Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNNWX7E)

• DOT Name: GEL complex subunit OPTI (RAB5IF)
• Synonyms: Obligate partner of TMCO1 insertase; Rab5-interacting protein; RIP5; Respirasome Complex Assembly Factor 1
• Gene Name: RAB5IF
• Related Disease:
  B-cell neoplasm
  Hepatocellular carcinoma
  Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome 2
• UniProt ID: RCAF1_HUMAN
• Pfam ID: PF07019
• Sequence:
  MSGGRRKEEPPQPQLANGALKVSVWSKVLRSDAAWEDKDEFLDVIYWFRQIIAVVLGVIW
  GVLPLRGFLGIAGFCLINAGVLYLYFSNYLQIDEEEYGGTWELTKEGFMTSFALFMVCVA
  DSFTTGHLDHLLHCHPL
• Function: Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes. The MPT complex takes over after the SEC61 complex: following membrane insertion of the first few transmembrane segments of proteins by the SEC61 complex, the MPT complex occludes the lateral gate of the SEC61 complex to promote insertion of subsequent transmembrane regions. Within the MPT complex, the GEL subcomplex may mediate insertion of transmembrane regions into the membrane. In addition to its role in multi-pass membrane insertion, RAB5IF/OPTI also acts as an assembly factor for mitochondrial respiratory complexes.
• Tissue Specificity: Expressed in embryonic stem cells and differentiated neuronal cells.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[1]
Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome 2	DISNV74J	Limited	Autosomal recessive	[2]

8 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 GEL complex subunit OPTI (RAB5IF).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of GEL complex subunit OPTI (RAB5IF).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of GEL complex subunit OPTI (RAB5IF).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of GEL complex subunit OPTI (RAB5IF).	[6]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of GEL complex subunit OPTI (RAB5IF).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of GEL complex subunit OPTI (RAB5IF).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of GEL complex subunit OPTI (RAB5IF).	[10]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of GEL complex subunit OPTI (RAB5IF).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of GEL complex subunit OPTI (RAB5IF).	[9]

References

• [1] The Pivotal Role of Long Noncoding RNA RAB5IF in the Proliferation of Hepatocellular Carcinoma Via LGR5 Mediated -Catenin and c-Myc Signaling.Biomolecules. 2019 Nov 8;9(11):718. doi: 10.3390/biom9110718.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [7] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [8] 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.
• [9] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [10] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [11] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.