Details of Drug Off-Target (DOT)

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

• DOT Name: Glycogen synthase, muscle (GYS1)
• Synonyms: EC 2.4.1.11; Glycogen synthase 1
• Gene Name: GYS1
• Related Disease:
  Arthritis
  Glycogen storage disease due to muscle and heart glycogen synthase deficiency
  Myocardial infarction
  Rheumatoid arthritis
  High blood pressure
  Huntington disease
  Hyperglycemia
  Hyperinsulinemia
  Myelodysplastic syndrome
  Myopathy
  Hypoglycemia
  Type-1 diabetes
  Cardiomyopathy
  Type-1/2 diabetes
• UniProt ID: GYS1_HUMAN
• PDB ID: 7Q0B; 7Q0S; 7Q12; 7Q13; 7ZBN; 8CVX; 8CVY; 8CVZ
• EC Number: 2.4.1.11
• Pfam ID: PF05693
• Sequence:
  MPLNRTLSMSSLPGLEDWEDEFDLENAVLFEVAWEVANKVGGIYTVLQTKAKVTGDEWGD
  NYFLVGPYTEQGVRTQVELLEAPTPALKRTLDSMNSKGCKVYFGRWLIEGGPLVVLLDVG
  ASAWALERWKGELWDTCNIGVPWYDREANDAVLFGFLTTWFLGEFLAQSEEKPHVVAHFH
  EWLAGVGLCLCRARRLPVATIFTTHATLLGRYLCAGAVDFYNNLENFNVDKEAGERQIYH
  RYCMERAAAHCAHVFTTVSQITAIEAQHLLKRKPDIVTPNGLNVKKFSAMHEFQNLHAQS
  KARIQEFVRGHFYGHLDFNLDKTLYFFIAGRYEFSNKGADVFLEALARLNYLLRVNGSEQ
  TVVAFFIMPARTNNFNVETLKGQAVRKQLWDTANTVKEKFGRKLYESLLVGSLPDMNKML
  DKEDFTMMKRAIFATQRQSFPPVCTHNMLDDSSDPILTTIRRIGLFNSSADRVKVIFHPE
  FLSSTSPLLPVDYEEFVRGCHLGVFPSYYEPWGYTPAECTVMGIPSISTNLSGFGCFMEE
  HIADPSAYGIYILDRRFRSLDDSCSQLTSFLYSFCQQSRRQRIIQRNRTERLSDLLDWKY
  LGRYYMSARHMALSKAFPEHFTYEPNEADAAQGYRYPRPASVPPSPSLSRHSSPHQSEDE
  EDPRNGPLEEDGERYDEDEEAAKDRRNIRAPEWPRRASCTSSTSGSKRNSVDTATSSSLS
  TPSEPLSPTSSLGEERN
• Function: Glycogen synthase participates in the glycogen biosynthetic process along with glycogenin and glycogen branching enzyme. Extends the primer composed of a few glucose units formed by glycogenin by adding new glucose units to it. In this context, glycogen synthase transfers the glycosyl residue from UDP-Glc to the non-reducing end of alpha-1,4-glucan.
• Tissue Specificity: Expressed in skeletal muscle and most other cell types where glycogen is present.
• KEGG Pathway:
  Starch and sucrose metabolism (hsa00500)
  Metabolic pathways (hsa01100)
  PI3K-Akt sig.ling pathway (hsa04151)
  AMPK sig.ling pathway (hsa04152)
  Insulin sig.ling pathway (hsa04910)
  Glucagon sig.ling pathway (hsa04922)
  Insulin resistance (hsa04931)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Myoclonic epilepsy of Lafora (R-HSA-3785653)
  Glycogen storage disease type XV (GYG1) (R-HSA-3814836)
  Glycogen storage disease type 0 (muscle GYS1) (R-HSA-3828062)
  Glycogen synthesis (R-HSA-3322077)
• BioCyc Pathway: MetaCyc:HS02622-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthritis	DIST1YEL	Definitive	Biomarker	[1]
Glycogen storage disease due to muscle and heart glycogen synthase deficiency	DIS9D0M0	Definitive	Autosomal recessive	[2]
Myocardial infarction	DIS655KI	Definitive	Genetic Variation	[3]
Rheumatoid arthritis	DISTSB4J	Definitive	Altered Expression	[1]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[4]
Huntington disease	DISQPLA4	Strong	Altered Expression	[5]
Hyperglycemia	DIS0BZB5	Strong	Altered Expression	[6]
Hyperinsulinemia	DISIDWT6	Strong	Biomarker	[7]
Myelodysplastic syndrome	DISYHNUI	Strong	Altered Expression	[8]
Myopathy	DISOWG27	Strong	Genetic Variation	[9]
Hypoglycemia	DISRCKR7	moderate	Biomarker	[10]
Type-1 diabetes	DIS7HLUB	moderate	Biomarker	[11]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[12]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[13]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Piroxicam	DMTK234	Approved	Glycogen synthase, muscle (GYS1) increases the Hepatic function abnormal ADR of Piroxicam.	[28]

4 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 Glycogen synthase, muscle (GYS1).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the phosphorylation of Glycogen synthase, muscle (GYS1).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Glycogen synthase, muscle (GYS1).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Glycogen synthase, muscle (GYS1).	[24]

10 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 Glycogen synthase, muscle (GYS1).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Glycogen synthase, muscle (GYS1).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Glycogen synthase, muscle (GYS1).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glycogen synthase, muscle (GYS1).	[18]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Glycogen synthase, muscle (GYS1).	[19]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Glycogen synthase, muscle (GYS1).	[21]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Glycogen synthase, muscle (GYS1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Glycogen synthase, muscle (GYS1).	[25]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Glycogen synthase, muscle (GYS1).	[26]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Glycogen synthase, muscle (GYS1).	[27]

References

• [1] Glycogen Metabolism and Rheumatoid Arthritis: The Role of Glycogen Synthase 1 in Regulation of Synovial Inflammation via Blocking AMP-Activated Protein Kinase Activation.Front Immunol. 2018 Jul 27;9:1714. doi: 10.3389/fimmu.2018.01714. eCollection 2018.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Variation in GYS1 interacts with exercise and gender to predict cardiovascular mortality.PLoS One. 2007 Mar 14;2(3):e285. doi: 10.1371/journal.pone.0000285.
• [4] A paired-sibling analysis of the XbaI polymorphism in the muscle glycogen synthase gene.Diabetologia. 1999 Sep;42(9):1138-45. doi: 10.1007/s001250051282.
• [5] Altered hypothalamic protein expression in a rat model of Huntington's disease.PLoS One. 2012;7(10):e47240. doi: 10.1371/journal.pone.0047240. Epub 2012 Oct 18.
• [6] Neonatal hyperglycemia alters the neurochemical profile, dendritic arborization and gene expression in the developing rat hippocampus.NMR Biomed. 2018 May;31(5):e3910. doi: 10.1002/nbm.3910. Epub 2018 Mar 13.
• [7] Impaired insulin-stimulated expression of the glycogen synthase gene in skeletal muscle of type 2 diabetic patients is acquired rather than inherited.J Clin Endocrinol Metab. 2000 Apr;85(4):1584-90. doi: 10.1210/jcem.85.4.6535.
• [8] Overexpression of GYS1, MIF, and MYC is associated with adverse outcome and poor response to azacitidine in myelodysplastic syndromes and acute myeloid leukemia.Clin Lymphoma Myeloma Leuk. 2015 Apr;15(4):236-44. doi: 10.1016/j.clml.2014.10.003. Epub 2014 Oct 23.
• [9] Association between population structure and allele frequencies of the glycogen synthase 1 mutation in the Austrian Noriker draft horse.Anim Genet. 2017 Feb;48(1):108-112. doi: 10.1111/age.12481. Epub 2016 Aug 1.
• [10] Exercise in transgenic mice overexpressing GLUT4 glucose transporters: effects on substrate metabolism and glycogen regulation.Metabolism. 1997 Nov;46(11):1349-57. doi: 10.1016/s0026-0495(97)90243-2.
• [11] A missense mutation of the muscle glycogen synthase gene (M416V) is associated with insulin resistance in the Japanese population.Diabetologia. 1997 Aug;40(8):947-52. doi: 10.1007/s001250050772.
• [12] Identification of a novel mutation in GYS1 (muscle-specific glycogen synthase) resulting in sudden cardiac death, that is diagnosable from skin fibroblasts.Mol Genet Metab. 2009 Dec;98(4):378-82. doi: 10.1016/j.ymgme.2009.07.012. Epub 2009 Jul 26.
• [13] AJS1669, a novel small-molecule muscle glycogen synthase activator, improves glucose metabolism and reduces body fat mass in mice.Int J Mol Med. 2017 Apr;39(4):841-850. doi: 10.3892/ijmm.2017.2909. Epub 2017 Mar 7.
• [14] 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.
• [15] 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.
• [16] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [17] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [18] 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.
• [19] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [20] Taurine improves low-level inorganic arsenic-induced insulin resistance by activating PPAR-mTORC2 signalling and inhibiting hepatic autophagy. J Cell Physiol. 2019 Apr;234(4):5143-5152. doi: 10.1002/jcp.27318. Epub 2018 Oct 26.
• [21] Testosterone or 17{beta}-estradiol exposure reveals sex-specific effects on glucose and lipid metabolism in human myotubes. J Endocrinol. 2011 Aug;210(2):219-29. doi: 10.1530/JOE-10-0497. Epub 2011 Jun 1.
• [22] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [23] 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.
• [24] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [25] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [26] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [27] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [28] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.