Details of Drug Off-Target (DOT)

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

• DOT Name: Probable E3 ubiquitin-protein ligase MID2 (MID2)
• Synonyms: EC 2.3.2.27; Midin-2; Midline defect 2; Midline-2; RING finger protein 60; RING-type E3 ubiquitin transferase MID2; Tripartite motif-containing protein 1
• Gene Name: MID2
• Related Disease:
  Intellectual disability, X-linked 1
  FG syndrome
  X-linked intellectual disability
  X-linked Opitz G/BBB syndrome
  Intellectual disability
  Non-syndromic X-linked intellectual disability
  Intellectual disability, X-linked 101
• UniProt ID: TRIM1_HUMAN
• PDB ID: 2DJA; 2DMK; 7QRZ
• EC Number: 2.3.2.27
• Pfam ID: PF18568 ; PF00622 ; PF00643 ; PF13445
• Sequence:
  MGESPASVVLNASGGLFSLKMETLESELTCPICLELFEDPLLLPCAHSLCFSCAHRILVS
  SCSSGESIEPITAFQCPTCRYVISLNHRGLDGLKRNVTLQNIIDRFQKASVSGPNSPSES
  RRERTYRPTTAMSSERIACQFCEQDPPRDAVKTCITCEVSYCDRCLRATHPNKKPFTSHR
  LVEPVPDTHLRGITCLDHENEKVNMYCVSDDQLICALCKLVGRHRDHQVASLNDRFEKLK
  QTLEMNLTNLVKRNSELENQMAKLIQICQQVEVNTAMHEAKLMEECDELVEIIQQRKQMI
  AVKIKETKVMKLRKLAQQVANCRQCLERSTVLINQAEHILKENDQARFLQSAKNIAERVA
  MATASSQVLIPDINFNDAFENFALDFSREKKLLEGLDYLTAPNPPSIREELCTASHDTIT
  VHWISDDEFSISSYELQYTIFTGQANFISKSWCSWGLWPEIRKCKEAVSCSRLAGAPRGL
  YNSVDSWMIVPNIKQNHYTVHGLQSGTRYIFIVKAINQAGSRNSEPTRLKTNSQPFKLDP
  KMTHKKLKISNDGLQMEKDESSLKKSHTPERFSGTGCYGAAGNIFIDSGCHYWEVVMGSS
  TWYAIGIAYKSAPKNEWIGKNASSWVFSRCNSNFVVRHNNKEMLVDVPPHLKRLGVLLDY
  DNNMLSFYDPANSLHLHTFDVTFILPVCPTFTIWNKSLMILSGLPAPDFIDYPERQECNC
  RPQESPYVSGMKTCH
• Function: E3 ubiquitin ligase that plays a role in microtubule stabilization. Mediates the 'Lys-48'-linked polyubiquitination of LRRK2 to drive its localization to microtubules and its proteasomal degradation in neurons. This ubiquitination inhibits LRRK2 kinase activation by RAB29.
• Tissue Specificity: Low level in fetal kidney and lung, and in adult prostate, ovary and small intestine.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, X-linked 1	DISET38E	Definitive	GermlineCausalMutation	[1]
FG syndrome	DIS2MEFU	Strong	Biomarker	[2]
X-linked intellectual disability	DISYJBY3	Strong	Genetic Variation	[1]
X-linked Opitz G/BBB syndrome	DISQ14EC	Strong	Biomarker	[3]
Intellectual disability	DISMBNXP	moderate	Biomarker	[1]
Non-syndromic X-linked intellectual disability	DIS71AI3	Supportive	X-linked	[1]
Intellectual disability, X-linked 101	DISA0LAP	Limited	Unknown	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Probable E3 ubiquitin-protein ligase MID2 (MID2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Probable E3 ubiquitin-protein ligase MID2 (MID2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Probable E3 ubiquitin-protein ligase MID2 (MID2).	[6]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Probable E3 ubiquitin-protein ligase MID2 (MID2).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Probable E3 ubiquitin-protein ligase MID2 (MID2).	[9]

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 affects the methylation of Probable E3 ubiquitin-protein ligase MID2 (MID2).	[8]

References

• [1] Targeted deep resequencing identifies MID2 mutation for X-linked intellectual disability with varied disease severity in a large kindred from India. Hum Mutat. 2014 Jan;35(1):41-4. doi: 10.1002/humu.22453. Epub 2013 Oct 21.
• [2] An Xq22.3 duplication detected by comparative genomic hybridization microarray (Array-CGH) defines a new locus (FGS5) for FG syndrome.Am J Med Genet A. 2005 Dec 15;139(3):221-6. doi: 10.1002/ajmg.a.30991.
• [3] MID1 and MID2 homo- and heterodimerise to tether the rapamycin-sensitive PP2A regulatory subunit, alpha 4, to microtubules: implications for the clinical variability of X-linked Opitz GBBB syndrome and other developmental disorders.BMC Cell Biol. 2002;3:1. doi: 10.1186/1471-2121-3-1. Epub 2002 Jan 4.
• [4] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [5] 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.
• [6] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [7] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [8] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [9] 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.