Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS1TJXG)

• DOT Name: Protein amnionless (AMN)
• Gene Name: AMN
• Related Disease:
  Myelopathy
  Acute kidney injury
  Acute lymphocytic leukaemia
  Adrenoleukodystrophy
  Adrenomyeloneuropathy
  Congenital nervous system disorder
  Cystic fibrosis
  Hereditary intrinsic factor deficiency
  Hypercholesterolemia, familial, 4
  Hypothyroidism
  Imerslund-Grasbeck syndrome type 1
  Leukemia
  Neoplasm
  Imerslund-Grasbeck syndrome
  Malabsorption syndrome
  Megaloblastic anemia
  Melanocytic nevus
• UniProt ID: AMNLS_HUMAN
• PDB ID: 6GJE
• Pfam ID: PF14828
• Sequence:
  MGVLGRVLLWLQLCALTQAVSKLWVPNTDFDVAANWSQNRTPCAGGAVEFPADKMVSVLV
  QEGHAVSDMLLPLDGELVLASGAGFGVSDVGSHLDCGAGEPAVFRDSDRFSWHDPHLWRS
  GDEAPGLFFVDAERVPCRHDDVFFPPSASFRVGLGPGASPVRVRSISALGRTFTRDEDLA
  VFLASRAGRLRFHGPGALSVGPEDCADPSGCVCGNAEAQPWICAALLQPLGGRCPQAACH
  SALRPQGQCCDLCGAVVLLTHGPAFDLERYRARILDTFLGLPQYHGLQVAVSKVPRSSRL
  READTEIQVVLVENGPETGGAGRLARALLADVAENGEALGVLEATMRESGAHVWGSSAAG
  LAGGVAAAVLLALLVLLVAPPLLRRAGRLRWRRHEAAAPAGAPLGFRNPVFDVTASEELP
  LPRRLSLVPKAAADSTSHSYFVNPLFAGAEAEA
• Function: Membrane-bound component of the endocytic receptor formed by AMN and CUBN. Required for normal CUBN glycosylation and trafficking to the cell surface. The complex formed by AMN and CUBN is required for efficient absorption of vitamin B12. Required for normal CUBN-mediated protein transport in the kidney (Probable).
• Tissue Specificity: Detected in proximal tubules in the kidney cortex (at protein level) . Long isoforms are highly expressed in small intestine, colon and kidney (renal proximal tubule epithelial cells). Shorter isoforms are detected at lower levels in testis, thymus and peripheral blood leukocytes.
• KEGG Pathway: Vitamin digestion and absorption (hsa04977)
• Reactome Pathway:
  Defective CUBN causes MGA1 (R-HSA-3359463)
  HDL clearance (R-HSA-8964011)
  Uptake of dietary cobalamins into enterocytes (R-HSA-9758881)
  Defective AMN causes MGA1 (R-HSA-3359462)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Myelopathy	DISXV8FG	Definitive	Genetic Variation	[1]
Acute kidney injury	DISXZG0T	Strong	Therapeutic	[2]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[3]
Adrenoleukodystrophy	DISTUD1F	Strong	Genetic Variation	[4]
Adrenomyeloneuropathy	DISPTS3P	Strong	Biomarker	[1]
Congenital nervous system disorder	DIS2BIP8	Strong	Biomarker	[5]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[6]
Hereditary intrinsic factor deficiency	DISCZQBU	Strong	Genetic Variation	[7]
Hypercholesterolemia, familial, 4	DISFLNLI	Strong	Biomarker	[8]
Hypothyroidism	DISR0H6D	Strong	Biomarker	[9]
Imerslund-Grasbeck syndrome type 1	DISUTENN	Strong	Autosomal recessive	[10]
Leukemia	DISNAKFL	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Imerslund-Grasbeck syndrome	DISQ84S1	Supportive	Autosomal recessive	[11]
Malabsorption syndrome	DISGMUVS	Limited	Genetic Variation	[12]
Megaloblastic anemia	DISVIZPC	Limited	Genetic Variation	[13]
Melanocytic nevus	DISYS32D	Limited	Biomarker	[14]

2 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 Protein amnionless (AMN).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein amnionless (AMN).	[22]

6 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 Protein amnionless (AMN).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Protein amnionless (AMN).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein amnionless (AMN).	[18]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Protein amnionless (AMN).	[19]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Protein amnionless (AMN).	[20]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Protein amnionless (AMN).	[21]

References

• [1] Enzymatic characterization of ELOVL1, a key enzyme in very long-chain fatty acid synthesis.Biochim Biophys Acta. 2015 Feb;1851(2):231-7. doi: 10.1016/j.bbalip.2014.12.005. Epub 2014 Dec 11.
• [2] Pituitary adenylate cyclase-activating polypeptide prevents cisplatin-induced renal failure.J Mol Neurosci. 2011 Jan;43(1):58-66. doi: 10.1007/s12031-010-9394-1. Epub 2010 Jun 1.
• [3] Is AMN-107 a step forward from imatinib in the treatment of chronic myeloid leukaemia?.Expert Opin Investig Drugs. 2005 Aug;14(8):1063-6. doi: 10.1517/13543784.14.8.1063.
• [4] Clinical, neuroimaging, biochemical, and genetic features in six Chinese patients with Adrenomyeloneuropathy.BMC Neurol. 2019 Sep 16;19(1):227. doi: 10.1186/s12883-019-1449-5.
• [5] Multiligand endocytosis and congenital defects: roles of cubilin, megalin and amnionless.Curr Pharm Des. 2007;13(29):3038-46. doi: 10.2174/138161207782110507.
• [6] The core polypeptide of cystic fibrosis tracheal mucin contains a tandem repeat structure. Evidence for a common mucin in airway and gastrointestinal tissue.J Clin Invest. 1990 Dec;86(6):1921-7. doi: 10.1172/JCI114925.
• [7] Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns.Orphanet J Rare Dis. 2012 Aug 28;7:56. doi: 10.1186/1750-1172-7-56.
• [8] AMN directs endocytosis of the intrinsic factor-vitamin B(12) receptor cubam by engaging ARH or Dab2.Traffic. 2010 May;11(5):706-20. doi: 10.1111/j.1600-0854.2010.01042.x. Epub 2010 Jan 18.
• [9] Multiple endocrine disorders associated with adrenomyeloneuropathy and a novel mutation of the ABCD1 gene.Pediatr Neurol. 2014 Jun;50(6):622-4. doi: 10.1016/j.pediatrneurol.2014.01.027. Epub 2014 Jan 16.
• [10] Amnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anemia. Nat Genet. 2003 Mar;33(3):426-9. doi: 10.1038/ng1098. Epub 2003 Feb 18.
• [11] Luminal expression of cubilin is impaired in Imerslund-Grasbeck syndrome with compound AMN mutations in intron 3 and exon 7. Haematologica. 2011 Nov;96(11):1715-9. doi: 10.3324/haematol.2011.043984. Epub 2011 Jul 12.
• [12] Ancient founder mutation is responsible for Imerslund-Grsbeck Syndrome among diverse ethnicities.Orphanet J Rare Dis. 2011 Nov 13;6:74. doi: 10.1186/1750-1172-6-74.
• [13] Homozygous AMN mutation in hereditary selective intestinal malabsorption of vitamin B12 in Jordan.Saudi Med J. 2005 Jul;26(7):1061-4.
• [14] Expression profiles of melanogenesis-related genes and proteins in acquired melanocytic nevus.J Cutan Pathol. 2006 Mar;33(3):207-15. doi: 10.1111/j.0303-6987.2006.00479.x.
• [15] 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.
• [16] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [17] Molecular characterization of a toxicological tipping point during human stem cell differentiation. Reprod Toxicol. 2020 Jan;91:1-13. doi: 10.1016/j.reprotox.2019.10.001. Epub 2019 Oct 7.
• [18] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [19] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [20] 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.
• [21] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [22] 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.