Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJZWXE8)

• DOT Name: Ammonium transporter Rh type A (RHAG)
• Synonyms: Erythrocyte membrane glycoprotein Rh50; Erythrocyte plasma membrane 50 kDa glycoprotein; Rh50A; Rhesus blood group family type A glycoprotein; Rh family type A glycoprotein; Rh type A glycoprotein; Rhesus blood group-associated ammonia channel; Rhesus blood group-associated glycoprotein; CD antigen CD241
• Gene Name: RHAG
• Related Disease:
  Overhydrated hereditary stomatocytosis
  Rh deficiency syndrome
• UniProt ID: RHAG_HUMAN
• PDB ID: 7UZQ; 7V0K; 7V0S; 8CRT; 8CS9; 8CSL; 8CSX; 8CTE
• Pfam ID: PF00909
• Sequence:
  MRFTFPLMAIVLEIAMIVLFGLFVEYETDQTVLEQLNITKPTDMGIFFELYPLFQDVHVM
  IFVGFGFLMTFLKKYGFSSVGINLLVAALGLQWGTIVQGILQSQGQKFNIGIKNMINADF
  SAATVLISFGAVLGKTSPTQMLIMTILEIVFFAHNEYLVSEIFKASDIGASMTIHAFGAY
  FGLAVAGILYRSGLRKGHENEESAYYSDLFAMIGTLFLWMFWPSFNSAIAEPGDKQCRAI
  VNTYFSLAACVLTAFAFSSLVEHRGKLNMVHIQNATLAGGVAVGTCADMAIHPFGSMIIG
  SIAGMVSVLGYKFLTPLFTTKLRIHDTCGVHNLHGLPGVVGGLAGIVAVAMGASNTSMAM
  QAAALGSSIGTAVVGGLMTGLILKLPLWGQPSDQNCYDDSVYWKVPKTR
• Function: Component of the ankyrin-1 complex, a multiprotein complex involved in the stability and shape of the erythrocyte membrane. Heterotrimer with RHCE (RHAG)2(RHCE), that transports ammonium and its related derivative methylammonium, in both neutral and ionic forms, across the erythrocyte membrane. The transport of NH4(+) is electrogenic and masks the NH3 transport. Also, may act as a CO2 channel. In vitro, leaks monovalent cations. Moreover in erythrocyte, regulates RHD membrane expression and is associated with rhesus blood group antigen expression.
• Tissue Specificity: Erythrocytes.
• Reactome Pathway:
  Erythrocytes take up oxygen and release carbon dioxide (R-HSA-1247673)
  Rhesus glycoproteins mediate ammonium transport. (R-HSA-444411)
  Defective RHAG causes regulator type Rh-null hemolytic anemia (RHN) (R-HSA-5619042)
  Erythrocytes take up carbon dioxide and release oxygen (R-HSA-1237044)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Overhydrated hereditary stomatocytosis	DIS6TF7I	Strong	Autosomal dominant	[1]
Rh deficiency syndrome	DISW2W1R	Strong	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Ammonium transporter Rh type A (RHAG).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ammonium transporter Rh type A (RHAG).	[4]

1 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 increases the methylation of Ammonium transporter Rh type A (RHAG).	[5]

References

• [1] The monovalent cation leak in overhydrated stomatocytic red blood cells results from amino acid substitutions in the Rh-associated glycoprotein. Blood. 2009 Feb 5;113(6):1350-7. doi: 10.1182/blood-2008-07-171140. Epub 2008 Oct 17.
• [2] First report of Rh(null) individuals in the Indian population and characterization of the underlying molecular mechanisms. Transfusion. 2017 Aug;57(8):1944-1948. doi: 10.1111/trf.14150. Epub 2017 May 3.
• [3] 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.
• [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] 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.