Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWBM7WY)

• DOT Name: Glycogen debranching enzyme (AGL)
• Synonyms: Glycogen debrancher
• Gene Name: AGL
• Related Disease:
  Glycogen storage disease III
  Bladder cancer
  Colon cancer
  Colon carcinoma
  Giardiasis
  Hepatitis C virus infection
  Metabolic disorder
  Muscular dystrophy
  Neoplasm
  Non-small-cell lung cancer
  Urinary bladder cancer
  Acquired partial lipodystrophy
  Atrichia with papular lesions
  Congenital generalized lipodystrophy
  Disorder of glycogen metabolism
  Familial partial lipodystrophy
  Lipodystrophy
  Partial lipodystrophy
  Promyelocytic leukaemia
  Cardiomyopathy
  Glycogen storage disease type II
  Hypoglycemia
  Myopathy
  Urinary bladder neoplasm
• UniProt ID: GDE_HUMAN
• EC Number: 2.4.1.25; 3.2.1.33
• Pfam ID: PF06202 ; PF14701 ; PF14702 ; PF14699
• Sequence:
  MGHSKQIRILLLNEMEKLEKTLFRLEQGYELQFRLGPTLQGKAVTVYTNYPFPGETFNRE
  KFRSLDWENPTEREDDSDKYCKLNLQQSGSFQYYFLQGNEKSGGGYIVVDPILRVGADNH
  VLPLDCVTLQTFLAKCLGPFDEWESRLRVAKESGYNMIHFTPLQTLGLSRSCYSLANQLE
  LNPDFSRPNRKYTWNDVGQLVEKLKKEWNVICITDVVYNHTAANSKWIQEHPECAYNLVN
  SPHLKPAWVLDRALWRFSCDVAEGKYKEKGIPALIENDHHMNSIRKIIWEDIFPKLKLWE
  FFQVDVNKAVEQFRRLLTQENRRVTKSDPNQHLTIIQDPEYRRFGCTVDMNIALTTFIPH
  DKGPAAIEECCNWFHKRMEELNSEKHRLINYHQEQAVNCLLGNVFYERLAGHGPKLGPVT
  RKHPLVTRYFTFPFEEIDFSMEESMIHLPNKACFLMAHNGWVMGDDPLRNFAEPGSEVYL
  RRELICWGDSVKLRYGNKPEDCPYLWAHMKKYTEITATYFQGVRLDNCHSTPLHVAEYML
  DAARNLQPNLYVVAELFTGSEDLDNVFVTRLGISSLIREAMSAYNSHEEGRLVYRYGGEP
  VGSFVQPCLRPLMPAIAHALFMDITHDNECPIVHRSAYDALPSTTIVSMACCASGSTRGY
  DELVPHQISVVSEERFYTKWNPEALPSNTGEVNFQSGIIAARCAISKLHQELGAKGFIQV
  YVDQVDEDIVAVTRHSPSIHQSVVAVSRTAFRNPKTSFYSKEVPQMCIPGKIEEVVLEAR
  TIERNTKPYRKDENSINGTPDITVEIREHIQLNESKIVKQAGVATKGPNEYIQEIEFENL
  SPGSVIIFRVSLDPHAQVAVGILRNHLTQFSPHFKSGSLAVDNADPILKIPFASLASRLT
  LAELNQILYRCESEEKEDGGGCYDIPNWSALKYAGLQGLMSVLAEIRPKNDLGHPFCNNL
  RSGDWMIDYVSNRLISRSGTIAEVGKWLQAMFFYLKQIPRYLIPCYFDAILIGAYTTLLD
  TAWKQMSSFVQNGSTFVKHLSLGSVQLCGVGKFPSLPILSPALMDVPYRLNEITKEKEQC
  CVSLAAGLPHFSSGIFRCWGRDTFIALRGILLITGRYVEARNIILAFAGTLRHGLIPNLL
  GEGIYARYNCRDAVWWWLQCIQDYCKMVPNGLDILKCPVSRMYPTDDSAPLPAGTLDQPL
  FEVIQEAMQKHMQGIQFRERNAGPQIDRNMKDEGFNITAGVDEETGFVYGGNRFNCGTWM
  DKMGESDRARNRGIPATPRDGSAVEIVGLSKSAVRWLLELSKKNIFPYHEVTVKRHGKAI
  KVSYDEWNRKIQDNFEKLFHVSEDPSDLNEKHPNLVHKRGIYKDSYGASSPWCDYQLRPN
  FTIAMVVAPELFTTEKAWKALEIAEKKLLGPLGMKTLDPDDMVYCGIYDNALDNDNYNLA
  KGFNYHQGPEWLWPIGYFLRAKLYFSRLMGPETTAKTIVLVKNVLSRHYVHLERSPWKGL
  PELTNENAQYCPFSCETQAWSIATILETLYDL
• Function: Multifunctional enzyme acting as 1,4-alpha-D-glucan:1,4-alpha-D-glucan 4-alpha-D-glycosyltransferase and amylo-1,6-glucosidase in glycogen degradation.
• Tissue Specificity: Liver, kidney and lymphoblastoid cells express predominantly isoform 1; whereas muscle and heart express not only isoform 1, but also muscle-specific isoform mRNAs (isoforms 2, 3 and 4). Isoforms 5 and 6 are present in both liver and muscle.
• KEGG Pathway:
  Starch and sucrose metabolism (hsa00500)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Glycogen breakdown (glycogenolysis) (R-HSA-70221)
  Neutrophil degranulation (R-HSA-6798695)
• BioCyc Pathway: MetaCyc:HS08717-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glycogen storage disease III	DISTXQ1P	Definitive	Autosomal recessive	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Giardiasis	DISWUNWK	Strong	Biomarker	[4]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[5]
Metabolic disorder	DIS71G5H	Strong	Genetic Variation	[6]
Muscular dystrophy	DISJD6P7	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[2]
Acquired partial lipodystrophy	DISWXX4G	moderate	Genetic Variation	[10]
Atrichia with papular lesions	DIS80CUB	moderate	Genetic Variation	[10]
Congenital generalized lipodystrophy	DIS4XF8N	moderate	Genetic Variation	[10]
Disorder of glycogen metabolism	DISYGNOB	moderate	Genetic Variation	[11]
Familial partial lipodystrophy	DISFVL9J	moderate	Genetic Variation	[12]
Lipodystrophy	DIS3SGVD	moderate	Genetic Variation	[10]
Partial lipodystrophy	DIS2HKKW	moderate	Genetic Variation	[10]
Promyelocytic leukaemia	DISYGG13	moderate	Genetic Variation	[10]
Cardiomyopathy	DISUPZRG	Limited	Altered Expression	[13]
Glycogen storage disease type II	DISXZPBC	Limited	Genetic Variation	[14]
Hypoglycemia	DISRCKR7	Limited	Altered Expression	[15]
Myopathy	DISOWG27	Limited	Altered Expression	[13]
Urinary bladder neoplasm	DIS7HACE	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Glycogen debranching enzyme (AGL) affects the response to substance of Doxorubicin.	[30]
Cyclophosphamide	DM4O2Z7	Approved	Glycogen debranching enzyme (AGL) affects the response to substance of Cyclophosphamide.	[30]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
D-glucose	DMMG2TO	Investigative	Glycogen debranching enzyme (AGL) increases the uptake of D-glucose.	[31]

3 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 debranching enzyme (AGL).	[16]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Glycogen debranching enzyme (AGL).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Glycogen debranching enzyme (AGL).	[28]

12 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 debranching enzyme (AGL).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Glycogen debranching enzyme (AGL).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glycogen debranching enzyme (AGL).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glycogen debranching enzyme (AGL).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glycogen debranching enzyme (AGL).	[21]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Glycogen debranching enzyme (AGL).	[23]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Glycogen debranching enzyme (AGL).	[24]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Glycogen debranching enzyme (AGL).	[25]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Glycogen debranching enzyme (AGL).	[26]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial decreases the expression of Glycogen debranching enzyme (AGL).	[27]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium decreases the expression of Glycogen debranching enzyme (AGL).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Glycogen debranching enzyme (AGL).	[29]

References

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• [10] Exploring the pathophysiology behind the more common genetic and acquired lipodystrophies.J Hum Genet. 2014 Jan;59(1):16-23. doi: 10.1038/jhg.2013.107. Epub 2013 Oct 24.
• [11] Spectrum of AGL mutations in Chinese patients with glycogen storage disease type III: identification of 31 novel mutations.J Hum Genet. 2016 Jul;61(7):641-5. doi: 10.1038/jhg.2016.24. Epub 2016 Mar 17.
• [12] Determining residual adipose tissue characteristics with MRI in patients with various subtypes of lipodystrophy.Diagn Interv Radiol. 2017 Nov-Dec;23(6):428-434. doi: 10.5152/dir.2017.17019.
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• [14] Clinicopathological analysis of the homozygous p.W1327X AGL mutation in glycogen storage disease type 3.Am J Med Genet A. 2008 Nov 15;146A(22):2911-5. doi: 10.1002/ajmg.a.32529.
• [15] A Japanese patient with cardiomyopathy caused by a novel mutation R285X in the AGL gene.Circ J. 2007 Oct;71(10):1653-6. doi: 10.1253/circj.71.1653.
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• [18] 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.
• [19] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] 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.
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• [23] 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.
• [24] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [25] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [26] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [27] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [28] 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.
• [29] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [30] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [31] Role in tumor growth of a glycogen debranching enzyme lost in glycogen storage disease. J Natl Cancer Inst. 2014 Apr 3;106(5):dju062. doi: 10.1093/jnci/dju062.