Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSBNRT5)

• DOT Name: Glucose 1,6-bisphosphate synthase (PGM2L1)
• Synonyms: EC 2.7.1.106; PMMLP; Phosphoglucomutase-2-like 1
• Gene Name: PGM2L1
• Related Disease: Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skin abnormalities
• UniProt ID: PGM2L_HUMAN
• EC Number: 2.7.1.106
• Pfam ID: PF02878 ; PF02879 ; PF02880
• Sequence:
  MAENTEGDLNSNLLHAPYHTGDPQLDTAIGQWLRWDKNPKTKEQIENLLRNGMNKELRDR
  LCCRMTFGTAGLRSAMGAGFCYINDLTVIQSTQGMYKYLERCFSDFKQRGFVVGYDTRGQ
  VTSSCSSQRLAKLTAAVLLAKDVPVYLFSRYVPTPFVPYAVQKLKAVAGVMITASHNRKE
  DNGYKVYWETGAQITSPHDKEILKCIEECVEPWNGSWNDNLVDTSPLKRDPLQDICRRYM
  EDLKKICFYRELNSKTTLKFVHTSFHGVGHDYVQLAFKVFGFKPPIPVPEQKDPDPDFST
  VKCPNPEEGESVLELSLRLAEKENARVVLATDPDADRLAAAELQENGCWKVFTGNELAAL
  FGWWMFDCWKKNKSRNADVKNVYMLATTVSSKILKAIALKEGFHFEETLPGFKWIGSRII
  DLLENGKEVLFAFEESIGFLCGTSVLDKDGVSAAVVVAEMASYLETMNITLKQQLVKVYE
  KYGYHISKTSYFLCYEPPTIKSIFERLRNFDSPKEYPKFCGTFAILHVRDVTTGYDSSQP
  NKKSVLPVSKNSQMITFTFQNGCVATLRTSGTEPKIKYYAEMCASPDQSDTALLEEELKK
  LIDALIENFLQPSKNGLIWRSV
• Function: Glucose 1,6-bisphosphate synthase using 1,3-bisphosphoglycerate as a phosphate donor and a series of 1-phosphate sugars, including glucose 1-phosphate, mannose 1-phosphate, ribose 1-phosphate and deoxyribose 1-phosphate, as acceptors. In vitro, also exhibits very low phosphopentomutase and phosphoglucomutase activity which are most probably not physiologically relevant.
• KEGG Pathway:
  Starch and sucrose metabolism (hsa00500)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Glycolysis (R-HSA-70171)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skin abnormalities	DISDOXT0	Strong	Autosomal recessive	[1]

21 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 Glucose 1,6-bisphosphate synthase (PGM2L1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[12]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[16]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[20]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[21]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Glucose 1,6-bisphosphate synthase (PGM2L1).	[22]

References

• [1] Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder. Am J Hum Genet. 2021 Jun 3;108(6):1151-1160. doi: 10.1016/j.ajhg.2021.04.017. Epub 2021 May 11.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Gene expression profiling of A549 cells exposed to Milan PM2.5. Toxicol Lett. 2012 Mar 7;209(2):136-45.
• [16] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [17] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [18] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [19] 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.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [21] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [22] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.