Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3FLH7U)

• DOT Name: Carbohydrate sulfotransferase 14 (CHST14)
• Synonyms: EC 2.8.2.35; Dermatan 4-sulfotransferase 1; D4ST-1; hD4ST1
• Gene Name: CHST14
• Related Disease:
  Ehlers-Danlos syndrome, musculocontractural type 1
  Clubfoot
  Ehlers-Danlos syndrome
  Myopathy
  Prostate cancer
  Prostate neoplasm
  Ehlers-Danlos syndrome, musculocontractural type
  Marden-Walker syndrome
  Van den Ende-Gupta syndrome
• UniProt ID: CHSTE_HUMAN
• EC Number: 2.8.2.35
• Pfam ID: PF03567
• Sequence:
  MFPRPLTPLAAPNGAEPLGRALRRAPLGRARAGLGGPPLLLPSMLMFAVIVASSGLLLMI
  ERGILAEMKPLPLHPPGREGTAWRGKAPKPGGLSLRAGDADLQVRQDVRNRTLRAVCGQP
  GMPRDPWDLPVGQRRTLLRHILVSDRYRFLYCYVPKVACSNWKRVMKVLAGVLDSVDVRL
  KMDHRSDLVFLADLRPEEIRYRLQHYFKFLFVREPLERLLSAYRNKFGEIREYQQRYGAE
  IVRRYRAGAGPSPAGDDVTFPEFLRYLVDEDPERMNEHWMPVYHLCQPCAVHYDFVGSYE
  RLEADANQVLEWVRAPPHVRFPARQAWYRPASPESLHYHLCSAPRALLQDVLPKYILDFS
  LFAYPLPNVTKEACQQ
• Function: Catalyzes the transfer of sulfate to position 4 of the N-acetylgalactosamine (GalNAc) residue of dermatan sulfate. Plays a pivotal role in the formation of 4-0-sulfated IdoA blocks in dermatan sulfate. Transfers sulfate to the C-4 hydroxyl of beta1,4-linked GalNAc that is substituted with an alpha-linked iduronic acid (IdoUA) at the C-3 hydroxyl. Transfers sulfate more efficiently to GalNAc residues in -IdoUA-GalNAc-IdoUA- than in -GlcUA-GalNAc-GlcUA-sequences. Has preference for partially desulfated dermatan sulfate. Addition of sulfate to GalNAc may occur immediately after epimerization of GlcUA to IdoUA. Appears to have an important role in the formation of the cerebellar neural network during postnatal brain development.
• Tissue Specificity: Widely expressed. Expressed at high level in pituitary gland, placenta, uterus and thyroid.
• KEGG Pathway: Glycosaminoglycan biosynthesis - chondroitin sulfate / dermatan sulfate (hsa00532)
• Reactome Pathway:
  Defective CHST14 causes EDS, musculocontractural type (R-HSA-3595174)
  Dermatan sulfate biosynthesis (R-HSA-2022923)
• BioCyc Pathway: MetaCyc:ENSG00000169105-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
Ehlers-Danlos syndrome, musculocontractural type 1	DIS7VNDZ	Definitive	Autosomal recessive	[1]
Clubfoot	DISLXT4S	Strong	Genetic Variation	[2]
Ehlers-Danlos syndrome	DISSVBRR	Strong	Biomarker	[3]
Myopathy	DISOWG27	Strong	Biomarker	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[5]
Ehlers-Danlos syndrome, musculocontractural type	DIS6XBQP	Supportive	Autosomal recessive	[6]
Marden-Walker syndrome	DISUAMD9	Limited	Biomarker	[7]
Van den Ende-Gupta syndrome	DISS3UH3	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Carbohydrate sulfotransferase 14 (CHST14).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Carbohydrate sulfotransferase 14 (CHST14).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Carbohydrate sulfotransferase 14 (CHST14).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Carbohydrate sulfotransferase 14 (CHST14).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Carbohydrate sulfotransferase 14 (CHST14).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Carbohydrate sulfotransferase 14 (CHST14).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Carbohydrate sulfotransferase 14 (CHST14).	[14]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Carbohydrate sulfotransferase 14 (CHST14).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Carbohydrate sulfotransferase 14 (CHST14).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Carbohydrate sulfotransferase 14 (CHST14).	[18]

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 Carbohydrate sulfotransferase 14 (CHST14).	[17]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Defect in dermatan sulfate in urine of patients with Ehlers-Danlos syndrome caused by a CHST14/D4ST1 deficiency.Clin Biochem. 2017 Aug;50(12):670-677. doi: 10.1016/j.clinbiochem.2017.02.018. Epub 2017 Feb 24.
• [3] Vascular abnormalities in the placenta of Chst14-/- fetuses: implications in the pathophysiology of perinatal lethality of the murine model and vascular lesions in human CHST14/D4ST1 deficiency.Glycobiology. 2018 Feb 1;28(2):80-89. doi: 10.1093/glycob/cwx099.
• [4] Myopathy in a 20-year-old female patient with D4ST-1 deficient Ehlers-Danlos syndrome due to a homozygous CHST14 mutation.Am J Med Genet A. 2012 Apr;158A(4):850-5. doi: 10.1002/ajmg.a.35232. Epub 2012 Mar 9.
• [5] DNA methylome changes by estradiol benzoate and bisphenol A links early-life environmental exposures to prostate cancer risk.Epigenetics. 2016 Sep;11(9):674-689. doi: 10.1080/15592294.2016.1208891. Epub 2016 Jul 14.
• [6] Extracellular matrix and platelet function in patients with musculocontractural Ehlers-Danlos syndrome caused by mutations in the CHST14 gene. Am J Med Genet A. 2012 Jun;158A(6):1344-54. doi: 10.1002/ajmg.a.35339. Epub 2012 May 11.
• [7] Diagnosis of Van den Ende-Gupta syndrome: Approach to the Marden-Walker-like spectrum of disorders.Am J Med Genet A. 2016 Sep;170(9):2310-21. doi: 10.1002/ajmg.a.37831. Epub 2016 Jul 4.
• [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] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [10] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [15] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] 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.