Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJD4ROQ)

• DOT Name: Myeloid cell surface antigen CD33 (CD33)
• Synonyms: Sialic acid-binding Ig-like lectin 3; Siglec-3; gp67; CD antigen CD33
• Gene Name: CD33
• UniProt ID: CD33_HUMAN
• PDB ID: 5IHB; 5J06; 5J0B; 6D48; 6D49; 6D4A; 6TL8; 7AW6
• Pfam ID: PF00047 ; PF07686
• Sequence:
  MPLLLLLPLLWAGALAMDPNFWLQVQESVTVQEGLCVLVPCTFFHPIPYYDKNSPVHGYW
  FREGAIISRDSPVATNKLDQEVQEETQGRFRLLGDPSRNNCSLSIVDARRRDNGSYFFRM
  ERGSTKYSYKSPQLSVHVTDLTHRPKILIPGTLEPGHSKNLTCSVSWACEQGTPPIFSWL
  SAAPTSLGPRTTHSSVLIITPRPQDHGTNLTCQVKFAGAGVTTERTIQLNVTYVPQNPTT
  GIFPGDGSGKQETRAGVVHGAIGGAGVTALLALCLCLIFFIVKTHRRKAARTAVGRNDTH
  PTTGSASPKHQKKSKLHGPTETSSCSGAAPTVEMDEELHYASLNFHGMNPSKDTSTEYSE
  VRTQ
• Function: Sialic-acid-binding immunoglobulin-like lectin (Siglec) that plays a role in mediating cell-cell interactions and in maintaining immune cells in a resting state. Preferentially recognizes and binds alpha-2,3- and more avidly alpha-2,6-linked sialic acid-bearing glycans. Upon engagement of ligands such as C1q or syalylated glycoproteins, two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) located in CD33 cytoplasmic tail are phosphorylated by Src-like kinases such as LCK. These phosphorylations provide docking sites for the recruitment and activation of protein-tyrosine phosphatases PTPN6/SHP-1 and PTPN11/SHP-2. In turn, these phosphatases regulate downstream pathways through dephosphorylation of signaling molecules. One of the repressive effect of CD33 on monocyte activation requires phosphoinositide 3-kinase/PI3K.
• Tissue Specificity: Monocytic/myeloid lineage cells. In the brain, CD33 is mainly expressed on microglial cells.
• KEGG Pathway: Hematopoietic cell lineage (hsa04640)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Myeloid cell surface antigen CD33 (CD33).	[1]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Myeloid cell surface antigen CD33 (CD33).	[2]
Tesmilifene	DMPB36I	Discontinued in Phase 2	Tesmilifene decreases the expression of Myeloid cell surface antigen CD33 (CD33).	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Myeloid cell surface antigen CD33 (CD33).	[5]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos decreases the expression of Myeloid cell surface antigen CD33 (CD33).	[6]

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 decreases the methylation of Myeloid cell surface antigen CD33 (CD33).	[3]

References

• [1] Granulocyte colony-stimulating factor-induced terminal maturation of human myeloid cells is specifically associated with up-regulation of receptor-mediated function and CD10 expression. Int J Hematol. 2003 Feb;77(2):142-51.
• [2] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [3] 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.
• [4] Inhibition of effects of endogenously synthesized histamine disturbs in vitro human dendritic cell differentiation. Immunol Lett. 2001 Apr 2;76(3):175-82. doi: 10.1016/s0165-2478(01)00184-5.
• [5] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [6] Influence of organophosphate poisoning on human dendritic cells. Chem Biol Interact. 2013 Dec 5;206(3):472-8. doi: 10.1016/j.cbi.2013.08.011. Epub 2013 Aug 29.