Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD229X7)

• DOT Name: Molecule interacting with CasL protein 3 (MICAL-3)
• Synonyms: EC 1.14.13.225; Molecule interacting with CasL protein 3; MICAL-3
• Gene Name: MICAL3
• Related Disease:
  Chronic obstructive pulmonary disease
  Ciliopathy
  Osteoarthritis
  Pancreatic cancer
  Breast cancer
  Breast carcinoma
  Neoplasm
• UniProt ID: MICA3_HUMAN
• PDB ID: 2D88; 5SZG; 6ICI
• EC Number: 1.14.13.225
• Pfam ID: PF12130 ; PF00307 ; PF01494 ; PF00412
• Sequence:
  MEERKHETMNPAHVLFDRFVQATTCKGTLKAFQELCDHLELKPKDYRSFYHKLKSKLNYW
  KAKALWAKLDKRGSHKDYKKGKACTNTKCLIIGAGPCGLRTAIDLSLLGAKVVVIEKRDA
  FSRNNVLHLWPFTIHDLRGLGAKKFYGKFCAGAIDHISIRQLQLILLKVALILGIEIHVN
  VEFQGLIQPPEDQENERIGWRALVHPKTHPVSEYEFEVIIGGDGRRNTLEGFRRKEFRGK
  LAIAITANFINRNTTAEAKVEEISGVAFIFNQKFFQELREATGIDLENIVYYKDDTHYFV
  MTAKKQSLLDKGVILHDYADTELLLSRENVDQEALLSYAREAADFSTQQQLPSLDFAINH
  YGQPDVAMFDFTCMYASENAALVREQNGHQLLVALVGDSLLEPFWPMGTGIARGFLAAMD
  SAWMVRSWSLGTSPLEVLAERESIYRLLPQTTPENVSKNFSQYSIDPVTRYPNINVNFLR
  PSQVRHLYDTGETKDIHLEMESLVNSRTTPKLTRNESVARSSKLLGWCQRQTDGYAGVNV
  TDLTMSWKSGLALCAIIHRYRPDLIDFDSLDEQNVEKNNQLAFDIAEKELGISPIMTGKE
  MASVGEPDKLSMVMYLTQFYEMFKDSLPSSDTLDLNAEEKAVLIASTRSPISFLSKLGQT
  ISRKRSPKDKKEKDLDGAGKRRKTSQSEEEEAPRGHRGERPTLVSTLTDRRMDVAVGNQN
  KVKYMATQLLAKFEENAPAQSIGIRRQGSMKKEFPQNLGGSDTCYFCQKRVYVMERLSAE
  GKFFHRSCFKCEYCATTLRLSAYAYDIEDGKFYCKPHYCYRLSGYAQRKRPAVAPLSGKE
  AKGPLQDGATTDANGRANAVASSTERTPGSGVNGLEEPSIAKRLRGTPERIELENYRLSL
  RQAEALQEVPEETQAEHNLSSVLDTGAEEDVASSSSESEMEEEGEEEEEEPRLPPSDLGG
  VPWKEAVRIHALLKGKSEEELEASKSFGPGNEEEEEEEEEYEEEEEEDYDEEEEESSEAG
  NQRLQQVMHAADPLEIQADVHWTHIREREEEERMAPASESSASGAPLDENDLEEDVDSEP
  AEIEGEAAEDGDPGDTGAELDDDQHWSDSPSDADRELRLPCPAEGEAELELRVSEDEEKL
  PASPKHQERGPSQATSPIRSPQESALLFIPVHSPSTEGPQLPPVPAATQEKSPEERLFPE
  PLLPKEKPKADAPSDLKAVHSPIRSQPVTLPEARTPVSPGSPQPQPPVAASTPPPSPLPI
  CSQPQPSTEATVPSPTQSPIRFQPAPAKTSTPLAPLPVQSQSDTKDRLGSPLAVDEALRR
  SDLVEEFWMKSAEIRRSLGLTPVDRSKGPEPSFPTPAFRPVSLKSYSVEKSPQDEGLHLL
  KPLSIPKRLGLPKPEGEPLSLPTPRSPSDRELRSAQEERRELSSSSGLGLHGSSSNMKTL
  GSQSFNTSDSAMLTPPSSPPPPPPPGEEPATLRRKLREAEPNASVVPPPLPATWMRPPRE
  PAQPPREEVRKSFVESVEEIPFADDVEDTYDDKTEDSSLQEKFFTPPSCWPRPEKPRHPP
  LAKENGRLPALEGTLQPQKRGLPLVSAEAKELAEERMRAREKSVKSQALRDAMARQLSRM
  QQMELASGAPRPRKASSAPSQGKERRPDSPTRPTLRGSEEPTLKHEATSEEVLSPPSDSG
  GPDGSFTSSEGSSGKSKKRSSLFSPRRNKKEKKSKGEGRPPEKPSSNLLEEAAAKPKSLW
  KSVFSGYKKDKKKKADDKSCPSTPSSGATVDSGKHRVLPVVRAELQLRRQLSFSEDSDLS
  SDDVLEKSSQKSRREPRTYTEEELNAKLTRRVQKAARRQAKQEELKRLHRAQIIQRQLQQ
  VEERQRRLEERGVAVEKALRGEAGMGKKDDPKLMQEWFKLVQEKNAMVRYESELMIFARE
  LELEDRQSRLQQELRERMAVEDHLKTEEELSEEKQILNEMLEVVEQRDSLVALLEEQRLR
  EREEDKDLEAAMLSKGFSLNWS
• Function: Monooxygenase that promotes depolymerization of F-actin by mediating oxidation of specific methionine residues on actin to form methionine-sulfoxide, resulting in actin filament disassembly and preventing repolymerization. In the absence of actin, it also functions as a NADPH oxidase producing H(2)O(2). Seems to act as Rab effector protein and plays a role in vesicle trafficking. Involved in exocytic vesicles tethering and fusion: the monooxygenase activity is required for this process and implicates RAB8A associated with exocytotic vesicles. Required for cytokinesis. Contributes to stabilization and/or maturation of the intercellular bridge independently of its monooxygenase activity. Promotes recruitment of Rab8 and ERC1 to the intercellular bridge, and together these proteins are proposed to function in timely abscission.
• Tissue Specificity: Ubiquitous.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[1]
Ciliopathy	DIS10G4I	Strong	Genetic Variation	[2]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[3]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	moderate	Biomarker	[5]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[5]
Neoplasm	DISZKGEW	moderate	Altered Expression	[5]

15 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 Molecule interacting with CasL protein 3 (MICAL-3).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Molecule interacting with CasL protein 3 (MICAL-3).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Molecule interacting with CasL protein 3 (MICAL-3).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Molecule interacting with CasL protein 3 (MICAL-3).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Molecule interacting with CasL protein 3 (MICAL-3).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Molecule interacting with CasL protein 3 (MICAL-3).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Molecule interacting with CasL protein 3 (MICAL-3).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Molecule interacting with CasL protein 3 (MICAL-3).	[13]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Molecule interacting with CasL protein 3 (MICAL-3).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Molecule interacting with CasL protein 3 (MICAL-3).	[15]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Molecule interacting with CasL protein 3 (MICAL-3).	[16]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Molecule interacting with CasL protein 3 (MICAL-3).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Molecule interacting with CasL protein 3 (MICAL-3).	[18]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Molecule interacting with CasL protein 3 (MICAL-3).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Molecule interacting with CasL protein 3 (MICAL-3).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Molecule interacting with CasL protein 3 (MICAL-3).	[21]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Molecule interacting with CasL protein 3 (MICAL-3).	[22]

References

• [1] Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.Nat Genet. 2019 Mar;51(3):494-505. doi: 10.1038/s41588-018-0342-2. Epub 2019 Feb 25.
• [2] The Ciliopathy Protein CC2D2A Associates with NINL and Functions in RAB8-MICAL3-Regulated Vesicle Trafficking.PLoS Genet. 2015 Oct 20;11(10):e1005575. doi: 10.1371/journal.pgen.1005575. eCollection 2015 Oct.
• [3] Allelic expression analysis of the osteoarthritis susceptibility locus that maps to MICAL3.BMC Med Genet. 2012 Mar 2;13:12. doi: 10.1186/1471-2350-13-12.
• [4] Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer.Nat Commun. 2018 Feb 8;9(1):556. doi: 10.1038/s41467-018-02942-5.
• [5] Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells.Proc Natl Acad Sci U S A. 2019 Jan 8;116(2):625-630. doi: 10.1073/pnas.1806851116. Epub 2018 Dec 26.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [13] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [20] 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.
• [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] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.