Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8H3S3G)

• DOT Name: Carboxymethylenebutenolidase homolog (CMBL)
• Synonyms: EC 3.1.-.-
• Gene Name: CMBL
• UniProt ID: CMBL_HUMAN
• EC Number: 3.1.-.-
• Pfam ID: PF01738
• Sequence:
  MANEAYPCPCDIGHRLEYGGLGREVQVEHIKAYVTKSPVDAGKAVIVIQDIFGWQLPNTR
  YIADMISGNGYTTIVPDFFVGQEPWDPSGDWSIFPEWLKTRNAQKIDREISAILKYLKQQ
  CHAQKIGIVGFCWGGTAVHHLMMKYSEFRAGVSVYGIVKDSEDIYNLKNPTLFIFAENDV
  VIPLKDVSLLTQKLKEHCKVEYQIKTFSGQTHGFVHRKREDCSPADKPYIDEARRNLIEW
  LNKYM
• Function: Cysteine hydrolase. Can convert the prodrug olmesartan medoxomil into its pharmacologically active metabolite olmerstatan, an angiotensin receptor blocker, in liver and intestine. May also activate beta-lactam antibiotics faropenem medoxomil and lenampicillin.
• Tissue Specificity: Widely expressed, with highest levels in liver, followed by kidney, small intestine and colon. Present in liver and intestine (at protein level).
• KEGG Pathway: Metabolic pathways (hsa01100)
• Reactome Pathway: Phase I - Functionalization of compounds (R-HSA-211945)

Molecular Interaction Atlas (MIA) of This DOT

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 Carboxymethylenebutenolidase homolog (CMBL).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Carboxymethylenebutenolidase homolog (CMBL).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Carboxymethylenebutenolidase homolog (CMBL).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Carboxymethylenebutenolidase homolog (CMBL).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Carboxymethylenebutenolidase homolog (CMBL).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Carboxymethylenebutenolidase homolog (CMBL).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Carboxymethylenebutenolidase homolog (CMBL).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Carboxymethylenebutenolidase homolog (CMBL).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Carboxymethylenebutenolidase homolog (CMBL).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Carboxymethylenebutenolidase homolog (CMBL).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Carboxymethylenebutenolidase homolog (CMBL).	[12]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Carboxymethylenebutenolidase homolog (CMBL).	[13]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Carboxymethylenebutenolidase homolog (CMBL).	[13]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Carboxymethylenebutenolidase homolog (CMBL).	[13]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the expression of Carboxymethylenebutenolidase homolog (CMBL).	[13]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil increases the expression of Carboxymethylenebutenolidase homolog (CMBL).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Carboxymethylenebutenolidase homolog (CMBL).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Carboxymethylenebutenolidase homolog (CMBL).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Carboxymethylenebutenolidase homolog (CMBL).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Carboxymethylenebutenolidase homolog (CMBL).	[19]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Carboxymethylenebutenolidase homolog (CMBL).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Carboxymethylenebutenolidase homolog (CMBL).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Carboxymethylenebutenolidase homolog (CMBL).	[17]

References

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• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
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• [5] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [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.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [13] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [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] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] 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.
• [19] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.