Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOB6Z3F)

• DOT Name: Heparan sulfate glucosamine 3-O-sulfotransferase 5 (HS3ST5)
• Synonyms: EC 2.8.2.23; Heparan sulfate D-glucosaminyl 3-O-sulfotransferase 5; 3-OST-5; Heparan sulfate 3-O-sulfotransferase 5; h3-OST-5
• Gene Name: HS3ST5
• Related Disease:
  Schizophrenia
  Melanoma
• UniProt ID: HS3S5_HUMAN
• PDB ID: 3BD9; 7SCD; 7SCE
• EC Number: 2.8.2.23
• Pfam ID: PF00685
• Sequence:
  MLFKQQAWLRQKLLVLGSLAVGSLLYLVARVGSLDRLQPICPIEGRLGGARTQAEFPLRA
  LQFKRGLLHEFRKGNASKEQVRLHDLVQQLPKAIIIGVRKGGTRALLEMLNLHPAVVKAS
  QEIHFFDNDENYGKGIEWYRKKMPFSYPQQITIEKSPAYFITEEVPERIYKMNSSIKLLI
  IVREPTTRAISDYTQVLEGKERKNKTYYKFEKLAIDPNTCEVNTKYKAVRTSIYTKHLER
  WLKYFPIEQFHVVDGDRLITEPLPELQLVEKFLNLPPRISQYNLYFNATRGFYCLRFNII
  FNKCLAGSKGRIHPEVDPSVITKLRKFFHPFNQKFYQITGRTLNWP
• Function: Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to position 3 of glucosamine residues in heparan. Catalyzes the rate limiting step in the biosynthesis of heparan sulfate (HSact). This modification is a crucial step in the biosynthesis of anticoagulant heparan sulfate as it completes the structure of the antithrombin pentasaccharide binding site. Also generates GlcUA-GlcNS or IdoUA-GlcNS and IdoUA2S-GlcNH2. The substrate-specific O-sulfation generates an enzyme-modified heparan sulfate which acts as a binding receptor to Herpes simplex virus-1 (HSV-1) and permits its entry.
• Tissue Specificity: Highly expressed in skeletal muscle and fetal brain, and also found in adult brain, spinal cord, cerebellum and colon.
• KEGG Pathway: Glycosaminoglycan biosynthesis - heparan sulfate / heparin (hsa00534)
• Reactome Pathway: HS-GAG biosynthesis (R-HSA-2022928)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[1]
Melanoma	DIS1RRCY	moderate	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 5 (HS3ST5).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 5 (HS3ST5).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 5 (HS3ST5).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 5 (HS3ST5).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 5 (HS3ST5).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 5 (HS3ST5).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 5 (HS3ST5).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 5 (HS3ST5).	[8]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 5 (HS3ST5).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 5 (HS3ST5).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 5 (HS3ST5).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 5 (HS3ST5).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 5 (HS3ST5).	[14]

References

• [1] Genome-wide association analysis with gray matter volume as a quantitative phenotype in first-episode treatment-nave patients with schizophrenia.PLoS One. 2013 Sep 24;8(9):e75083. doi: 10.1371/journal.pone.0075083. eCollection 2013.
• [2] Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.Oncotarget. 2012 Apr;3(4):399-413. doi: 10.18632/oncotarget.473.
• [3] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [11] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [14] 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.