Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBIGB1D)

• DOT Name: RalA-binding protein 1 (RALBP1)
• Synonyms: RalBP1; 76 kDa Ral-interacting protein; Dinitrophenyl S-glutathione ATPase; DNP-SG ATPase; EC 7.6.2.2, EC 7.6.2.3; Ral-interacting protein 1
• Gene Name: RALBP1
• UniProt ID: RBP1_HUMAN
• PDB ID: 2KWH; 2KWI; 2MBG; 6ZQT; 6ZRN
• EC Number: 7.6.2.2; 7.6.2.3
• Pfam ID: PF00620 ; PF20924
• Sequence:
  MTECFLPPTSSPSEHRRVEHGSGLTRTPSSEEISPTKFPGLYRTGEPSPPHDILHEPPDV
  VSDDEKDHGKKKGKFKKKEKRTEGYAAFQEDSSGDEAESPSKMKRSKGIHVFKKPSFSKK
  KEKDFKIKEKPKEEKHKEEKHKEEKHKEKKSKDLTAADVVKQWKEKKKKKKPIQEPEVPQ
  IDVPNLKPIFGIPLADAVERTMMYDGIRLPAVFRECIDYVEKYGMKCEGIYRVSGIKSKV
  DELKAAYDREESTNLEDYEPNTVASLLKQYLRDLPENLLTKELMPRFEEACGRTTETEKV
  QEFQRLLKELPECNYLLISWLIVHMDHVIAKELETKMNIQNISIVLSPTVQISNRVLYVF
  FTHVQELFGNVVLKQVMKPLRWSNMATMPTLPETQAGIKEEIRRQEFLLNCLHRDLQGGI
  KDLSKEERLWEVQRILTALKRKLREAKRQECETKIAQEIASLSKEDVSKEEMNENEEVIN
  ILLAQENEILTEQEELLAMEQFLRRQIASEKEEIERLRAEIAEIQSRQQHGRSETEEYSS
  ESESESEDEEELQIILEDLQRQNEELEIKNNHLNQAIHEEREAIIELRVQLRLLQMQRAK
  AEQQAQEDEEPEWRGGAVQPPRDGVLEPKAAKEQPKAGKEPAKPSPSRDRKETSI
• Function: Multifunctional protein that functions as a downstream effector of RALA and RALB. As a GTPase-activating protein/GAP can inactivate CDC42 and RAC1 by stimulating their GTPase activity. As part of the Ral signaling pathway, may also regulate ligand-dependent EGF and insulin receptors-mediated endocytosis. During mitosis, may act as a scaffold protein in the phosphorylation of EPSIN/EPN1 by the mitotic kinase cyclin B-CDK1, preventing endocytosis during that phase of the cell cycle. During mitosis, also controls mitochondrial fission as an effector of RALA. Recruited to mitochondrion by RALA, acts as a scaffold to foster the mitotic kinase cyclin B-CDK1-mediated phosphorylation and activation of DNM1L ; Could also function as a primary ATP-dependent active transporter for glutathione conjugates of electrophiles. May also actively catalyze the efflux of a wide range of substrates including xenobiotics like doxorubicin (DOX) contributing to cell multidrug resistance.
• Tissue Specificity: Expressed ubiquitously but at low levels. Shows a strong expression in the erythrocytes.
• KEGG Pathway:
  Ras sig.ling pathway (hsa04014)
  Pathways in cancer (hsa05200)
  Pancreatic cancer (hsa05212)
• Reactome Pathway:
  RAC1 GTPase cycle (R-HSA-9013149)
  CDC42 GTPase cycle (R-HSA-9013148)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	RalA-binding protein 1 (RALBP1) decreases the response to substance of Doxorubicin.	[13]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	RalA-binding protein 1 (RALBP1) decreases the response to substance of 4-hydroxy-2-nonenal.	[13]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Colchicine	DM2POTE	Approved	RalA-binding protein 1 (RALBP1) affects the transport of Colchicine.	[14]
LTC4	DM702WR	Investigative	RalA-binding protein 1 (RALBP1) affects the transport of LTC4.	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of RalA-binding protein 1 (RALBP1).	[1]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of RalA-binding protein 1 (RALBP1).	[3]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of RalA-binding protein 1 (RALBP1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of RalA-binding protein 1 (RALBP1).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of RalA-binding protein 1 (RALBP1).	[3]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of RalA-binding protein 1 (RALBP1).	[3]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of RalA-binding protein 1 (RALBP1).	[11]
RO-316233	DMAGLPW	Investigative	RO-316233 decreases the phosphorylation of RalA-binding protein 1 (RALBP1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of RalA-binding protein 1 (RALBP1).	[2]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of RalA-binding protein 1 (RALBP1).	[4]
Selenium	DM25CGV	Approved	Selenium decreases the expression of RalA-binding protein 1 (RALBP1).	[5]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of RalA-binding protein 1 (RALBP1).	[7]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of RalA-binding protein 1 (RALBP1).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of RalA-binding protein 1 (RALBP1).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of RalA-binding protein 1 (RALBP1).	[10]

References

• [1] 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.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] 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.
• [4] A comprehensive analysis of Wnt/beta-catenin signaling pathway-related genes and crosstalk pathways in the treatment of As2O3 in renal cancer. Ren Fail. 2018 Nov;40(1):331-339.
• [5] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [6] 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.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [9] 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.
• [10] 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.
• [11] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
• [12] The role of PKCalpha and RLIP76 in transport-mediated doxorubicin-resistance in lung cancer. FEBS Lett. 2005 Aug 29;579(21):4635-41. doi: 10.1016/j.febslet.2005.07.032.
• [13] Depletion of RLIP76 sensitizes lung cancer cells to doxorubicin. Biochem Pharmacol. 2005 Aug 1;70(3):481-8. doi: 10.1016/j.bcp.2005.05.005.
• [14] RLIP76 (RALBP1)-mediated transport of leukotriene C4 (LTC4) in cancer cells: implications in drug resistance. Int J Cancer. 2004 Dec 20;112(6):934-42. doi: 10.1002/ijc.20516.