Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPX3UGY)

• DOT Name: Lactosylceramide 4-alpha-galactosyltransferase (A4GALT)
• Synonyms: EC 2.4.1.228; Alpha-1,4-N-acetylglucosaminyltransferase; Alpha-1,4-galactosyltransferase; Alpha4Gal-T1; CD77 synthase; Globotriaosylceramide synthase; Gb3 synthase; P1/Pk synthase; UDP-galactose:beta-D-galactosyl-beta1-R 4-alpha-D-galactosyltransferase
• Gene Name: A4GALT
• Related Disease:
  Acute megakaryoblastic leukemia
  Adenocarcinoma
  Advanced cancer
  Burkitt lymphoma
  Gastric adenocarcinoma
  Haematological malignancy
  Leukemia
  Venous thromboembolism
  Hemolytic-uremic syndrome
• UniProt ID: A4GAT_HUMAN
• EC Number: 2.4.1.228
• Pfam ID: PF04572 ; PF04488
• Sequence:
  MSKPPDLLLRLLRGAPRQRVCTLFIIGFKFTFFVSIMIYWHVVGEPKEKGQLYNLPAEIP
  CPTLTPPTPPSHGPTPGNIFFLETSDRTNPNFLFMCSVESAARTHPESHVLVLMKGLPGG
  NASLPRHLGISLLSCFPNVQMLPLDLRELFRDTPLADWYAAVQGRWEPYLLPVLSDASRI
  ALMWKFGGIYLDTDFIVLKNLRNLTNVLGTQSRYVLNGAFLAFERRHEFMALCMRDFVDH
  YNGWIWGHQGPQLLTRVFKKWCSIRSLAESRACRGVTTLPPEAFYPIPWQDWKKYFEDIN
  PEELPRLLSATYAVHVWNKKSQGTRFEATSRALLAQLHARYCPTTHEAMKMYL
• Function: Catalyzes the transfer of galactose from UDP-alpha-D-galactose to lactosylceramide/beta-D-galactosyl-(1->4)-beta-D-glucosyl-(1<->1)-ceramide(d18:1(4E)) to produce globotriaosylceramide/globoside Gb3Cer (d18:1(4E)). Also able to transfer galactose to galactosylceramide/beta-D-Gal-(1<->1')-Cer. Globoside Gb3Cer is a glycosphingolipid of the globo serie, one of the major types of neutral root structures of glycosphingolipids, that constitute a significant portion of mammalian cell membranes (Probable). Globotriaosylceramide/globoside Gb3Cer in blood and tissue cell membranes is the antigen Pk of blood histogroup P ; (Microbial infection) Globotriaosylceramide is one of the cellular ligands for bacterial verotoxins.
• Tissue Specificity: Ubiquitous. Highly expressed in kidney, heart, spleen, liver, testis and placenta.
• KEGG Pathway:
  Glycosphingolipid biosynthesis - lacto and neolacto series (hsa00601)
  Glycosphingolipid biosynthesis - globo and isoglobo series (hsa00603)
  Metabolic pathways (hsa01100)
• BioCyc Pathway: MetaCyc:HS05171-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute megakaryoblastic leukemia	DIS0JX3M	Strong	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Burkitt lymphoma	DIS9D5XU	Strong	Biomarker	[4]
Gastric adenocarcinoma	DISWWLTC	Strong	Biomarker	[5]
Haematological malignancy	DISCDP7W	Strong	Altered Expression	[1]
Leukemia	DISNAKFL	Strong	Altered Expression	[1]
Venous thromboembolism	DISUR7CR	Strong	Genetic Variation	[6]
Hemolytic-uremic syndrome	DISSCBGW	Limited	Altered Expression	[7]

1 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 Lactosylceramide 4-alpha-galactosyltransferase (A4GALT).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Lactosylceramide 4-alpha-galactosyltransferase (A4GALT).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Lactosylceramide 4-alpha-galactosyltransferase (A4GALT).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Lactosylceramide 4-alpha-galactosyltransferase (A4GALT).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Lactosylceramide 4-alpha-galactosyltransferase (A4GALT).	[11]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Lactosylceramide 4-alpha-galactosyltransferase (A4GALT).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Lactosylceramide 4-alpha-galactosyltransferase (A4GALT).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Lactosylceramide 4-alpha-galactosyltransferase (A4GALT).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Lactosylceramide 4-alpha-galactosyltransferase (A4GALT).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Lactosylceramide 4-alpha-galactosyltransferase (A4GALT).	[16]

References

• [1] Expression of the Gb3/CD77 synthase gene in megakaryoblastic leukemia cells: implication in the sensitivity to verotoxins.J Biol Chem. 2002 Mar 29;277(13):11247-54. doi: 10.1074/jbc.M109519200. Epub 2002 Jan 8.
• [2] Reduced GlcNAc glycosylation on gastric gland mucin is a biomarker of malignant potential for gastric cancer, Barrett's adenocarcinoma, and pancreatic cancer.Histochem Cell Biol. 2018 Jun;149(6):569-575. doi: 10.1007/s00418-018-1667-8. Epub 2018 Apr 16.
• [3] Transition of Mesenchymal and Epithelial Cancer Cells Depends on 1-4 Galactosyltransferase-Mediated Glycosphingolipids.Cancer Res. 2018 Jun 1;78(11):2952-2965. doi: 10.1158/0008-5472.CAN-17-2223. Epub 2018 Mar 23.
• [4] Flavopiridol induces apoptosis and caspase-3 activation of a newly characterized Burkitt's lymphoma cell line containing mutant p53 genes. Blood Cells Mol Dis. 2001 May-Jun;27(3):610-24. doi: 10.1006/bcmd.2001.0428.
• [5] GlcNAc and its catalyst 4GnT are diagnostic and prognostic markers in uterine cervical tumor, gastric type.Sci Rep. 2019 Sep 10;9(1):13043. doi: 10.1038/s41598-019-49376-7.
• [6] Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.Blood. 2019 Nov 7;134(19):1645-1657. doi: 10.1182/blood.2019000435.
• [7] Identification and characterization of the human Gb3/CD77 synthase gene promoter.Glycobiology. 2008 Dec;18(12):1028-35. doi: 10.1093/glycob/cwn082. Epub 2008 Aug 29.
• [8] 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.
• [9] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Chlorophyllin significantly reduces benzo[a]pyrene-DNA adduct formation and alters cytochrome P450 1A1 and 1B1 expression and EROD activity in normal human mammary epithelial cells. Environ Mol Mutagen. 2009 Mar;50(2):134-44.
• [15] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [16] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.