Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT47DJW0)

• DOT Name: Kell blood group glycoprotein (KEL)
• Synonyms: EC 3.4.24.-; CD antigen CD238
• Gene Name: KEL
• Related Disease:
  McLeod neuroacanthocytosis syndrome
  Influenza
  X-linked hypophosphatemic rickets
  Non-insulin dependent diabetes
• UniProt ID: KELL_HUMAN
• EC Number: 3.4.24.-
• Pfam ID: PF01431 ; PF05649
• Sequence:
  MEGGDQSEEEPRERSQAGGMGTLWSQESTPEERLPVEGSRPWAVARRVLTAILILGLLLC
  FSVLLFYNFQNCGPRPCETSVCLDLRDHYLASGNTSVAPCTDFFSFACGRAKETNNSFQE
  LATKNKNRLRRILEVQNSWHPGSGEEKAFQFYNSCMDTLAIEAAGTGPLRQVIEELGGWR
  ISGKWTSLNFNRTLRLLMSQYGHFPFFRAYLGPHPASPHTPVIQIDQPEFDVPLKQDQEQ
  KIYAQIFREYLTYLNQLGTLLGGDPSKVQEHSSLSISITSRLFQFLRPLEQRRAQGKLFQ
  MVTIDQLKEMAPAIDWLSCLQATFTPMSLSPSQSLVVHDVEYLKNMSQLVEEMLLKQRDF
  LQSHMILGLVVTLSPALDSQFQEARRKLSQKLRELTEQPPMPARPRWMKCVEETGTFFEP
  TLAALFVREAFGPSTRSAAMKLFTAIRDALITRLRNLPWMNEETQNMAQDKVAQLQVEMG
  ASEWALKPELARQEYNDIQLGSSFLQSVLSCVRSLRARIVQSFLQPHPQHRWKVSPWDVN
  AYYSVSDHVVVFPAGLLQPPFFHPGYPRAVNFGAAGSIMAHELLHIFYQLLLPGGCLACD
  NHALQEAHLCLKRHYAAFPLPSRTSFNDSLTFLENAADVGGLAIALQAYSKRLLRHHGET
  VLPSLDLSPQQIFFRSYAQVMCRKPSPQDSHDTHSPPHLRVHGPLSSTPAFARYFRCARG
  ALLNPSSRCQLW
• Function: Zinc endopeptidase with endothelin-3-converting enzyme activity. Cleaves EDN1, EDN2 and EDN3, with a marked preference for EDN3.
• Tissue Specificity: Expressed at high levels in erythrocytes and testis (in Sertoli cells), and, at lower levels, in skeletal muscle, tonsils (in follicular dendritic cells), lymph node, spleen and appendix (at protein level). Also expressed in many adult and fetal nonerythroid tissues, including brain, spleen, lymph nodes and bone marrow.
• Reactome Pathway: Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
McLeod neuroacanthocytosis syndrome	DISA8FUX	Strong	Genetic Variation	[1]
Influenza	DIS3PNU3	moderate	Biomarker	[2]
X-linked hypophosphatemic rickets	DISFTLIR	moderate	Genetic Variation	[3]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kell blood group glycoprotein (KEL).	[5]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Kell blood group glycoprotein (KEL).	[7]

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 Kell blood group glycoprotein (KEL).	[6]

References

• [1] An individual with McLeod syndrome and the Kell blood group antigen K(K1).Transfusion. 1983 Jul-Aug;23(4):336-8. doi: 10.1046/j.1537-2995.1983.23483276871.x.
• [2] Type 1 IFN signaling critically regulates influenza-induced alloimmunization to transfused KEL RBCs in a murine model.Transfusion. 2019 Oct;59(10):3243-3252. doi: 10.1111/trf.15482. Epub 2019 Aug 12.
• [3] The neprilysin family in health and disease.Adv Exp Med Biol. 2000;477:229-40. doi: 10.1007/0-306-46826-3_25.
• [4] Three novel alleles in the Kell blood group system resulting in the Knull phenotype and the first in a Native American.Transfusion. 2013 Nov;53(11 Suppl 2):2867-71. doi: 10.1111/trf.12205. Epub 2013 Apr 15.
• [5] 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.
• [6] 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.
• [7] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.