Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLBWM7X)

• DOT Name: Melanocortin-2 receptor accessory protein (MRAP)
• Synonyms: B27; Fat cell-specific low molecular weight protein; Fat tissue-specific low MW protein
• Gene Name: MRAP
• Related Disease:
  Glucocorticoid deficiency 1
  Glucocorticoid deficiency 2
  Spondyloarthropathy
  Aarskog-Scott syndrome, X-linked
  Arthritis
  Uveitis
  Familial glucocorticoid deficiency
• UniProt ID: MRAP_HUMAN
• PDB ID: 8GY7
• Pfam ID: PF15183
• Sequence:
  MANGTNASAPYYSYEYYLDYLDLIPVDEKKLKAHKHSIVIAFWVSLAAFVVLLFLILLYM
  SWSASPQMRNSPKHHQTCPWSHGLNLHLCIQKCLPCHREPLATSQAQASSVEPGSRTGPD
  QPLRQESSSTLPLGGFQTHPTLLWELTLNGGPLVRSKPSEPPPGDRTSQLQS
• Function: Modulator of melanocortin receptors (MC1R, MC2R, MC3R, MC4R and MC5R). Acts by increasing ligand-sensitivity of melanocortin receptors and enhancing generation of cAMP by the receptors. Required both for MC2R trafficking to the cell surface of adrenal cells and for signaling in response to corticotropin (ACTH). May be involved in the intracellular trafficking pathways in adipocyte cells.
• Tissue Specificity: Expressed in adrenal cortex, testis, breast, thyroid, lymph node, ovary and fat. Expressed in adipose tissues.
• KEGG Pathway:
  Cortisol synthesis and secretion (hsa04927)
  Cushing syndrome (hsa04934)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glucocorticoid deficiency 1	DISCTX0T	Definitive	GermlineCausalMutation	[1]
Glucocorticoid deficiency 2	DISULP1I	Definitive	Autosomal recessive	[2]
Spondyloarthropathy	DISBPYCZ	Definitive	Biomarker	[3]
Aarskog-Scott syndrome, X-linked	DISNHV62	Strong	Biomarker	[4]
Arthritis	DIST1YEL	Strong	Genetic Variation	[5]
Uveitis	DISV0RYS	Strong	Biomarker	[6]
Familial glucocorticoid deficiency	DISG7TB4	Supportive	Autosomal recessive	[7]

3 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 Melanocortin-2 receptor accessory protein (MRAP).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Melanocortin-2 receptor accessory protein (MRAP).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Melanocortin-2 receptor accessory protein (MRAP).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Melanocortin-2 receptor accessory protein (MRAP).	[9]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Melanocortin-2 receptor accessory protein (MRAP).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Melanocortin-2 receptor accessory protein (MRAP).	[13]

References

• [1] Missense mutations in the melanocortin 2 receptor accessory protein that lead to late onset familial glucocorticoid deficiency type 2.J Clin Endocrinol Metab. 2010 Jul;95(7):3497-501. doi: 10.1210/jc.2009-2731. Epub 2010 Apr 28.
• [2] Phenotypic characteristics of familial glucocorticoid deficiency (FGD) type 1 and 2. Clin Endocrinol (Oxf). 2010 May;72(5):589-94. doi: 10.1111/j.1365-2265.2009.03663.x. Epub 2009 Jun 24.
• [3] HLA-B27 transgenic rat: an animal model mimicking gut and joint involvement in human spondyloarthritides.Ann N Y Acad Sci. 2009 Sep;1173:570-4. doi: 10.1111/j.1749-6632.2009.04757.x.
• [4] ACTH signalling and adrenal development: lessons from mouse models.Endocr Connect. 2019 Jul;8(7):R122-R130. doi: 10.1530/EC-19-0190.
• [5] High-throughput screening of chemical libraries for modulators of gene promoter activity of HLA-B2705: environmental pathogenesis and therapeutics of ankylosing spondylitis.J Rheumatol. 2011 Jun;38(6):1061-5. doi: 10.3899/jrheum.101109. Epub 2011 Apr 1.
• [6] High Levels of Serum Ubiquitin and Proteasome in a Case of HLA-B27 Uveitis.Int J Mol Sci. 2017 Feb 26;18(3):505. doi: 10.3390/ijms18030505.
• [7] Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat Genet. 2005 Feb;37(2):166-70. doi: 10.1038/ng1501. Epub 2005 Jan 16.
• [8] 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.
• [9] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [10] 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.
• [11] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [12] 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.
• [13] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.