Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2ZTJT0)

• DOT Name: Glycogen phosphorylase, brain form (PYGB)
• Synonyms: EC 2.4.1.1
• Gene Name: PYGB
• Related Disease:
  Non-insulin dependent diabetes
  Acute myocardial infarction
  Advanced cancer
  Myocardial ischemia
  Adenocarcinoma
  Breast cancer
  Breast carcinoma
  Non-small-cell lung cancer
• UniProt ID: PYGB_HUMAN
• PDB ID: 5IKO; 5IKP
• EC Number: 2.4.1.1
• Pfam ID: PF00343
• Sequence:
  MAKPLTDSEKRKQISVRGLAGLGDVAEVRKSFNRHLHFTLVKDRNVATPRDYFFALAHTV
  RDHLVGRWIRTQQHYYERDPKRIYYLSLEFYMGRTLQNTMVNLGLQNACDEAIYQLGLDL
  EELEEIEEDAGLGNGGLGRLAACFLDSMATLGLAAYGYGIRYEFGIFNQKIVNGWQVEEA
  DDWLRYGNPWEKARPEYMLPVHFYGRVEHTPDGVKWLDTQVVLAMPYDTPVPGYKNNTVN
  TMRLWSAKAPNDFKLQDFNVGDYIEAVLDRNLAENISRVLYPNDNFFEGKELRLKQEYFV
  VAATLQDIIRRFKSSKFGCRDPVRTCFETFPDKVAIQLNDTHPALSIPELMRILVDVEKV
  DWDKAWEITKKTCAYTNHTVLPEALERWPVSMFEKLLPRHLEIIYAINQRHLDHVAALFP
  GDVDRLRRMSVIEEGDCKRINMAHLCVIGSHAVNGVARIHSEIVKQSVFKDFYELEPEKF
  QNKTNGITPRRWLLLCNPGLADTIVEKIGEEFLTDLSQLKKLLPLVSDEVFIRDVAKVKQ
  ENKLKFSAFLEKEYKVKINPSSMFDVHVKRIHEYKRQLLNCLHVVTLYNRIKRDPAKAFV
  PRTVMIGGKAAPGYHMAKLIIKLVTSIGDVVNHDPVVGDRLKVIFLENYRVSLAEKVIPA
  ADLSQQISTAGTEASGTGNMKFMLNGALTIGTMDGANVEMAEEAGAENLFIFGLRVEDVE
  ALDRKGYNAREYYDHLPELKQAVDQISSGFFSPKEPDCFKDIVNMLMHHDRFKVFADYEA
  YMQCQAQVDQLYRNPKEWTKKVIRNIACSGKFSSDRTITEYAREIWGVEPSDLQIPPPNI
  PRD
• Function: Glycogen phosphorylase that regulates glycogen mobilization. Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties.
• KEGG Pathway:
  Starch and sucrose metabolism (hsa00500)
  Metabolic pathways (hsa01100)
  Necroptosis (hsa04217)
  Insulin sig.ling pathway (hsa04910)
  Glucagon sig.ling pathway (hsa04922)
  Insulin resistance (hsa04931)
• Reactome Pathway:
  Glycogen breakdown (glycogenolysis) (R-HSA-70221)
  Neutrophil degranulation (R-HSA-6798695)
• BioCyc Pathway: MetaCyc:HS02178-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Genetic Variation	[1]
Acute myocardial infarction	DISE3HTG	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[4]
Adenocarcinoma	DIS3IHTY	moderate	Altered Expression	[5]
Breast cancer	DIS7DPX1	moderate	Biomarker	[6]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[6]
Non-small-cell lung cancer	DIS5Y6R9	moderate	Altered Expression	[5]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Capecitabine	DMTS85L	Approved	Glycogen phosphorylase, brain form (PYGB) increases the response to substance of Capecitabine.	[23]
Flavopiridol	DMKSUOI	Phase 2	Glycogen phosphorylase, brain form (PYGB) affects the binding of Flavopiridol.	[24]

2 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 Glycogen phosphorylase, brain form (PYGB).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Glycogen phosphorylase, brain form (PYGB).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Glycogen phosphorylase, brain form (PYGB).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Glycogen phosphorylase, brain form (PYGB).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Glycogen phosphorylase, brain form (PYGB).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glycogen phosphorylase, brain form (PYGB).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Glycogen phosphorylase, brain form (PYGB).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Glycogen phosphorylase, brain form (PYGB).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of Glycogen phosphorylase, brain form (PYGB).	[14]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Glycogen phosphorylase, brain form (PYGB).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Glycogen phosphorylase, brain form (PYGB).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Glycogen phosphorylase, brain form (PYGB).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Glycogen phosphorylase, brain form (PYGB).	[14]
BAICALEIN	DM4C7E6	Phase 2	BAICALEIN decreases the activity of Glycogen phosphorylase, brain form (PYGB).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Glycogen phosphorylase, brain form (PYGB).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Glycogen phosphorylase, brain form (PYGB).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Glycogen phosphorylase, brain form (PYGB).	[22]

References

• [1] Identification of novel alleles associated with insulin resistance in childhood obesity using pooled-DNA genome-wide association study approach.Int J Obes (Lond). 2018 Apr;42(4):686-695. doi: 10.1038/ijo.2017.293. Epub 2017 Nov 30.
• [2] Using SERS-based microfluidic paper-based device (PAD) for calibration-free quantitative measurement of AMI cardiac biomarkers.Biosens Bioelectron. 2020 Jan 1;147:111792. doi: 10.1016/j.bios.2019.111792. Epub 2019 Oct 18.
• [3] Glycogen phosphorylase B promotes ovarian cancer progression via Wnt/-catenin signaling and is regulated by miR-133a-3p.Biomed Pharmacother. 2019 Dec;120:109449. doi: 10.1016/j.biopha.2019.109449. Epub 2019 Oct 15.
• [4] Cardioplegia prevents ischemia-induced transcriptional alterations of cytoprotective genes in rat hearts: a DNA microarray study.J Thorac Cardiovasc Surg. 2005 Oct;130(4):1151. doi: 10.1016/j.jtcvs.2005.06.027.
• [5] Clinicopathological significance of BGP expression in non-small-cell lung carcinoma: relationship with histological type, microvessel density and patients' survival.Pathology. 2006 Dec;38(6):555-60. doi: 10.1080/00313020601024029.
• [6] Breast cancers utilize hypoxic glycogen stores via PYGB, the brain isoform of glycogen phosphorylase, to promote metastatic phenotypes.PLoS One. 2019 Sep 19;14(9):e0220973. doi: 10.1371/journal.pone.0220973. eCollection 2019.
• [7] 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.
• [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] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] 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.
• [13] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [14] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [15] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [18] Multidisciplinary docking, kinetics and X-ray crystallography studies of baicalein acting as a glycogen phosphorylase inhibitor and determination of its' potential against glioblastoma in cellular models. Chem Biol Interact. 2023 Sep 1;382:110568. doi: 10.1016/j.cbi.2023.110568. Epub 2023 Jun 3.
• [19] 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.
• [20] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [21] 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.
• [22] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [23] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.
• [24] The cyclin-dependent kinase (CDK) inhibitor flavopiridol inhibits glycogen phosphorylase. Arch Biochem Biophys. 2001 Feb 15;386(2):179-87. doi: 10.1006/abbi.2000.2220.