Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZAMDO2)

• DOT Name: Repulsive guidance molecule A (RGMA)
• Synonyms: RGM domain family member A
• Gene Name: RGMA
• UniProt ID: RGMA_HUMAN
• PDB ID: 4UHY; 6Z3G
• Pfam ID: PF06534 ; PF06535
• Sequence:
  MQPPRERLVVTGRAGWMGMGRGAGRSALGFWPTLAFLLCSFPAATSPCKILKCNSEFWSA
  TSGSHAPASDDTPEFCAALRSYALCTRRTARTCRGDLAYHSAVHGIEDLMSQHNCSKDGP
  TSQPRLRTLPPAGDSQERSDSPEICHYEKSFHKHSATPNYTHCGLFGDPHLRTFTDRFQT
  CKVQGAWPLIDNNYLNVQVTNTPVLPGSAATATSKLTIIFKNFQECVDQKVYQAEMDELP
  AAFVDGSKNGGDKHGANSLKITEKVSGQHVEIQAKYIGTTIVVRQVGRYLTFAVRMPEEV
  VNAVEDWDSQGLYLCLRGCPLNQQIDFQAFHTNAEGTGARRLAAASPAPTAPETFPYETA
  VAKCKEKLPVEDLYYQACVFDLLTTGDVNFTLAAYYALEDVKMLHSNKDKLHLYERTRDL
  PGRAAAGLPLAPRPLLGALVPLLALLPVFC
• Function: Member of the repulsive guidance molecule (RGM) family that performs several functions in the developing and adult nervous system. Regulates cephalic neural tube closure, inhibits neurite outgrowth and cortical neuron branching, and the formation of mature synapses. Binding to its receptor NEO1/neogenin induces activation of RHOA-ROCK1/Rho-kinase signaling pathway through UNC5B-ARHGEF12/LARG-PTK2/FAK1 cascade, leading to collapse of the neuronal growth cone and neurite outgrowth inhibition. Furthermore, RGMA binding to NEO1/neogenin leads to HRAS inactivation by influencing HRAS-PTK2/FAK1-AKT1 pathway. It also functions as a bone morphogenetic protein (BMP) coreceptor that may signal through SMAD1, SMAD5, and SMAD8.
• KEGG Pathway:
  TGF-beta sig.ling pathway (hsa04350)
  Axon guidance (hsa04360)
• Reactome Pathway: Netrin-1 signaling (R-HSA-373752)

Molecular Interaction Atlas (MIA) of This DOT

5 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 Repulsive guidance molecule A (RGMA).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Repulsive guidance molecule A (RGMA).	[5]
Triclosan	DMZUR4N	Approved	Triclosan increases the methylation of Repulsive guidance molecule A (RGMA).	[7]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Repulsive guidance molecule A (RGMA).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Repulsive guidance molecule A (RGMA).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Repulsive guidance molecule A (RGMA).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Repulsive guidance molecule A (RGMA).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Repulsive guidance molecule A (RGMA).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Repulsive guidance molecule A (RGMA).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Repulsive guidance molecule A (RGMA).	[8]
Marinol	DM70IK5	Approved	Marinol increases the expression of Repulsive guidance molecule A (RGMA).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Repulsive guidance molecule A (RGMA).	[6]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Repulsive guidance molecule A (RGMA).	[11]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Repulsive guidance molecule A (RGMA).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Repulsive guidance molecule A (RGMA).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Repulsive guidance molecule A (RGMA).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Repulsive guidance molecule A (RGMA).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Repulsive guidance molecule A (RGMA).	[17]

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] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [3] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] 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.
• [7] Pregnancy exposure to synthetic phenols and placental DNA methylation - An epigenome-wide association study in male infants from the EDEN cohort. Environ Pollut. 2021 Dec 1;290:118024. doi: 10.1016/j.envpol.2021.118024. Epub 2021 Aug 21.
• [8] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [9] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [10] 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.
• [11] 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.
• [12] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [16] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [17] Epigenetic changes and disturbed neural development in a human embryonic stem cell-based model relating to the fetal valproate syndrome. Hum Mol Genet. 2012 Sep 15;21(18):4104-14. doi: 10.1093/hmg/dds239. Epub 2012 Jun 20.