Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK43VNA)

• DOT Name: E3 ubiquitin-protein ligase MARCHF4 (MARCHF4)
• Synonyms: EC 2.3.2.27; Membrane-associated RING finger protein 4; Membrane-associated RING-CH protein IV; MARCH-IV; RING finger protein 174; RING-type E3 ubiquitin transferase MARCHF4
• Gene Name: MARCHF4
• Related Disease:
  Advanced cancer
  Migraine disorder
  Acute myelogenous leukaemia
• UniProt ID: MARH4_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF12906
• Sequence:
  MLMPLCGLLWWWWCCCSGWYCYGLCAPAPQMLRHQGLLKCRCRMLFNDLKVFLLRRPPQA
  PLPMHGDPQPPGLAANNTLPALGAGGWAGWRGPREVVGREPPPVPPPPPLPPSSVEDDWG
  GPATEPPASLLSSASSDDFCKEKTEDRYSLGSSLDSGMRTPLCRICFQGPEQGELLSPCR
  CDGSVKCTHQPCLIKWISERGCWSCELCYYKYHVIAISTKNPLQWQAISLTVIEKVQVAA
  AILGSLFLIASISWLIWSTFSPSARWQRQDLLFQICYGMYGFMDVVCIGLIIHEGPSVYR
  IFKRWQAVNQQWKVLNYDKTKDLEDQKAGGRTNPRTSSSTQANIPSSEEETAGTPAPEQG
  PAQAAGHPSGPLSHHHCAYTILHILSHLRPHEQRSPPGSSRELVMRVTTV
• Function: E3 ubiquitin-protein ligase that may mediate ubiquitination of MHC-I and CD4, and promote their subsequent endocytosis and sorting to lysosomes via multivesicular bodies. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates.
• Tissue Specificity: Expressed in brain and placenta.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Migraine disorder	DISFCQTG	Strong	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[3]

9 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 E3 ubiquitin-protein ligase MARCHF4 (MARCHF4).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of E3 ubiquitin-protein ligase MARCHF4 (MARCHF4).	[5]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of E3 ubiquitin-protein ligase MARCHF4 (MARCHF4).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of E3 ubiquitin-protein ligase MARCHF4 (MARCHF4).	[8]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of E3 ubiquitin-protein ligase MARCHF4 (MARCHF4).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of E3 ubiquitin-protein ligase MARCHF4 (MARCHF4).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of E3 ubiquitin-protein ligase MARCHF4 (MARCHF4).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of E3 ubiquitin-protein ligase MARCHF4 (MARCHF4).	[12]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of E3 ubiquitin-protein ligase MARCHF4 (MARCHF4).	[13]

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 E3 ubiquitin-protein ligase MARCHF4 (MARCHF4).	[7]

References

• [1] Cancer risk susceptibility loci in a Swedish population.Oncotarget. 2017 Nov 25;8(66):110300-110310. doi: 10.18632/oncotarget.22687. eCollection 2017 Dec 15.
• [2] Genome-wide association analysis identifies susceptibility loci for migraine without aura.Nat Genet. 2012 Jun 10;44(7):777-82. doi: 10.1038/ng.2307.
• [3] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [6] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [7] 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.
• [8] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [9] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [10] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [11] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [12] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [13] 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.