Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCQS7DB)

• DOT Name: Melanocortin-2 receptor accessory protein 2 (MRAP2)
• Synonyms: MC2R accessory protein 2
• Gene Name: MRAP2
• Related Disease:
  High blood pressure
  Hyperglycemia
  Adrenocortical carcinoma
  Aplasia cutis congenita
  Corpus callosum, agenesis of
  Obesity
  Prader-Willi syndrome
• UniProt ID: MRAP2_HUMAN
• Pfam ID: PF15183
• Sequence:
  MSAQRLISNRTSQQSASNSDYTWEYEYYEIGPVSFEGLKAHKYSIVIGFWVGLAVFVIFM
  FFVLTLLTKTGAPHQDNAESSEKRFRMNSFVSDFGRPLEPDKVFSRQGNEESRSLFHCYI
  NEVERLDRAKACHQTTALDSDVQLQEAIRSSGQPEEELNRLMKFDIPNFVNTDQNYFGED
  DLLISEPPIVLETKPLSQTSHKDLD
• Function: Modulator of melanocortin receptor 4 (MC4R), a receptor involved in energy homeostasis. Plays a central role in the control of energy homeostasis and body weight regulation by increasing ligand-sensitivity of MC4R and MC4R-mediated generation of cAMP. May also act as a negative regulator of MC2R: competes with MRAP for binding to MC2R and impairs the binding of corticotropin (ACTH) to MC2R. May also regulate activity of other melanocortin receptors (MC1R, MC3R and MC5R); however, additional evidence is required in vivo.
• Tissue Specificity: Expressed in the adrenal gland and brain. Not expressed in other tissues.
• KEGG Pathway: Growth hormone synthesis, secretion and action (hsa04935)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
High blood pressure	DISY2OHH	Strong	Genetic Variation	[1]
Hyperglycemia	DIS0BZB5	Strong	Genetic Variation	[1]
Adrenocortical carcinoma	DISZF4HX	Limited	Altered Expression	[2]
Aplasia cutis congenita	DISMDAYM	Limited	Altered Expression	[2]
Corpus callosum, agenesis of	DISO9P40	Limited	Altered Expression	[2]
Obesity	DIS47Y1K	Limited	Genetic Variation	[1]
Prader-Willi syndrome	DISYWMLU	Limited	Biomarker	[3]

7 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 Melanocortin-2 receptor accessory protein 2 (MRAP2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Melanocortin-2 receptor accessory protein 2 (MRAP2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Melanocortin-2 receptor accessory protein 2 (MRAP2).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Melanocortin-2 receptor accessory protein 2 (MRAP2).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Melanocortin-2 receptor accessory protein 2 (MRAP2).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Melanocortin-2 receptor accessory protein 2 (MRAP2).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Melanocortin-2 receptor accessory protein 2 (MRAP2).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Melanocortin-2 receptor accessory protein 2 (MRAP2).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Melanocortin-2 receptor accessory protein 2 (MRAP2).	[12]

References

• [1] Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension.Nat Med. 2019 Nov;25(11):1733-1738. doi: 10.1038/s41591-019-0622-0. Epub 2019 Nov 7.
• [2] Melanocortin 2 receptor-associated protein (MRAP) and MRAP2 in human adrenocortical tissues: regulation of expression and association with ACTH responsiveness.J Clin Endocrinol Metab. 2012 May;97(5):E747-54. doi: 10.1210/jc.2011-2328. Epub 2012 Mar 14.
• [3] Copy number variation (CNV) analysis and mutation analysis of the 6q14.1-6q16.3 genes SIM1 and MRAP2 in Prader Willi like patients.Mol Genet Metab. 2016 Mar;117(3):383-8. doi: 10.1016/j.ymgme.2016.01.003. Epub 2016 Jan 9.
• [4] 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.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] 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.
• [10] 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.
• [11] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [12] 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.