Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXFS5B3)

• DOT Name: Lactoylglutathione lyase (GLO1)
• Synonyms: EC 4.4.1.5; Aldoketomutase; Glyoxalase I; Glx I; Ketone-aldehyde mutase; Methylglyoxalase; S-D-lactoylglutathione methylglyoxal lyase
• Gene Name: GLO1
• UniProt ID: LGUL_HUMAN
• PDB ID: 1BH5; 1FRO; 1QIN; 1QIP; 3VW9; 3W0T; 3W0U; 7WSZ; 7WT0; 7WT1; 7WT2
• EC Number: 4.4.1.5
• Pfam ID: PF00903
• Sequence:
  MAEPQPPSGGLTDEAALSCCSDADPSTKDFLLQQTMLRVKDPKKSLDFYTRVLGMTLIQK
  CDFPIMKFSLYFLAYEDKNDIPKEKDEKIAWALSRKATLELTHNWGTEDDETQSYHNGNS
  DPRGFGHIGIAVPDVYSACKRFEELGVKFVKKPDDGKMKGLAFIQDPDGYWIEILNPNKM
  ATLM
• Function: Catalyzes the conversion of hemimercaptal, formed from methylglyoxal and glutathione, to S-lactoylglutathione. Involved in the regulation of TNF-induced transcriptional activity of NF-kappa-B. Required for normal osteoclastogenesis.
• KEGG Pathway:
  Pyruvate metabolism (hsa00620)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Pyruvate metabolism (R-HSA-70268)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Lactoylglutathione lyase (GLO1) decreases the response to substance of Doxorubicin.	[21]
Dihydroxyacetone	DMM1LG2	Approved	Lactoylglutathione lyase (GLO1) affects the response to substance of Dihydroxyacetone.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Lactoylglutathione lyase (GLO1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lactoylglutathione lyase (GLO1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Lactoylglutathione lyase (GLO1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Lactoylglutathione lyase (GLO1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Lactoylglutathione lyase (GLO1).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Lactoylglutathione lyase (GLO1).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Lactoylglutathione lyase (GLO1).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Lactoylglutathione lyase (GLO1).	[8]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the activity of Lactoylglutathione lyase (GLO1).	[9]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Lactoylglutathione lyase (GLO1).	[10]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Lactoylglutathione lyase (GLO1).	[11]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the activity of Lactoylglutathione lyase (GLO1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Lactoylglutathione lyase (GLO1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Lactoylglutathione lyase (GLO1).	[14]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Lactoylglutathione lyase (GLO1).	[15]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Lactoylglutathione lyase (GLO1).	[16]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Lactoylglutathione lyase (GLO1).	[17]
Okadaic acid	DM47CO1	Investigative	Okadaic acid decreases the expression of Lactoylglutathione lyase (GLO1).	[18]
methylglyoxal	DMRC3OZ	Investigative	methylglyoxal increases the expression of Lactoylglutathione lyase (GLO1).	[19]
Benzotetronic acid	DM4OKXI	Investigative	Benzotetronic acid decreases the activity of Lactoylglutathione lyase (GLO1).	[20]

References

• [1] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Differential protein expression of peroxiredoxin I and II by benzo(a)pyrene and quercetin treatment in 22Rv1 and PrEC prostate cell lines. Toxicol Appl Pharmacol. 2007 Apr 15;220(2):197-210. doi: 10.1016/j.taap.2006.12.030. Epub 2007 Jan 9.
• [7] 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.
• [8] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [9] Troglitazone selectively inhibits glyoxalase I gene expression. Diabetologia. 2001 Nov;44(11):2004-12. doi: 10.1007/s001250100004.
• [10] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [11] Resveratrol upregulates Nrf2 expression to attenuate methylglyoxal-induced insulin resistance in Hep G2 cells. J Agric Food Chem. 2012 Sep 12;60(36):9180-7. doi: 10.1021/jf302831d. Epub 2012 Aug 29.
• [12] Curcumin inhibits glyoxalase 1: a possible link to its anti-inflammatory and anti-tumor activity. PLoS One. 2008;3(10):e3508. doi: 10.1371/journal.pone.0003508. Epub 2008 Oct 23.
• [13] Chemopreventive mechanisms of methionine on inhibition of benzo(a)pyrene-DNA adducts formation in human hepatocellular carcinoma HepG2 cells. Toxicol Lett. 2012 Feb 5;208(3):232-8.
• [14] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [15] Neuroprotective effect of sulforaphane against methylglyoxal cytotoxicity. Chem Res Toxicol. 2015 Jun 15;28(6):1234-45. doi: 10.1021/acs.chemrestox.5b00067. Epub 2015 May 11.
• [16] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [17] Hyperglycemia-induced reactive oxygen species increase expression of the receptor for advanced glycation end products (RAGE) and RAGE ligands. Diabetes. 2010 Jan;59(1):249-55. doi: 10.2337/db09-0801. Epub 2009 Oct 15.
• [18] Proteomic analysis reveals multiple patterns of response in cells exposed to a toxin mixture. Chem Res Toxicol. 2009 Jun;22(6):1077-85.
• [19] Methylglyoxal disturbs the expression of antioxidant, apoptotic and glycation responsive genes and triggers programmed cell death in human leukocytes. Toxicol In Vitro. 2019 Mar;55:33-42.
• [20] Molecular docking and dynamic studies of a potential therapeutic target inhibiting glyoxalase system: Metabolic action of the 3, 3 '- [3- (5-chloro-2-hydroxyphenyl) -3-oxopropane-1, 1-diyl] - Bis-4-hydroxycoumarin leads overexpression of the intracellular level of methylglyoxal and induction of a pro-apoptotic phenomenon in a hepatocellular carcinoma model. Chem Biol Interact. 2021 Aug 25;345:109511. doi: 10.1016/j.cbi.2021.109511. Epub 2021 May 11.
• [21] Troglitazone overcomes doxorubicin-resistance in resistant K562 leukemia cells. Leuk Lymphoma. 2005 Aug;46(8):1199-206. doi: 10.1080/10428190500102555.
• [22] The sunless tanning agent dihydroxyacetone induces stress response gene expression and signaling in cultured human keratinocytes and reconstructed epidermis. Redox Biol. 2020 Sep;36:101594. doi: 10.1016/j.redox.2020.101594. Epub 2020 May 29.