Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3EFUK8)

• DOT Name: Band 3 anion transport protein (SLC4A1)
• Synonyms: Anion exchange protein 1; AE 1; Anion exchanger 1; Solute carrier family 4 member 1; CD antigen CD233
• Gene Name: SLC4A1
• Related Disease:
  Autosomal dominant distal renal tubular acidosis
  Hereditary spherocytosis type 4
  Renal tubular acidosis, distal, 4, with hemolytic anemia
  Southeast Asian ovalocytosis
  Cryohydrocytosis
  Dehydrated hereditary stomatocytosis
  Hereditary spherocytosis
• UniProt ID: B3AT_HUMAN
• PDB ID: 1BH7 ; 1BNX ; 1BTQ ; 1BTR ; 1BTS ; 1BTT ; 1BZK ; 1HYN ; 2BTA ; 2BTB ; 3BTB ; 4KY9 ; 4YZF ; 7TVZ ; 7TW0 ; 7TW1 ; 7TW2 ; 7TW3 ; 7TW5 ; 7TW6 ; 7TY4 ; 7TY6 ; 7TY7 ; 7TY8 ; 7TYA ; 7UZ3 ; 7UZU ; 7UZV ; 7V07 ; 7V0K ; 7V0M ; 7V0T ; 7V0U ; 7V0Y ; 7V19 ; 8CRQ ; 8CRR ; 8CRT ; 8CS9 ; 8CSL ; 8CSV ; 8CSY ; 8CT3 ; 8CTE ; 8T6U ; 8T6V
• Pfam ID: PF07565 ; PF00955
• Sequence:
  MEELQDDYEDMMEENLEQEEYEDPDIPESQMEEPAAHDTEATATDYHTTSHPGTHKVYVE
  LQELVMDEKNQELRWMEAARWVQLEENLGENGAWGRPHLSHLTFWSLLELRRVFTKGTVL
  LDLQETSLAGVANQLLDRFIFEDQIRPQDREELLRALLLKHSHAGELEALGGVKPAVLTR
  SGDPSQPLLPQHSSLETQLFCEQGDGGTEGHSPSGILEKIPPDSEATLVLVGRADFLEQP
  VLGFVRLQEAAELEAVELPVPIRFLFVLLGPEAPHIDYTQLGRAAATLMSERVFRIDAYM
  AQSRGELLHSLEGFLDCSLVLPPTDAPSEQALLSLVPVQRELLRRRYQSSPAKPDSSFYK
  GLDLNGGPDDPLQQTGQLFGGLVRDIRRRYPYYLSDITDAFSPQVLAAVIFIYFAALSPA
  ITFGGLLGEKTRNQMGVSELLISTAVQGILFALLGAQPLLVVGFSGPLLVFEEAFFSFCE
  TNGLEYIVGRVWIGFWLILLVVLVVAFEGSFLVRFISRYTQEIFSFLISLIFIYETFSKL
  IKIFQDHPLQKTYNYNVLMVPKPQGPLPNTALLSLVLMAGTFFFAMMLRKFKNSSYFPGK
  LRRVIGDFGVPISILIMVLVDFFIQDTYTQKLSVPDGFKVSNSSARGWVIHPLGLRSEFP
  IWMMFASALPALLVFILIFLESQITTLIVSKPERKMVKGSGFHLDLLLVVGMGGVAALFG
  MPWLSATTVRSVTHANALTVMGKASTPGAAAQIQEVKEQRISGLLVAVLVGLSILMEPIL
  SRIPLAVLFGIFLYMGVTSLSGIQLFDRILLLFKPPKYHPDVPYVKRVKTWRMHLFTGIQ
  IICLAVLWVVKSTPASLALPFVLILTVPLRRVLLPLIFRNVELQCLDADDAKATFDEEEG
  RDEYDEVAMPV
• Function: Functions both as a transporter that mediates electroneutral anion exchange across the cell membrane and as a structural protein. Component of the ankyrin-1 complex of the erythrocyte membrane; required for normal flexibility and stability of the erythrocyte membrane and for normal erythrocyte shape via the interactions of its cytoplasmic domain with cytoskeletal proteins, glycolytic enzymes, and hemoglobin. Functions as a transporter that mediates the 1:1 exchange of inorganic anions across the erythrocyte membrane. Mediates chloride-bicarbonate exchange in the kidney, and is required for normal acidification of the urine ; (Microbial infection) Acts as a receptor for P.falciparum (isolate 3D7) MSP9 and thus, facilitates merozoite invasion of erythrocytes. Acts as a receptor for P.falciparum (isolate 3D7) MSP1 and thus, facilitates merozoite invasion of erythrocytes.
• Tissue Specificity: Detected in erythrocytes (at protein level).; [Isoform 2]: Expressed in kidney (at protein level).
• KEGG Pathway: Collecting duct acid secretion (hsa04966)
• Reactome Pathway:
  Erythrocytes take up oxygen and release carbon dioxide (R-HSA-1247673)
  Bicarbonate transporters (R-HSA-425381)
  Defective SLC4A1 causes hereditary spherocytosis type 4 (HSP4), distal renal tubular acidosis (dRTA) and dRTA with hemolytic anemia (dRTA-HA) (R-HSA-5619050)
  Erythrocytes take up carbon dioxide and release oxygen (R-HSA-1237044)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant distal renal tubular acidosis	DIS2NR2W	Strong	Autosomal dominant	[1]
Hereditary spherocytosis type 4	DISPYJ1G	Strong	Autosomal dominant	[2]
Renal tubular acidosis, distal, 4, with hemolytic anemia	DISWBUNQ	Strong	Autosomal recessive	[1]
Southeast Asian ovalocytosis	DISSANVQ	Strong	Autosomal dominant	[3]
Cryohydrocytosis	DISMQHL3	Supportive	Autosomal dominant	[4]
Dehydrated hereditary stomatocytosis	DISGQT6H	Supportive	Autosomal dominant	[4]
Hereditary spherocytosis	DISQYJP5	Supportive	Autosomal dominant	[5]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Adefovir	DMM278X	Approved	Band 3 anion transport protein (SLC4A1) increases the Extrapyramidal disorder ADR of Adefovir.	[13]

This DOT Affected the Regulation of Drug Effects of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
AMG 386	DMQJXL4	Phase 3	Band 3 anion transport protein (SLC4A1) affects the transport of AMG 386.	[4]
Chloride	DM1TJXA	Phase 3	Band 3 anion transport protein (SLC4A1) increases the transport of Chloride.	[14]
Sulfate	DMW0ZBF	Investigative	Band 3 anion transport protein (SLC4A1) decreases the transport of Sulfate.	[4]
Selenious acid	DMB7GPA	Investigative	Band 3 anion transport protein (SLC4A1) increases the uptake of Selenious acid.	[15]

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 Band 3 anion transport protein (SLC4A1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Band 3 anion transport protein (SLC4A1).	[11]

5 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 Band 3 anion transport protein (SLC4A1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Band 3 anion transport protein (SLC4A1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Band 3 anion transport protein (SLC4A1).	[9]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Band 3 anion transport protein (SLC4A1).	[10]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Band 3 anion transport protein (SLC4A1).	[12]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Hereditary spherocytosis. Lancet. 2008 Oct 18;372(9647):1411-26. doi: 10.1016/S0140-6736(08)61588-3.
• [3] Structural and functional characterization of band 3 from Southeast Asian ovalocytes. J Biol Chem. 1992 Dec 25;267(36):25792-7.
• [4] Monovalent cation leaks in human red cells caused by single amino-acid substitutions in the transport domain of the band 3 chloride-bicarbonate exchanger, AE1. Nat Genet. 2005 Nov;37(11):1258-63. doi: 10.1038/ng1656. Epub 2005 Oct 9.
• [5] Hereditary spherocytosis, elliptocytosis, and other red cell membrane disorders. Blood Rev. 2013 Jul;27(4):167-78. doi: 10.1016/j.blre.2013.04.003. Epub 2013 May 9.
• [6] 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.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Resveratrol induces human K562 cell apoptosis, erythroid differentiation, and autophagy. Tumour Biol. 2014 Jun;35(6):5381-8. doi: 10.1007/s13277-014-1701-y. Epub 2014 Feb 15.
• [11] 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.
• [12] Novel oxolane derivative DMTD mitigates high glucose-induced erythrocyte apoptosis by regulating oxidative stress. Toxicol Appl Pharmacol. 2017 Nov 1;334:167-179.
• [13] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [14] Lysine 539 of human band 3 is not essential for ion transport or inhibition by stilbene disulfonates. J Biol Chem. 1989 Nov 25;264(33):19607-13.
• [15] Human red blood cell uptake and sequestration of arsenite and selenite: Evidence of seleno-bis(S-glutathionyl) arsinium ion formation in human cells. Biochem Pharmacol. 2020 Oct;180:114141. doi: 10.1016/j.bcp.2020.114141. Epub 2020 Jul 8.