Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8ERGMH)

• DOT Name: Chondroitin sulfate synthase 3 (CHSY3)
• Synonyms: EC 2.4.1.175; EC 2.4.1.226; Carbohydrate synthase 2; Chondroitin glucuronyltransferase 3; Chondroitin synthase 2; ChSy-2; Glucuronosyl-N-acetylgalactosaminyl-proteoglycan 4-beta-N-acetylgalactosaminyltransferase II; N-acetylgalactosaminyl-proteoglycan 3-beta-glucuronosyltransferase 3; N-acetylgalactosaminyltransferase 3
• Gene Name: CHSY3
• Related Disease:
  Colorectal carcinoma
  Constipation
  Pancreatic cancer
  Breast cancer
  Breast carcinoma
  Glioma
• UniProt ID: CHSS3_HUMAN
• EC Number: 2.4.1.175; 2.4.1.226
• Pfam ID: PF05679
• Sequence:
  MAVRSRRPWMSVALGLVLGFTAASWLIAPRVAELSERKRRGSSLCSYYGRSAAGPRAGAQ
  QPLPQPQSRPRQEQSPPPARQDLQGPPLPEAAPGITSFRSSPWQQPPPLQQRRRGREPEG
  ATGLPGAPAAEGEPEEEDGGAAGQRRDGRPGSSHNGSGDGGAAAPSARPRDFLYVGVMTA
  QKYLGSRALAAQRTWARFIPGRVEFFSSQQPPNAGQPPPPLPVIALPGVDDSYPPQKKSF
  MMIKYMHDHYLDKYEWFMRADDDVYIKGDKLEEFLRSLNSSKPLYLGQTGLGNIEELGKL
  GLEPGENFCMGGPGMIFSREVLRRMVPHIGECLREMYTTHEDVEVGRCVRRFGGTQCVWS
  YEMQQLFHENYEHNRKGYIQDLHNSKIHAAITLHPNKRPAYQYRLHNYMLSRKISELRYR
  TIQLHRESALMSKLSNTEVSKEDQQLGVIPSFNHFQPRERNEVIEWEFLTGKLLYSAAEN
  QPPRQSLSSILRTALDDTVLQVMEMINENAKSRGRLIDFKEIQYGYRRVNPMHGVEYILD
  LLLLYKRHKGRKLTVPVRRHAYLQQLFSKPFFRETEELDVNSLVESINSETQSFSFISNS
  LKILSSFQGAKEMGGHNEKKVHILVPLIGRYDIFLRFMENFENMCLIPKQNVKLVIILFS
  RDSGQDSSKHIELIKGYQNKYPKAEMTLIPMKGEFSRGLGLEMASAQFDNDTLLLFCDVD
  LIFREDFLQRCRDNTIQGQQVYYPIIFSQYDPKVTNGGNPPTDDYFIFSKKTGFWRDYGY
  GITCIYKSDLLGAGGFDTSIQGWGLEDVDLYNKVILSGLRPFRSQEVGVVHIFHPVHCDP
  NLDPKQYKMCLGSKASTFASTMQLAELWLEKHLGVRYNRTLS
• Function: Has both beta-1,3-glucuronic acid and beta-1,4-N-acetylgalactosamine transferase activity. Transfers glucuronic acid (GlcUA) from UDP-GlcUA and N-acetylgalactosamine (GalNAc) from UDP-GalNAc to the non-reducing end of the elongating chondroitin polymer. Specific activity is much reduced compared to CHSY1.
• Tissue Specificity: Detected at low levels in brain, cerebral cortex, uterus and small intestine.
• KEGG Pathway:
  Glycosaminoglycan biosynthesis - chondroitin sulfate / dermatan sulfate (hsa00532)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Chondroitin sulfate biosynthesis (R-HSA-2022870)
• BioCyc Pathway: MetaCyc:HS11959-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[1]
Constipation	DISRQXWI	Strong	Biomarker	[2]
Pancreatic cancer	DISJC981	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Limited	Biomarker	[4]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[4]
Glioma	DIS5RPEH	Limited	Altered Expression	[4]

3 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 Chondroitin sulfate synthase 3 (CHSY3).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Chondroitin sulfate synthase 3 (CHSY3).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Chondroitin sulfate synthase 3 (CHSY3).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Chondroitin sulfate synthase 3 (CHSY3).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Chondroitin sulfate synthase 3 (CHSY3).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Chondroitin sulfate synthase 3 (CHSY3).	[8]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Chondroitin sulfate synthase 3 (CHSY3).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Chondroitin sulfate synthase 3 (CHSY3).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Chondroitin sulfate synthase 3 (CHSY3).	[13]

References

• [1] Genome-wide association study identifies two new susceptibility loci for colorectal cancer at 5q23.3 and 17q12 in Han Chinese.Oncotarget. 2015 Nov 24;6(37):40327-36. doi: 10.18632/oncotarget.5530.
• [2] Long-term comparison of physiologic anorectal changes and recurrence between transanal repair and transanal repair with posterior colporrhaphy in rectocele.Asian J Surg. 2020 Jan;43(1):265-271. doi: 10.1016/j.asjsur.2019.04.001. Epub 2019 Apr 26.
• [3] Loss of N-acetylgalactosaminyltransferase 3 in poorly differentiated pancreatic cancer: augmented aggressiveness and aberrant ErbB family glycosylation.Br J Cancer. 2016 Jun 14;114(12):1376-86. doi: 10.1038/bjc.2016.116. Epub 2016 May 17.
• [4] Tumor-dependent Effects of Proteoglycans and Various Glycosaminoglycan Synthesizing Enzymes and Sulfotransferases on Patients' Outcome.Curr Cancer Drug Targets. 2019;19(3):210-221. doi: 10.2174/1568009618666180706165845.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.