Details of Drug Off-Target (DOT)

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

• DOT Name: Ras-related GTP-binding protein D (RRAGD)
• Synonyms: Rag D; RagD; EC 3.6.5.-
• Gene Name: RRAGD
• Related Disease: Hypomagnesemia 7, renal, with or without dilated cardiomyopathy
• UniProt ID: RRAGD_HUMAN
• PDB ID: 2Q3F
• EC Number: 3.6.5.-
• Pfam ID: PF04670
• Sequence:
  MSQVLGKPQPQDEDDAEEEEEEDELVGLADYGDGPDSSDADPDSGTEEGVLDFSDPFSTE
  VKPRILLMGLRRSGKSSIQKVVFHKMSPNETLFLESTNKICREDVSNSSFVNFQIWDFPG
  QIDFFDPTFDYEMIFRGTGALIFVIDSQDDYMEALARLHLTVTRAYKVNTDINFEVFIHK
  VDGLSDDHKIETQRDIHQRANDDLADAGLEKIHLSFYLTSIYDHSIFEAFSKVVQKLIPQ
  LPTLENLLNIFISNSGIEKAFLFDVVSKIYIATDSTPVDMQTYELCCDMIDVVIDISCIY
  GLKEDGAGTPYDKESTAIIKLNNTTVLYLKEVTKFLALVCFVREESFERKGLIDYNFHCF
  RKAIHEVFEVRMKVVKSRKVQNRLQKKKRATPNGTPRVLL
• Function: Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade. Forms heterodimeric Rag complexes with RagA/RRAGA or RagB/RRAGB and cycles between an inactive GTP-bound and an active GDP-bound form: RagD/RRAGD is in its active form when GDP-bound RagD/RRAGD forms a complex with GTP-bound RagA/RRAGA (or RagB/RRAGB) and in an inactive form when GTP-bound RagD/RRAGD heterodimerizes with GDP-bound RagA/RRAGA (or RagB/RRAGB). In its active form, promotes the recruitment of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB. This is a crucial step in the activation of the MTOR signaling cascade by amino acids. Also plays a central role in the non-canonical mTORC1 complex, which acts independently of RHEB and specifically mediates phosphorylation of MiT/TFE factors TFEB and TFE3: GDP-bound RagD/RRAGD mediates recruitment of MiT/TFE factors TFEB and TFE3.
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  mTOR sig.ling pathway (hsa04150)
  Shigellosis (hsa05131)
• Reactome Pathway:
  MTOR signalling (R-HSA-165159)
  mTORC1-mediated signalling (R-HSA-166208)
  Energy dependent regulation of mTOR by LKB1-AMPK (R-HSA-380972)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Amino acids regulate mTORC1 (R-HSA-9639288)
  Macroautophagy (R-HSA-1632852)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypomagnesemia 7, renal, with or without dilated cardiomyopathy	DISWP1UK	Strong	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Ras-related GTP-binding protein D (RRAGD) increases the response to substance of Cisplatin.	[23]
Mitoxantrone	DMM39BF	Approved	Ras-related GTP-binding protein D (RRAGD) affects the response to substance of Mitoxantrone.	[24]

2 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 Ras-related GTP-binding protein D (RRAGD).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ras-related GTP-binding protein D (RRAGD).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ras-related GTP-binding protein D (RRAGD).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ras-related GTP-binding protein D (RRAGD).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras-related GTP-binding protein D (RRAGD).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ras-related GTP-binding protein D (RRAGD).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Ras-related GTP-binding protein D (RRAGD).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Ras-related GTP-binding protein D (RRAGD).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Ras-related GTP-binding protein D (RRAGD).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Ras-related GTP-binding protein D (RRAGD).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Ras-related GTP-binding protein D (RRAGD).	[11]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Ras-related GTP-binding protein D (RRAGD).	[12]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Ras-related GTP-binding protein D (RRAGD).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ras-related GTP-binding protein D (RRAGD).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Ras-related GTP-binding protein D (RRAGD).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ras-related GTP-binding protein D (RRAGD).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ras-related GTP-binding protein D (RRAGD).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ras-related GTP-binding protein D (RRAGD).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ras-related GTP-binding protein D (RRAGD).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Ras-related GTP-binding protein D (RRAGD).	[21]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Ras-related GTP-binding protein D (RRAGD).	[22]

References

• [1] mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy. J Am Soc Nephrol. 2021 Nov;32(11):2885-2899. doi: 10.1681/ASN.2021030333. Epub 2021 Oct 4.
• [2] 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.
• [3] 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.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] 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.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [10] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [13] Capsaicin inhibits the migration, invasion and EMT of renal cancer cells by inducing AMPK/mTOR-mediated autophagy. Chem Biol Interact. 2022 Oct 1;366:110043. doi: 10.1016/j.cbi.2022.110043. Epub 2022 Aug 28.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [16] 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.
• [17] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [18] 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.
• [19] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] 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.
• [23] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.
• [24] Prediction of doxorubicin sensitivity in breast tumors based on gene expression profiles of drug-resistant cell lines correlates with patient survival. Oncogene. 2005 Nov 17;24(51):7542-51. doi: 10.1038/sj.onc.1208908.