Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK54C63)

• DOT Name: L-amino-acid oxidase (IL4I1)
• Synonyms: LAAO; LAO; EC 1.4.3.2; EC 1.4.3.25; Interleukin-4-induced protein 1; IL4-induced protein 1; hIL4I1; Protein Fig-1; hFIG1
• Gene Name: IL4I1
• Related Disease:
  Adenocarcinoma
  B-cell neoplasm
  Colon cancer
  Colon carcinoma
  Hypochromic microcytic anemia
  Mediastinal large B-cell lymphoma
  Meningococcal disease
  Metastatic melanoma
  Neoplasm
  Uterine fibroids
  Advanced cancer
  Disseminated intravascular coagulation
  Hepatocellular carcinoma
  Methicillin-resistant staphylococci infection
  Thrombocytopenia
  Melanoma
  Mesothelioma
  Rheumatoid arthritis
  Sarcoidosis
  Schistosomiasis
• UniProt ID: OXLA_HUMAN
• EC Number: 1.4.3.2; 1.4.3.25
• Pfam ID: PF01593
• Sequence:
  MAPLALHLLVLVPILLSLVASQDWKAERSQDPFEKCMQDPDYEQLLKVVTWGLNRTLKPQ
  RVIVVGAGVAGLVAAKVLSDAGHKVTILEADNRIGGRIFTYRDQNTGWIGELGAMRMPSS
  HRILHKLCQGLGLNLTKFTQYDKNTWTEVHEVKLRNYVVEKVPEKLGYALRPQEKGHSPE
  DIYQMALNQALKDLKALGCRKAMKKFERHTLLEYLLGEGNLSRPAVQLLGDVMSEDGFFY
  LSFAEALRAHSCLSDRLQYSRIVGGWDLLPRALLSSLSGLVLLNAPVVAMTQGPHDVHVQ
  IETSPPARNLKVLKADVVLLTASGPAVKRITFSPPLPRHMQEALRRLHYVPATKVFLSFR
  RPFWREEHIEGGHSNTDRPSRMIFYPPPREGALLLASYTWSDAAAAFAGLSREEALRLAL
  DDVAALHGPVVRQLWDGTGVVKRWAEDQHSQGGFVVQPPALWQTEKDDWTVPYGRIYFAG
  EHTAYPHGWVETAVKSALRAAIKINSRKGPASDTASPEGHASDMEGQGHVHGVASSPSHD
  LAKEEGSHPPVQGQLSLQNTTHTRTSH
• Function: Secreted L-amino-acid oxidase that acts as a key immunoregulator. Has preference for L-aromatic amino acids: converts phenylalanine (Phe), tyrosine (Tyr) and tryptophan (Trp) to phenylpyruvic acid (PP), hydroxyphenylpyruvic acid (HPP), and indole-3-pyruvic acid (I3P), respectively. Also has weak L-arginine oxidase activity. Acts as a negative regulator of anti-tumor immunity by mediating Trp degradation via an indole pyruvate pathway that activates the transcription factor AHR. IL4I1-mediated Trp catabolism generates I3P, giving rise to indole metabolites (indole-3-acetic acid (IAA) and indole-3-aldehyde (I3A)) and kynurenic acid, which act as ligands for AHR, a ligand-activated transcription factor that plays important roles in immunity and cancer. AHR activation by indoles following IL4I1-mediated Trp degradation enhances tumor progression by promoting cancer cell motility and suppressing adaptive immunity. Also has an immunoregulatory function in some immune cells, probably by mediating Trp degradation and promoting downstream AHR activation: inhibits T-cell activation and proliferation, promotes the differentiation of naive CD4(+) T-cells into FOXP3(+) regulatory T-cells (Treg) and regulates the development and function of B-cells. Also regulates M2 macrophage polarization by inhibiting T-cell activation. Also has antibacterial properties by inhibiting growth of Gram negative and Gram positive bacteria through the production of NH4(+) and H2O2.
• Tissue Specificity: Primarily found in immune tissues, with the highest expression in lymph nodes and spleen . Present in germinal center macrophages and inflammatory myeloid cells and antigen-presenting cells (at protein level) . Also present in spermatozoa (at protein level) . Highly expressed in primary mediastinal large B-cell lymphoma, a specific subtype of diffuse large B-cell lymphoma . Expressed by neoplastic cells of several B-cell lymphomas and by tumor-associated macrophages .
• KEGG Pathway:
  Alanine, aspartate and glutamate metabolism (hsa00250)
  Cysteine and methionine metabolism (hsa00270)
  Valine, leucine and isoleucine degradation (hsa00280)
  Tyrosine metabolism (hsa00350)
  Phenylalanine metabolism (hsa00360)
  Tryptophan metabolism (hsa00380)
  Phenylalanine, tyrosine and tryptophan biosynthesis (hsa00400)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Phenylalanine metabolism (R-HSA-8964208)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[1]
B-cell neoplasm	DISVY326	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Altered Expression	[3]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[3]
Hypochromic microcytic anemia	DIS0RMTQ	Strong	Genetic Variation	[4]
Mediastinal large B-cell lymphoma	DISAUA10	Strong	Altered Expression	[5]
Meningococcal disease	DISGDM2Z	Strong	Genetic Variation	[6]
Metastatic melanoma	DISSL43L	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Uterine fibroids	DISBZRMJ	Strong	Genetic Variation	[9]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[10]
Disseminated intravascular coagulation	DISCAVOZ	moderate	Genetic Variation	[11]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[12]
Methicillin-resistant staphylococci infection	DIS6DRDZ	moderate	Biomarker	[13]
Thrombocytopenia	DISU61YW	moderate	Biomarker	[11]
Melanoma	DIS1RRCY	Limited	Biomarker	[7]
Mesothelioma	DISKWK9M	Limited	Biomarker	[2]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[14]
Sarcoidosis	DISE5B8Z	Limited	Altered Expression	[15]
Schistosomiasis	DIS6PD44	Limited	Altered Expression	[15]

1 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 L-amino-acid oxidase (IL4I1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of L-amino-acid oxidase (IL4I1).	[17]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of L-amino-acid oxidase (IL4I1).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of L-amino-acid oxidase (IL4I1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of L-amino-acid oxidase (IL4I1).	[20]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of L-amino-acid oxidase (IL4I1).	[21]

References

• [1] Cellular mechanism of resistance of human colorectal adenocarcinoma cells against apoptosis-induction by Russell's Viper venom l-amino acid oxidase (Rusvinoxidase).Biochimie. 2018 Jul;150:8-15. doi: 10.1016/j.biochi.2018.04.017. Epub 2018 Apr 25.
• [2] IL4I1: an inhibitor of the CD8?antitumor T-cell response in vivo.Eur J Immunol. 2011 Jun;41(6):1629-38. doi: 10.1002/eji.201041119. Epub 2011 May 13.
• [3] Cytotoxic, Anti-Proliferative and Apoptosis Activity of l-Amino Acid Oxidase from Malaysian Cryptelytrops purpureomaculatus (CP-LAAO) Venom on Human Colon Cancer Cells.Molecules. 2018 Jun 8;23(6):1388. doi: 10.3390/molecules23061388.
• [4] A 50-Year-Old Woman With Uterine Myomatosis, Rapidly Progressive Dyspnea, and Lower Extremity Edema.Chest. 2019 Sep;156(3):e69-e72. doi: 10.1016/j.chest.2019.05.018.
• [5] Interleukin 4-induced gene 1 is activated in primary mediastinal large B-cell lymphoma.Blood. 2003 Apr 1;101(7):2756-61. doi: 10.1182/blood-2002-07-2215. Epub 2002 Nov 21.
• [6] Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease.Nat Genet. 2010 Sep;42(9):772-6. doi: 10.1038/ng.640. Epub 2010 Aug 8.
• [7] Interleukin 4-Induced Gene 1 as an Emerging Regulator of B-Cell Biology and its Role in Cutaneous Melanoma.Crit Rev Immunol. 2019;39(1):39-57. doi: 10.1615/CritRevImmunol.2019030020.
• [8] The IL4I1 Enzyme: A New Player in the Immunosuppressive Tumor Microenvironment.Cells. 2019 Jul 20;8(7):757. doi: 10.3390/cells8070757.
• [9] Which Patients With Cervical Squamous Cell Carcinoma Might Benefit From Neoadjuvant Chemotherapy?.J Clin Oncol. 2018 Jun 1;36(16):1543-1547. doi: 10.1200/JCO.2017.77.3416. Epub 2018 Apr 18.
• [10] CR-LAAO, an L-amino acid oxidase from Calloselasma rhodostoma venom, as a potential tool for developing novel immunotherapeutic strategies against cancer.Sci Rep. 2017 Feb 16;7:42673. doi: 10.1038/srep42673.
• [11] Comparative proteomes, immunoreactivities and neutralization of procoagulant activities of Calloselasma rhodostoma (Malayan pit viper) venoms from four regions in Southeast Asia.Toxicon. 2019 Nov;169:91-102. doi: 10.1016/j.toxicon.2019.08.004. Epub 2019 Aug 22.
• [12] Cytotoxic, genotoxic, and oxidative stress-inducing effect of an l-amino acid oxidase isolated from Bothrops jararacussu venom in a co-culture model of HepG2 and HUVEC cells.Int J Biol Macromol. 2019 Apr 15;127:425-432. doi: 10.1016/j.ijbiomac.2019.01.059. Epub 2019 Jan 15.
• [13] Synergistic antibacterial effect of co-administering adipose-derived mesenchymal stromal cells and Ophiophagus hannah L-amino acid oxidase in a mouse model of methicillin-resistant Staphylococcus aureus-infected wounds.Stem Cell Res Ther. 2017 Jan 23;8(1):5. doi: 10.1186/s13287-016-0457-2.
• [14] Identification of a two-loci epistatic interaction associated with susceptibility to rheumatoid arthritis through reverse engineering and multifactor dimensionality reduction.Genomics. 2007 Jul;90(1):6-13. doi: 10.1016/j.ygeno.2007.03.011. Epub 2007 May 4.
• [15] Dichotomy between factors inducing the immunosuppressive enzyme IL-4-induced gene 1 (IL4I1) in B lymphocytes and mononuclear phagocytes.Eur J Immunol. 2010 Sep;40(9):2557-68. doi: 10.1002/eji.201040428.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [19] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [20] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [21] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.