Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ43JCE)

• DOT Name: Maleylacetoacetate isomerase (GSTZ1)
• Synonyms: MAAI; EC 5.2.1.2; GSTZ1-1; Glutathione S-transferase zeta 1; EC 2.5.1.18
• Gene Name: GSTZ1
• Related Disease: Maleylacetoacetate isomerase deficiency
• UniProt ID: MAAI_HUMAN
• PDB ID: 1FW1; 8E8P
• EC Number: 2.5.1.18; 5.2.1.2
• Pfam ID: PF14497 ; PF13409
• Sequence:
  MQAGKPILYSYFRSSCSWRVRIALALKGIDYKTVPINLIKDRGQQFSKDFQALNPMKQVP
  TLKIDGITIHQSLAIIEYLEEMRPTPRLLPQDPKKRASVRMISDLIAGGIQPLQNLSVLK
  QVGEEMQLTWAQNAITCGFNALEQILQSTAGIYCVGDEVTMADLCLVPQVANAERFKVDL
  TPYPTISSINKRLLVLEAFQVSHPCRQPDTPTELRA
• Function: Bifunctional enzyme showing minimal glutathione-conjugating activity with ethacrynic acid and 7-chloro-4-nitrobenz-2-oxa-1,3-diazole and maleylacetoacetate isomerase activity. Has also low glutathione peroxidase activity with T-butyl and cumene hydroperoxides. Is able to catalyze the glutathione dependent oxygenation of dichloroacetic acid to glyoxylic acid.
• Tissue Specificity: Mostly expressed in liver followed by kidney, skeletal muscle and brain. Also expressed in melanocytes, synovium, placenta, breast and fetal liver and heart.
• KEGG Pathway:
  Tyrosine metabolism (hsa00350)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Regulation of pyruvate dehydrogenase (PDH) complex (R-HSA-204174)
  Tyrosine catabolism (R-HSA-8963684)
  Glutathione conjugation (R-HSA-156590)
• BioCyc Pathway: MetaCyc:HS02114-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Maleylacetoacetate isomerase deficiency	DIS4JQQ8	Moderate	Autosomal recessive	[1]

This DOT Affected the Regulation of Drug Effects of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Maleylacetoacetate isomerase (GSTZ1) affects the metabolism of Hydrogen peroxide.	[20]
Ethacrynic acid	DM60QMR	Approved	Maleylacetoacetate isomerase (GSTZ1) affects the metabolism of Ethacrynic acid.	[22]
DNCB	DMDTVYC	Phase 2	Maleylacetoacetate isomerase (GSTZ1) affects the metabolism of DNCB.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Artesunate	DMR27C8	Approved	Maleylacetoacetate isomerase (GSTZ1) affects the response to substance of Artesunate.	[21]
Deoxythymidine	DMR90HY	Investigative	Maleylacetoacetate isomerase (GSTZ1) affects the response to substance of Deoxythymidine.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Maleylacetoacetate isomerase (GSTZ1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Maleylacetoacetate isomerase (GSTZ1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Maleylacetoacetate isomerase (GSTZ1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Maleylacetoacetate isomerase (GSTZ1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Maleylacetoacetate isomerase (GSTZ1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Maleylacetoacetate isomerase (GSTZ1).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Maleylacetoacetate isomerase (GSTZ1).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Maleylacetoacetate isomerase (GSTZ1).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Maleylacetoacetate isomerase (GSTZ1).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Maleylacetoacetate isomerase (GSTZ1).	[11]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Maleylacetoacetate isomerase (GSTZ1).	[12]
Beta-carotene	DM0RXBT	Approved	Beta-carotene decreases the expression of Maleylacetoacetate isomerase (GSTZ1).	[13]
Isoflavone	DM7U58J	Phase 4	Isoflavone affects the expression of Maleylacetoacetate isomerase (GSTZ1).	[15]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Maleylacetoacetate isomerase (GSTZ1).	[16]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Maleylacetoacetate isomerase (GSTZ1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Maleylacetoacetate isomerase (GSTZ1).	[3]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Maleylacetoacetate isomerase (GSTZ1).	[18]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Maleylacetoacetate isomerase (GSTZ1).	[19]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Maleylacetoacetate isomerase (GSTZ1).	[7]
Protoporphyrin IX	DMWYE7A	Investigative	Protoporphyrin IX decreases the activity of Maleylacetoacetate isomerase (GSTZ1).	[20]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Glutathione	DMAHMT9	Approved	Glutathione affects the binding of Maleylacetoacetate isomerase (GSTZ1).	[14]

References

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• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
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• [4] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [5] 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.
• [6] 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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• [9] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
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• [11] Xenobiotic CAR activators induce Dlk1-Dio3 locus noncoding RNA expression in mouse liver. Toxicol Sci. 2017 Aug 1;158(2):367-378.
• [12] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [13] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [14] Crystal structure of maleylacetoacetate isomerase/glutathione transferase zeta reveals the molecular basis for its remarkable catalytic promiscuity. Biochemistry. 2001 Feb 13;40(6):1567-76. doi: 10.1021/bi002249z.
• [15] Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells. J Nutr. 2006 Jan;136(1):75-82.
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• [19] Microphysiological system modeling of ochratoxin A-associated nephrotoxicity. Toxicology. 2020 Nov;444:152582. doi: 10.1016/j.tox.2020.152582. Epub 2020 Sep 6.
• [20] Purification and characterization of human muscle glutathione S-transferases: evidence that glutathione S-transferase zeta corresponds to a locus distinct from GST1, GST2, and GST3. Arch Biochem Biophys. 1991 Feb 15;285(1):64-73. doi: 10.1016/0003-9861(91)90329-h.
• [21] Glutathione-related enzymes contribute to resistance of tumor cells and low toxicity in normal organs to artesunate. In Vivo. 2005 Jan-Feb;19(1):225-32.
• [22] Zeta, a novel class of glutathione transferases in a range of species from plants to humans. Biochem J. 1997 Dec 15;328 ( Pt 3)(Pt 3):929-35. doi: 10.1042/bj3280929.
• [23] Polymorphisms in GSTT1, GSTZ1, and CYP2E1, disinfection by-products, and risk of bladder cancer in Spain. Environ Health Perspect. 2010 Nov;118(11):1545-50. doi: 10.1289/ehp.1002206.