catalyzes the regio and stereo-specific incorporation of a single molecule of dioxygen into free and esterified polyunsaturated fatty acids generating lipid hydroperoxides that can be further reduced to the corresponding hydroxy species. In the skin, acts upstream of ALOXE3 on the lineolate 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. May also play a role in the regulation of the expression of airway mucins.
• Tissue Specificity: Expressed in B-cells, hair follicles, foreskin keratinocytes and adult skin. Also expressed in psoriatic tissue.
• KEGG Pathway:
  Arachidonic acid metabolism (hsa00590)
  Metabolic pathways (hsa01100)
  Serotonergic sy.pse (hsa04726)
• Reactome Pathway: Synthesis of 12-eicosatetraenoic acid derivatives (R-HSA-2142712)
• BioCyc Pathway: MetaCyc:ENSG00000179477-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive congenital ichthyosis 2	DISKFZSE	Strong	Autosomal recessive	[1]
Congenital ichthyosiform erythroderma	DISV8HQX	Strong	Autosomal recessive	[1]
Lamellar ichthyosis	DIS714UN	Supportive	Autosomal recessive	[2]
Self-healing collodion baby	DIS1EEFN	Supportive	Autosomal recessive	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Arachidonate 12-lipoxygenase, 12R-type (ALOX12B).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Arachidonate 12-lipoxygenase, 12R-type (ALOX12B).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Arachidonate 12-lipoxygenase, 12R-type (ALOX12B).	[5]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Arachidonate 12-lipoxygenase, 12R-type (ALOX12B).	[5]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Arachidonate 12-lipoxygenase, 12R-type (ALOX12B).	[6]
Ibuprofen	DM8VCBE	Approved	Ibuprofen affects the expression of Arachidonate 12-lipoxygenase, 12R-type (ALOX12B).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Arachidonate 12-lipoxygenase, 12R-type (ALOX12B).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Arachidonate 12-lipoxygenase, 12R-type (ALOX12B).	[10]

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] 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.
• [3] 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.
• [4] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [5] Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers. Nat Commun. 2018 Sep 26;9(1):3931.
• [6] 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.
• [7] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [8] 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.
• [9] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.