Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAJ7YEW)

• DOT Name: Glycogenin-2 (GYG2)
• Synonyms: GN-2; GN2; EC 2.4.1.186
• Gene Name: GYG2
• Related Disease:
  Leigh syndrome
  Cardiomyopathy
  Disorder of glycogen metabolism
• UniProt ID: GLYG2_HUMAN
• PDB ID: 4UEG
• EC Number: 2.4.1.186
• Pfam ID: PF01501
• Sequence:
  MSETEFHHGAQAGLELLRSSNSPTSASQSAGMTVTDQAFVTLATNDIYCQGALVLGQSLR
  RHRLTRKLVVLITPQVSSLLRVILSKVFDEVIEVNLIDSADYIHLAFLKRPELGLTLTKL
  HCWTLTHYSKCVFLDADTLVLSNVDELFDRGEFSAAPDPGWPDCFNSGVFVFQPSLHTHK
  LLLQHAMEHGSFDGADQGLLNSFFRNWSTTDIHKHLPFIYNLSSNTMYTYSPAFKQFGSS
  AKVVHFLGSMKPWNYKYNPQSGSVLEQGSASSSQHQAAFLHLWWTVYQNNVLPLYKSVQA
  GEARASPGHTLCHSDVGGPCADSASGVGEPCENSTPSAGVPCANSPLGSNQPAQGLPEPT
  QIVDETLSLPEGRRSEDMIACPETETPAVITCDPLSQPSPQPADFTETETILQPANKVES
  VSSEETFEPSQELPAEALRDPSLQDALEVDLAVSVSQISIEEKVKELSPEEERRKWEEGR
  IDYMGKDAFARIQEKLDRFLQ
• Function: Glycogenin participates in the glycogen biosynthetic process along with glycogen synthase and glycogen branching enzyme. It self-glucosylates, via an inter-subunit mechanism, to form an oligosaccharide primer that serves as substrate for glycogen synthase.
• Tissue Specificity: Detected in liver (at protein level) . Expressed preferentially in liver, heart, and pancreas .
• KEGG Pathway:
  Starch and sucrose metabolism (hsa00500)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Glycogen storage disease type 0 (liver GYS2) (R-HSA-3858516)
  Glycogen storage disease type IV (GBE1) (R-HSA-3878781)
  Glycogen breakdown (glycogenolysis) (R-HSA-70221)
  Glycogen synthesis (R-HSA-3322077)
• BioCyc Pathway: MetaCyc:HS00703-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leigh syndrome	DISWQU45	Strong	Genetic Variation	[1]
Cardiomyopathy	DISUPZRG	Disputed	Biomarker	[2]
Disorder of glycogen metabolism	DISYGNOB	Limited	Biomarker	[3]

14 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 Glycogenin-2 (GYG2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glycogenin-2 (GYG2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glycogenin-2 (GYG2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glycogenin-2 (GYG2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Glycogenin-2 (GYG2).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glycogenin-2 (GYG2).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Glycogenin-2 (GYG2).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Glycogenin-2 (GYG2).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Glycogenin-2 (GYG2).	[12]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Glycogenin-2 (GYG2).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Glycogenin-2 (GYG2).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Glycogenin-2 (GYG2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Glycogenin-2 (GYG2).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Glycogenin-2 (GYG2).	[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 Glycogenin-2 (GYG2).	[15]

References

• [1] A hemizygous GYG2 mutation and Leigh syndrome: a possible link?.Hum Genet. 2014 Feb;133(2):225-34. doi: 10.1007/s00439-013-1372-6. Epub 2013 Oct 8.
• [2] Glycogenin is Dispensable for Glycogen Synthesis in Human Muscle, and Glycogenin Deficiency Causes Polyglucosan Storage.J Clin Endocrinol Metab. 2020 Feb 1;105(2):557-66. doi: 10.1210/clinem/dgz075.
• [3] Glycogenin-2 is dispensable for liver glycogen synthesis and glucagon-stimulated glucose release.J Clin Endocrinol Metab. 2015 May;100(5):E767-75. doi: 10.1210/jc.2014-4337. Epub 2015 Mar 9.
• [4] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [5] 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.
• [6] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [11] 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.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [17] 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.
• [18] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.