Details of Drug Off-Target (DOT)

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

• DOT Name: Glycogen synthase, liver (GYS2)
• Synonyms: EC 2.4.1.11; Glycogen synthase 2
• Gene Name: GYS2
• Related Disease:
  Hyperglycemia
  Disorder of glycogen metabolism
  Gerstmann-Straussler-Scheinker syndrome
  Glycogen storage disease III
  Glycogen storage disorder due to hepatic glycogen synthase deficiency
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Joubert syndrome
  Medulloblastoma
  Metabolic disorder
  Neoplasm
  Orofaciodigital syndrome
  Polycystic ovarian syndrome
• UniProt ID: GYS2_HUMAN
• EC Number: 2.4.1.11
• Pfam ID: PF05693
• Sequence:
  MLRGRSLSVTSLGGLPQWEVEELPVEELLLFEVAWEVTNKVGGIYTVIQTKAKTTADEWG
  ENYFLIGPYFEHNMKTQVEQCEPVNDAVRRAVDAMNKHGCQVHFGRWLIEGSPYVVLFDI
  GYSAWNLDRWKGDLWEACSVGIPYHDREANDMLIFGSLTAWFLKEVTDHADGKYVVAQFH
  EWQAGIGLILSRARKLPIATIFTTHATLLGRYLCAANIDFYNHLDKFNIDKEAGERQIYH
  RYCMERASVHCAHVFTTVSEITAIEAEHMLKRKPDVVTPNGLNVKKFSAVHEFQNLHAMY
  KARIQDFVRGHFYGHLDFDLEKTLFLFIAGRYEFSNKGADIFLESLSRLNFLLRMHKSDI
  TVMVFFIMPAKTNNFNVETLKGQAVRKQLWDVAHSVKEKFGKKLYDALLRGEIPDLNDIL
  DRDDLTIMKRAIFSTQRQSLPPVTTHNMIDDSTDPILSTIRRIGLFNNRTDRVKVILHPE
  FLSSTSPLLPMDYEEFVRGCHLGVFPSYYEPWGYTPAECTVMGIPSVTTNLSGFGCFMQE
  HVADPTAYGIYIVDRRFRSPDDSCNQLTKFLYGFCKQSRRQRIIQRNRTERLSDLLDWRY
  LGRYYQHARHLTLSRAFPDKFHVELTSPPTTEGFKYPRPSSVPPSPSGSQASSPQSSDVE
  DEVEDERYDEEEEAERDRLNIKSPFSLSHVPHGKKKLHGEYKN
• 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: Specifically expressed in liver (at protein level).
• 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:
  Glycogen storage disease type 0 (liver GYS2) (R-HSA-3858516)
  Glycogen storage disease type IV (GBE1) (R-HSA-3878781)
  Glycogen synthesis (R-HSA-3322077)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperglycemia	DIS0BZB5	Definitive	Genetic Variation	[1]
Disorder of glycogen metabolism	DISYGNOB	Strong	Genetic Variation	[2]
Gerstmann-Straussler-Scheinker syndrome	DISIO6KC	Strong	Altered Expression	[3]
Glycogen storage disease III	DISTXQ1P	Strong	Altered Expression	[3]
Glycogen storage disorder due to hepatic glycogen synthase deficiency	DISLV8CK	Strong	Autosomal recessive	[4]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Joubert syndrome	DIS7P5CO	Strong	Genetic Variation	[6]
Medulloblastoma	DISZD2ZL	Strong	Genetic Variation	[2]
Metabolic disorder	DIS71G5H	Strong	Genetic Variation	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Orofaciodigital syndrome	DISSB296	Strong	Biomarker	[6]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[7]

8 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, liver (GYS2).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glycogen synthase, liver (GYS2).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Glycogen synthase, liver (GYS2).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Glycogen synthase, liver (GYS2).	[8]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Glycogen synthase, liver (GYS2).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glycogen synthase, liver (GYS2).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Glycogen synthase, liver (GYS2).	[12]
P-Coumaric Acid	DMGJSVD	Investigative	P-Coumaric Acid increases the activity of Glycogen synthase, liver (GYS2).	[13]

References

• [1] Mutational analysis of the GYS2 gene in patients diagnosed with ketotic hypoglycaemia.J Pediatr Endocrinol Metab. 2012;25(9-10):963-7. doi: 10.1515/jpem-2012-0165.
• [2] Group 3 medulloblastoma in a patient with a GYS2 germline mutation and glycogen storage disease 0a.Childs Nerv Syst. 2018 Mar;34(3):581-584. doi: 10.1007/s00381-017-3666-9. Epub 2017 Nov 22.
• [3] Inhibition of Glycogen Synthase II with RNAi Prevents Liver Injury in Mouse Models of Glycogen Storage Diseases.Mol Ther. 2018 Jul 5;26(7):1771-1782. doi: 10.1016/j.ymthe.2018.04.023. Epub 2018 Apr 27.
• [4] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [5] A GYS2/p53 Negative Feedback Loop Restricts Tumor Growth in HBV-Related Hepatocellular Carcinoma.Cancer Res. 2019 Feb 1;79(3):534-545. doi: 10.1158/0008-5472.CAN-18-2357. Epub 2018 Dec 24.
• [6] Beyond the panel: preconception screening in consanguineous couples using the TruSight One "clinical exome".Genet Med. 2019 Mar;21(3):608-612. doi: 10.1038/s41436-018-0082-9. Epub 2018 Jul 2.
• [7] Genome-wide association study identifies GYS2 as a novel genetic factor for polycystic ovary syndrome through obesity-related condition.J Hum Genet. 2012 Oct;57(10):660-4. doi: 10.1038/jhg.2012.92. Epub 2012 Sep 6.
• [8] 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.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [12] Metabolomic modulations of HepG2 cells exposed to bisphenol analogues. Environ Int. 2019 Aug;129:59-67. doi: 10.1016/j.envint.2019.05.008. Epub 2019 May 20.
• [13] Procyanidin B1 and p-Coumaric Acid from Highland Barley Grain Showed Synergistic Effect on Modulating Glucose Metabolism via IRS-1/PI3K/Akt Pathway. Mol Nutr Food Res. 2021 Sep;65(18):e2100454. doi: 10.1002/mnfr.202100454. Epub 2021 Aug 16.