Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBML9D9)

• DOT Name: Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1)
• Synonyms: CsGalNAcT-1; EC 2.4.1.174; Chondroitin beta-1,4-N-acetylgalactosaminyltransferase 1; Beta4GalNAcT-1
• Gene Name: CSGALNACT1
• Related Disease:
  Anorexia nervosa cachexia
  Breast cancer
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Congenital disorder of glycosylation
  Desbuquois dysplasia
  Intervertebral disc degeneration
  Intestinal cancer
  Melanoma
  Multiple sclerosis
  Osteochondrodysplasia
  Skeletal dysplasia
  Skeletal dysplasia, mild, with joint laxity and advanced bone age
  Acute myelogenous leukaemia
  Type-1 diabetes
• UniProt ID: CGAT1_HUMAN
• EC Number: 2.4.1.174
• Pfam ID: PF05679
• Sequence:
  MMMVRRGLLAWISRVVVLLVLLCCAISVLYMLACTPKGDEEQLALPRANSPTGKEGYQAV
  LQEWEEQHRNYVSSLKRQIAQLKEELQERSEQLRNGQYQASDAAGLGLDRSPPEKTQADL
  LAFLHSQVDKAEVNAGVKLATEYAAVPFDSFTLQKVYQLETGLTRHPEEKPVRKDKRDEL
  VEAIESALETLNSPAENSPNHRPYTASDFIEGIYRTERDKGTLYELTFKGDHKHEFKRLI
  LFRPFGPIMKVKNEKLNMANTLINVIVPLAKRVDKFRQFMQNFREMCIEQDGRVHLTVVY
  FGKEEINEVKGILENTSKAANFRNFTFIQLNGEFSRGKGLDVGARFWKGSNVLLFFCDVD
  IYFTSEFLNTCRLNTQPGKKVFYPVLFSQYNPGIIYGHHDAVPPLEQQLVIKKETGFWRD
  FGFGMTCQYRSDFINIGGFDLDIKGWGGEDVHLYRKYLHSNLIVVRTPVRGLFHLWHEKR
  CMDELTPEQYKMCMQSKAMNEASHGQLGMLVFRHEIEAHLRKQKQKTSSKKT
• Function: Transfers 1,4-N-acetylgalactosamine (GalNAc) from UDP-GalNAc to the non-reducing end of glucuronic acid (GlcUA). Required for addition of the first GalNAc to the core tetrasaccharide linker and for elongation of chondroitin chains. Important role in chondroitin chain biosynthesis in cartilage formation and subsequent endochondral ossification. Moreover, is involved in the metabolism of aggrecan.
• Tissue Specificity: Ubiquitous, with the highest levels in placenta, thyroid, bladder, prostate and adrenal gland. Detected at low levels in the other tissues examined.
• KEGG Pathway:
  Glycosaminoglycan biosynthesis - chondroitin sulfate / dermatan sulfate (hsa00532)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Chondroitin sulfate biosynthesis (R-HSA-2022870)
• BioCyc Pathway: MetaCyc:HS07428-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anorexia nervosa cachexia	DISFO5RQ	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Colon cancer	DISVC52G	Strong	Altered Expression	[2]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[2]
Congenital disorder of glycosylation	DIS400QP	Strong	Biomarker	[3]
Desbuquois dysplasia	DISCBF04	Strong	Genetic Variation	[4]
Intervertebral disc degeneration	DISG3AIM	Strong	Biomarker	[5]
Intestinal cancer	DISYCNF1	Strong	Altered Expression	[2]
Melanoma	DIS1RRCY	Strong	Altered Expression	[2]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[6]
Osteochondrodysplasia	DIS9SPWW	Strong	Genetic Variation	[3]
Skeletal dysplasia	DIS5Z8U6	Strong	Genetic Variation	[3]
Skeletal dysplasia, mild, with joint laxity and advanced bone age	DISVOK8N	Strong	Autosomal recessive	[7]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[8]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[9]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1) affects the response to substance of Temozolomide.	[25]
Etoposide	DMNH3PG	Approved	Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1) affects the response to substance of Etoposide.	[26]
DTI-015	DMXZRW0	Approved	Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1) affects the response to substance of DTI-015.	[25]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1).	[13]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1).	[14]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1).	[18]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1).	[19]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1).	[20]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1).	[21]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGALNACT1).	[23]

References

• [1] High-throughput DNA methylation analysis in anorexia nervosa confirms TNXB hypermethylation.World J Biol Psychiatry. 2018 Apr;19(3):187-199. doi: 10.1080/15622975.2016.1190033. Epub 2016 Jul 1.
• [2] Evaluation of SAT-1, SAT-2 and GalNAcT-1 mRNA in colon cancer by real-time PCR.Mol Cell Biochem. 2007 Apr;298(1-2):59-68. doi: 10.1007/s11010-006-9350-0. Epub 2006 Nov 21.
• [3] CSGALNACT1-congenital disorder of glycosylation: A mild skeletal dysplasia with advanced bone age.Hum Mutat. 2020 Mar;41(3):655-667. doi: 10.1002/humu.23952. Epub 2019 Dec 3.
• [4] Chondroitin Sulfate N-acetylgalactosaminyltransferase-1 (CSGalNAcT-1) Deficiency Results in a Mild Skeletal Dysplasia and Joint Laxity.Hum Mutat. 2017 Jan;38(1):34-38. doi: 10.1002/humu.23070. Epub 2016 Sep 22.
• [5] Upregulation of glycosaminoglycan synthesis by Neurotropin in nucleus pulposus cells via stimulation of chondroitin sulfate N-acetylgalactosaminyltransferase 1: A new approach to attenuation of intervertebral disc degeneration.PLoS One. 2018 Aug 27;13(8):e0202640. doi: 10.1371/journal.pone.0202640. eCollection 2018.
• [6] Chondroitin sulfate -1,4-N-acetylgalactosaminyltransferase-1 (ChGn-1) polymorphism: Association with progression of multiple sclerosis.Neurosci Res. 2016 Jul;108:55-9. doi: 10.1016/j.neures.2016.01.002. Epub 2016 Jan 20.
• [7] Chondroitin sulfate N-acetylgalactosaminyltransferase 1 is necessary for normal endochondral ossification and aggrecan metabolism. J Biol Chem. 2011 Feb 18;286(7):5803-12. doi: 10.1074/jbc.M110.159244. Epub 2010 Dec 10.
• [8] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [9] Inflammatory microRNA-194 and -515 attenuate the biosynthesis of chondroitin sulfate during human intervertebral disc degeneration.Oncotarget. 2017 Jul 25;8(30):49303-49317. doi: 10.18632/oncotarget.17571.
• [10] 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.
• [11] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [12] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [15] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [16] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [17] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [18] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [19] 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.
• [20] 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.
• [21] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [22] 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.
• [23] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [24] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [25] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.
• [26] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.