Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS7YVHF)

• DOT Name: Gamma-aminobutyric acid receptor-associated protein-like 2 (GABARAPL2)
• Synonyms: GABA(A) receptor-associated protein-like 2; Ganglioside expression factor 2; GEF-2; General protein transport factor p16; Golgi-associated ATPase enhancer of 16 kDa; GATE-16; MAP1 light chain 3-related protein
• Gene Name: GABARAPL2
• Related Disease:
  Cytomegalovirus infection
  Diamond-Blackfan anemia
  Diamond-Blackfan anemia 1
  Parkinson disease
  Promyelocytic leukaemia
• UniProt ID: GBRL2_HUMAN
• PDB ID: 4CO7; 6H8C; 7LK3; 7YO8
• Pfam ID: PF02991
• Sequence:
  MKWMFKEDHSLEHRCVESAKIRAKYPDRVPVIVEKVSGSQIVDIDKRKYLVPSDITVAQF
  MWIIRKRIQLPSEKAIFLFVDKTVPQSSLTMGQLYEKEKDEDGFLYVAYSGENTFGF
• Function: Ubiquitin-like modifier involved in intra-Golgi traffic. Modulates intra-Golgi transport through coupling between NSF activity and SNAREs activation. It first stimulates the ATPase activity of NSF which in turn stimulates the association with GOSR1. Involved in autophagy. Plays a role in mitophagy which contributes to regulate mitochondrial quantity and quality by eliminating the mitochondria to a basal level to fulfill cellular energy requirements and preventing excess ROS production. Whereas LC3s are involved in elongation of the phagophore membrane, the GABARAP/GATE-16 subfamily is essential for a later stage in autophagosome maturation.
• Tissue Specificity: Ubiquitous. Expressed at high levels in the brain, heart, prostate, ovary, spleen and skeletal muscle. Expressed at very low levels in lung, thymus and small intestine.
• KEGG Pathway:
  FoxO sig.ling pathway (hsa04068)
  Autophagy - other (hsa04136)
  Mitophagy - animal (hsa04137)
  Autophagy - animal (hsa04140)
  NOD-like receptor sig.ling pathway (hsa04621)
  GABAergic sy.pse (hsa04727)
• Reactome Pathway:
  TBC/RABGAPs (R-HSA-8854214)
  Macroautophagy (R-HSA-1632852)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[1]
Diamond-Blackfan anemia	DISI2SNW	Strong	Biomarker	[2]
Diamond-Blackfan anemia 1	DISP4NUV	Strong	Biomarker	[2]
Parkinson disease	DISQVHKL	Strong	Biomarker	[3]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[4]

10 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 Gamma-aminobutyric acid receptor-associated protein-like 2 (GABARAPL2).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Gamma-aminobutyric acid receptor-associated protein-like 2 (GABARAPL2).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Gamma-aminobutyric acid receptor-associated protein-like 2 (GABARAPL2).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Gamma-aminobutyric acid receptor-associated protein-like 2 (GABARAPL2).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Gamma-aminobutyric acid receptor-associated protein-like 2 (GABARAPL2).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Gamma-aminobutyric acid receptor-associated protein-like 2 (GABARAPL2).	[10]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Gamma-aminobutyric acid receptor-associated protein-like 2 (GABARAPL2).	[11]
Trovafloxacin	DM6AN32	Approved	Trovafloxacin increases the expression of Gamma-aminobutyric acid receptor-associated protein-like 2 (GABARAPL2).	[12]
Chloroquine	DMSI5CB	Phase 3 Trial	Chloroquine increases the expression of Gamma-aminobutyric acid receptor-associated protein-like 2 (GABARAPL2).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Gamma-aminobutyric acid receptor-associated protein-like 2 (GABARAPL2).	[13]

References

• [1] Human cytomegalovirus hijacks the autophagic machinery and LC3 homologs in order to optimize cytoplasmic envelopment of mature infectious particles.Sci Rep. 2019 Mar 14;9(1):4560. doi: 10.1038/s41598-019-41029-z.
• [2] MicroRNA expression profiling of dibenzalacetone (DBA) treated intracellular amastigotes of Leishmania donovani.Exp Parasitol. 2018 Oct;193:5-19. doi: 10.1016/j.exppara.2018.07.018. Epub 2018 Aug 17.
• [3] A novel modelling mechanism of PAEL receptor and GABARAPL2 interaction involved in Parkinson's disease.Neurosci Lett. 2018 Apr 23;673:12-18. doi: 10.1016/j.neulet.2018.02.055. Epub 2018 Feb 26.
• [4] Induction of autophagy is a key component of all-trans-retinoic acid-induced differentiation in leukemia cells and a potential target for pharmacologic modulation.Exp Hematol. 2015 Sep;43(9):781-93.e2. doi: 10.1016/j.exphem.2015.04.012. Epub 2015 May 16.
• [5] 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.
• [6] 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.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 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.
• [11] Toxicoproteomics reveals an effect of clozapine on autophagy in human liver spheroids. Toxicol Mech Methods. 2023 Jun;33(5):401-410. doi: 10.1080/15376516.2022.2156005. Epub 2022 Dec 19.
• [12] TNF enhances trovafloxacin-induced in vitro hepatotoxicity by inhibiting protective autophagy. Toxicol Lett. 2021 May 15;342:73-84. doi: 10.1016/j.toxlet.2021.02.009. Epub 2021 Feb 17.
• [13] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.