Details of Drug Off-Target (DOT)

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

• DOT Name: Exostosin-1 (EXT1)
• Synonyms: EC 2.4.1.225; Exostosin glycosyltransferase 1; Heparan sulfate co-polymerase subunit EXT1; Multiple exostoses protein 1; N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase
• Gene Name: EXT1
• Related Disease:
  Acute lymphocytic leukaemia
  Childhood acute lymphoblastic leukemia
  Exostoses, multiple, type 1
  Hepatitis A virus infection
  Trichorhinophalangeal syndrome type II
  Astrocytoma
  Autism
  Bone disease
  Breast cancer
  Chondrosarcoma
  Epilepsy
  Exostoses, multiple, type 2
  Familial hypercholesterolemia
  Frontotemporal dementia
  Glioma
  Head-neck squamous cell carcinoma
  Hepatitis
  Hepatocellular carcinoma
  Hypercholesterolemia, familial, 1
  Idiopathic inflammatory myopathy
  Lentivirus infection
  leukaemia
  Leukemia
  Mental disorder
  Nephrotic syndrome
  Non-insulin dependent diabetes
  Osteoporosis
  Pick disease
  Rheumatoid arthritis
  Schizophrenia
  Trichorhinophalangeal syndrome
  Adenocarcinoma
  Endometrial carcinoma
  Exostosis
  Lupus nephritis
  Membranous glomerulonephritis
  Refractory multiple myeloma
  Advanced cancer
  Autoimmune disease
  Cervical Intraepithelial neoplasia
  Chromosomal disorder
  Hepatitis C virus infection
  Intellectual disability
  Osteosarcoma
  Plasma cell myeloma
  Premature aging syndrome
  Rectal carcinoma
  Venous thromboembolism
• UniProt ID: EXT1_HUMAN
• PDB ID: 7SCH; 7SCJ; 7SCK; 7UQX; 7UQY; 7ZAY
• EC Number: 2.4.1.225
• Pfam ID: PF03016 ; PF09258
• Sequence:
  MQAKKRYFILLSAGSCLALLFYFGGLQFRASRSHSRREEHSGRNGLHHPSPDHFWPRFPD
  ALRPFVPWDQLENEDSSVHISPRQKRDANSSIYKGKKCRMESCFDFTLCKKNGFKVYVYP
  QQKGEKIAESYQNILAAIEGSRFYTSDPSQACLFVLSLDTLDRDQLSPQYVHNLRSKVQS
  LHLWNNGRNHLIFNLYSGTWPDYTEDVGFDIGQAMLAKASISTENFRPNFDVSIPLFSKD
  HPRTGGERGFLKFNTIPPLRKYMLVFKGKRYLTGIGSDTRNALYHVHNGEDVVLLTTCKH
  GKDWQKHKDSRCDRDNTEYEKYDYREMLHNATFCLVPRGRRLGSFRFLEALQAACVPVML
  SNGWELPFSEVINWNQAAVIGDERLLLQIPSTIRSIHQDKILALRQQTQFLWEAYFSSVE
  KIVLTTLEIIQDRIFKHISRNSLIWNKHPGGLFVLPQYSSYLGDFPYYYANLGLKPPSKF
  TAVIHAVTPLVSQSQPVLKLLVAAAKSQYCAQIIVLWNCDKPLPAKHRWPATAVPVVVIE
  GESKVMSSRFLPYDNIITDAVLSLDEDTVLSTTEVDFAFTVWQSFPERIVGYPARSHFWD
  NSKERWGYTSKWTNDYSMVLTGAAIYHKYYHYLYSHYLPASLKNMVDQLANCEDILMNFL
  VSAVTKLPPIKVTQKKQYKETMMGQTSRASRWADPDHFAQRQSCMNTFASWFGYMPLIHS
  QMRLDPVLFKDQVSILRKKYRDIERL
• Function: Glycosyltransferase forming with EXT2 the heterodimeric heparan sulfate polymerase which catalyzes the elongation of the heparan sulfate glycan backbone. Glycan backbone extension consists in the alternating transfer of (1->4)-beta-D-GlcA and (1->4)-alpha-D-GlcNAc residues from their respective UDP-sugar donors. Both EXT1 and EXT2 are required for the full activity of the polymerase since EXT1 bears the N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase activity within the complex while EXT2 carries the glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity. Heparan sulfate proteoglycans are ubiquitous components of the extracellular matrix and play an important role in tissue homeostasis and signaling.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Glycosaminoglycan biosynthesis - heparan sulfate / heparin (hsa00534)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective EXT2 causes exostoses 2 (R-HSA-3656237)
  Defective EXT1 causes exostoses 1, TRPS2 and CHDS (R-HSA-3656253)
  HS-GAG biosynthesis (R-HSA-2022928)
• BioCyc Pathway: MetaCyc:HS00012-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Definitive	Altered Expression	[1]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Definitive	Altered Expression	[1]
Exostoses, multiple, type 1	DISF6DEA	Definitive	Autosomal dominant	[2]
Hepatitis A virus infection	DISUMFQV	Definitive	Biomarker	[3]
Trichorhinophalangeal syndrome type II	DISW4YZ1	Definitive	Autosomal dominant	[4]
Astrocytoma	DISL3V18	Strong	Biomarker	[5]
Autism	DISV4V1Z	Strong	Biomarker	[6]
Bone disease	DISE1F82	Strong	Genetic Variation	[7]
Breast cancer	DIS7DPX1	Strong	Biomarker	[8]
Chondrosarcoma	DIS4I7JB	Strong	Autosomal dominant	[9]
Epilepsy	DISBB28L	Strong	Biomarker	[10]
Exostoses, multiple, type 2	DISDMZ4W	Strong	Biomarker	[11]
Familial hypercholesterolemia	DISC06IX	Strong	Genetic Variation	[12]
Frontotemporal dementia	DISKYHXL	Strong	Biomarker	[13]
Glioma	DIS5RPEH	Strong	Genetic Variation	[14]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[15]
Hepatitis	DISXXX35	Strong	Genetic Variation	[16]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[17]
Hypercholesterolemia, familial, 1	DISU411W	Strong	Genetic Variation	[12]
Idiopathic inflammatory myopathy	DISGB1BZ	Strong	Biomarker	[18]
Lentivirus infection	DISX17PY	Strong	Altered Expression	[19]
leukaemia	DISS7D1V	Strong	Posttranslational Modification	[20]
Leukemia	DISNAKFL	Strong	Posttranslational Modification	[20]
Mental disorder	DIS3J5R8	Strong	Biomarker	[6]
Nephrotic syndrome	DISSPSC2	Strong	Genetic Variation	[21]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[22]
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[23]
Pick disease	DISP6X50	Strong	Biomarker	[13]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[18]
Schizophrenia	DISSRV2N	Strong	Biomarker	[24]
Trichorhinophalangeal syndrome	DISO1AEK	Strong	Genetic Variation	[25]
Adenocarcinoma	DIS3IHTY	moderate	Biomarker	[26]
Endometrial carcinoma	DISXR5CY	moderate	Genetic Variation	[27]
Exostosis	DIS3VKEI	moderate	Biomarker	[28]
Lupus nephritis	DISCVGPZ	moderate	Genetic Variation	[29]
Membranous glomerulonephritis	DISFSUKQ	moderate	Biomarker	[29]
Refractory multiple myeloma	DIS606GH	Supportive	Autosomal dominant	[30]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[31]
Autoimmune disease	DISORMTM	Limited	Biomarker	[29]
Cervical Intraepithelial neoplasia	DISXP757	Limited	Genetic Variation	[32]
Chromosomal disorder	DISM5BB5	Limited	Genetic Variation	[33]
Hepatitis C virus infection	DISQ0M8R	Limited	Biomarker	[34]
Intellectual disability	DISMBNXP	Limited	Biomarker	[35]
Osteosarcoma	DISLQ7E2	Limited	Genetic Variation	[36]
Plasma cell myeloma	DIS0DFZ0	Limited	Biomarker	[37]
Premature aging syndrome	DIS51AGT	Limited	Biomarker	[38]
Rectal carcinoma	DIS8FRR7	Limited	Genetic Variation	[39]
Venous thromboembolism	DISUR7CR	Limited	Biomarker	[40]

4 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 Exostosin-1 (EXT1).	[41]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Exostosin-1 (EXT1).	[48]
Cotinine	DMCEZ1B	Approved	Cotinine affects the methylation of Exostosin-1 (EXT1).	[52]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Exostosin-1 (EXT1).	[59]

18 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 Exostosin-1 (EXT1).	[42]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Exostosin-1 (EXT1).	[43]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Exostosin-1 (EXT1).	[44]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Exostosin-1 (EXT1).	[45]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Exostosin-1 (EXT1).	[46]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Exostosin-1 (EXT1).	[47]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Exostosin-1 (EXT1).	[49]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Exostosin-1 (EXT1).	[50]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Exostosin-1 (EXT1).	[51]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Exostosin-1 (EXT1).	[53]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the expression of Exostosin-1 (EXT1).	[54]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Exostosin-1 (EXT1).	[55]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Exostosin-1 (EXT1).	[56]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Exostosin-1 (EXT1).	[57]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Exostosin-1 (EXT1).	[58]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Exostosin-1 (EXT1).	[60]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Exostosin-1 (EXT1).	[61]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Exostosin-1 (EXT1).	[47]

References

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