Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHT5DW0)

• DOT Name: Ral GTPase-activating protein subunit alpha-1 (RALGAPA1)
• Synonyms: GAP-related-interacting partner to E12; GRIPE; GTPase-activating Rap/Ran-GAP domain-like 1; Tuberin-like protein 1; p240
• Gene Name: RALGAPA1
• Related Disease:
  Holoprosencephaly
  Intellectual disability
  Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation
  Complex neurodevelopmental disorder
  Glioblastoma multiforme
• UniProt ID: RGPA1_HUMAN
• Pfam ID: PF20412 ; PF02145
• Sequence:
  MFSKKPHGDVKKSTQKVLDTKKDALTRLKHLRIVIENAESIDLKQFFDQHFSHIYYVFFE
  NFVTIEASLKQKGHKSQREELDAILFIFEKILQLLPERIHQRWQFHSIGLILKKLLHTGN
  SLKIRREGVRLFLLWLQALQNNCSKEQLWMFSCLIPGFSAPQSEHGPRTLDNLINPPLNL
  QETQVTIEEITPLVPPQSGDKGQEDLTSYFLEALLKYIVIQVKSLEWKNKENQERGFSFL
  FSHFKKYYLPYIFPNICKENSLYHPILDIPQMRPKPHYVVIKKDAETNEAIYCTKEPFIK
  ARVIVIRWLVSFWLEPKPHTGPHIPGMEGEVLPKNIQRAAASLVSREESKNDNADKTDRT
  TEPEQSHSNTSTLTEREPSSSSLCSIDEEHLTDIEIVRRVFSSKRSNVNFVTEIFRQAFL
  LPICEAAAMRKVVKVYQEWIQQEEKPLFMQEPEEIVITSSDLPCIENVTDHDISMEEGEK
  REEENGTNTADHVRNSSWAKNGSYQGALHNASEEATEQNIRAGTQAVLQVFIINSSNIFL
  LEPANEIKNLLDEHTDMCKRILNIYRYMVVQVSMDKKTWEQMLLVLLRVTESVLKMPSQA
  FLQFQGKKNMTLAGRLAGPLFQTLIVAWIKANLNVYISRELWDDLLSVLSSLTYWEELAT
  EWSLTMETLTKVLARNLYSLDLSDLPLDKLSEQKQKKHKGKGVGHEFQKVSVDKSFSRGW
  SRDQPGQAPMRQRSATTTGSPGTEKARSIVRQKTVDIDDAQILPRSTRVRHFSQSEETGN
  EVFGALNEEQPLPRSSSTSDILEPFTVERAKVNKEDMSQKLPPLNSDIGGSSANVPDLMD
  EFIAERLRSGNASTMTRRGSSPGSLEIPKDLPDILNKQNQMRPIDDPGVPSEWTSPASAG
  SSDLISSDSHSDSFSAFQYDGRKFDNFGFGTDTGVTSSADVDSGSGHHQSAEEQEVASLT
  TLHIDSETSSLNQQAFSAEVATITGSESASPVHSPLGSRSQTPSPSTLNIDHMEQKDLQL
  DEKLHHSVLQTPDDLEISEFPSECCSVMAGGTLTGWHADVATVMWRRMLGILGDVNSIMD
  PEIHAQVFDYLCELWQNLAKIRDNLGISTDNLTSPSPPVLIPPLRILTPWLFKATMLTDK
  YKQGKLHAYKLICNTMKRRQDVSPNRDFLTHFYNIMHCGLLHIDQDIVNTIIKHCSPQFF
  SLGLPGATMLIMDFIVAAGRVASSAFLNAPRVEAQVLLGSLVCFPNLYCELPSLHPNIPD
  VAVSQFTDVKELIIKTVLSSARDEPSGPARCVALCSLGIWICEELVHESHHPQIKEALNV
  ICVSLKFTNKTVAHVACNMLHMLVHYVPRLQIYQPDSPLKIIQILIATITHLLPSTEASS
  YEMDKRLVVSLLLCLLDWIMALPLKTLLQPFHATGAESDKTEKSVLNCIYKVLHGCVYGA
  QCFSNPRYFPMSLSDLASVDYDPFMHLESLKEPEPLHSPDSERSSKLQPVTEVKTQMQHG
  LISIAARTVITHLVNHLGHYPMSGGPAMLTSQVCENHDNHYSESTELSPELFESPNIQFF
  VLNNTTLVSCIQIRSEENMPGGGLSAGLASANSNVRIIVRDLSGKYSWDSAILYGPPPVS
  GLSEPTSFMLSLSHQEKPEEPPTSNECLEDITVKDGLSLQFKRFRETVPTWDTIRDEEDV
  LDELLQYLGVTSPECLQRTGISLNIPAPQPVCISEKQENDVINAILKQHTEEKEFVEKHF
  NDLNMKAVEQDEPIPQKPQSAFYYCRLLLSILGMNSWDKRRSFHLLKKNEKLLRELRNLD
  SRQCRETHKIAVFYVAEGQEDKHSILTNTGGSQAYEDFVAGLGWEVNLTNHCGFMGGLQK
  NKSTGLTTPYFATSTVEVIFHVSTRMPSDSDDSLTKKLRHLGNDEVHIVWSEHTRDYRRG
  IIPTEFGDVLIVIYPMKNHMFSIQIMKKPEVPFFGPLFDGAIVNGKVLPIMVRATAINAS
  RALKSLIPLYQNFYEERARYLQTIVQHHLEPTTFEDFAAQVFSPAPYHHLPSDADH
• Function: Catalytic subunit of the heterodimeric RalGAP1 complex which acts as a GTPase activator for the Ras-like small GTPases RALA and RALB.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Ras sig.ling pathway (hsa04014)
• Reactome Pathway: RHOH GTPase cycle (R-HSA-9013407)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Holoprosencephaly	DISR35EC	Definitive	Biomarker	[1]
Intellectual disability	DISMBNXP	Strong	Biomarker	[2]
Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation	DIS5KBG8	Strong	Autosomal recessive	[3]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal dominant	[4]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Ral GTPase-activating protein subunit alpha-1 (RALGAPA1).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Ral GTPase-activating protein subunit alpha-1 (RALGAPA1).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Ral GTPase-activating protein subunit alpha-1 (RALGAPA1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ral GTPase-activating protein subunit alpha-1 (RALGAPA1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ral GTPase-activating protein subunit alpha-1 (RALGAPA1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ral GTPase-activating protein subunit alpha-1 (RALGAPA1).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Ral GTPase-activating protein subunit alpha-1 (RALGAPA1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ral GTPase-activating protein subunit alpha-1 (RALGAPA1).	[11]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Ral GTPase-activating protein subunit alpha-1 (RALGAPA1).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ral GTPase-activating protein subunit alpha-1 (RALGAPA1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ral GTPase-activating protein subunit alpha-1 (RALGAPA1).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Ral GTPase-activating protein subunit alpha-1 (RALGAPA1).	[15]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Ral GTPase-activating protein subunit alpha-1 (RALGAPA1).	[17]

References

• [1] 14q13.1-21.1 deletion encompassing the HPE8 locus in an adolescent with intellectual disability and bilateral microphthalmia, but without holoprosencephaly.Am J Med Genet A. 2012 Jun;158A(6):1427-33. doi: 10.1002/ajmg.a.35334. Epub 2012 May 11.
• [2] Bi-allelic Variants in RALGAPA1 Cause Profound Neurodevelopmental Disability, Muscular Hypotonia, Infantile Spasms, and Feeding Abnormalities.Am J Hum Genet. 2020 Feb 6;106(2):246-255. doi: 10.1016/j.ajhg.2020.01.002. Epub 2020 Jan 30.
• [3] TULIP1 (RALGAPA1) haploinsufficiency with brain development delay. Genomics. 2009 Dec;94(6):414-22. doi: 10.1016/j.ygeno.2009.08.015. Epub 2009 Sep 3.
• [4] 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.
• [5] Overexpression of mTOR and p(240-244)S6 in IDH1 Wild-Type Human Glioblastomas Is Predictive of Low Survival.J Histochem Cytochem. 2018 Jun;66(6):403-414. doi: 10.1369/0022155417750838. Epub 2018 Jan 12.
• [6] 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.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [12] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [15] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [16] 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.
• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.