Details of Drug Off-Target (DOT)

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

• DOT Name: Citramalyl-CoA lyase, mitochondrial (CLYBL)
• Synonyms: EC 4.1.3.25; (3S)-malyl-CoA thioesterase; EC 3.1.2.30; Beta-methylmalate synthase; EC 2.3.3.-; Citrate lyase subunit beta-like protein; Citrate lyase beta-like; Malate synthase; EC 2.3.3.9
• Gene Name: CLYBL
• Related Disease:
  Depression
  Lung cancer
  Lung carcinoma
  Neuroblastoma
  Paroxysmal nocturnal haemoglobinuria
  Rheumatoid arthritis
  Tuberculosis
  Wilms tumor
• UniProt ID: CLYBL_HUMAN
• PDB ID: 5VXC; 5VXO; 5VXS
• EC Number: 2.3.3.-; 2.3.3.9; 3.1.2.30; 4.1.3.25
• Pfam ID: PF03328
• Sequence:
  MALRLLRRAARGAAAAALLRLKASLAADIPRLGYSSSSHHKYIPRRAVLYVPGNDEKKIK
  KIPSLNVDCAVLDCEDGVAANKKNEARLRIVKTLEDIDLGPTEKCVRVNSVSSGLAEEDL
  ETLLQSRVLPSSLMLPKVESPEEIQWFADKFSFHLKGRKLEQPMNLIPFVETAMGLLNFK
  AVCEETLKVGPQVGLFLDAVVFGGEDFRASIGATSSKETLDILYARQKIVVIAKAFGLQA
  IDLVYIDFRDGAGLLRQSREGAAMGFTGKQVIHPNQIAVVQEQFSPSPEKIKWAEELIAA
  FKEHQQLGKGAFTFQGSMIDMPLLKQAQNTVTLATSIKEK
• Function: Mitochondrial citramalyl-CoA lyase indirectly involved in the vitamin B12 metabolism. Converts citramalyl-CoA into acetyl-CoA and pyruvate in the C5-dicarboxylate catabolism pathway. The C5-dicarboxylate catabolism pathway is required to detoxify itaconate, a vitamin B12-poisoning metabolite. Also acts as a malate synthase in vitro, converting glyoxylate and acetyl-CoA to malate. Also displays malyl-CoA thioesterase activity. Also acts as a beta-methylmalate synthase in vitro, by mediating conversion of glyoxylate and propionyl-CoA to beta-methylmalate. Also has very weak citramalate synthase activity in vitro.
• BioCyc Pathway: MetaCyc:HS04862-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Depression	DIS3XJ69	Strong	Genetic Variation	[1]
Lung cancer	DISCM4YA	Strong	Altered Expression	[2]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[2]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[3]
Paroxysmal nocturnal haemoglobinuria	DISBHMYH	Strong	Biomarker	[4]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[5]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[6]
Wilms tumor	DISB6T16	Strong	Genetic Variation	[7]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Daunorubicin	DMQUSBT	Approved	Citramalyl-CoA lyase, mitochondrial (CLYBL) affects the response to substance of Daunorubicin.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Citramalyl-CoA lyase, mitochondrial (CLYBL).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Citramalyl-CoA lyase, mitochondrial (CLYBL).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Citramalyl-CoA lyase, mitochondrial (CLYBL).	[18]

9 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 Citramalyl-CoA lyase, mitochondrial (CLYBL).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Citramalyl-CoA lyase, mitochondrial (CLYBL).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Citramalyl-CoA lyase, mitochondrial (CLYBL).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Citramalyl-CoA lyase, mitochondrial (CLYBL).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Citramalyl-CoA lyase, mitochondrial (CLYBL).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Citramalyl-CoA lyase, mitochondrial (CLYBL).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Citramalyl-CoA lyase, mitochondrial (CLYBL).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Citramalyl-CoA lyase, mitochondrial (CLYBL).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Citramalyl-CoA lyase, mitochondrial (CLYBL).	[19]

References

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• [2] Drug-induced apoptosis in lung cnacer cells is not mediated by the Fas/FasL (CD95/APO1) signaling pathway.Clin Cancer Res. 2000 Jan;6(1):203-12.
• [3] SV-Bay: structural variant detection in cancer genomes using a Bayesian approach with correction for GC-content and read mappability.Bioinformatics. 2016 Apr 1;32(7):984-92. doi: 10.1093/bioinformatics/btv751. Epub 2016 Jan 6.
• [4] Maternal genomic neutrophil FcRIII deficiency leading to neonatal isoimmune neutropenia.Blood. 1990 Nov 15;76(10):1927-32.
• [5] A genome-wide association study of rheumatoid arthritis without antibodies against citrullinated peptides.Ann Rheum Dis. 2015 Mar;74(3):e15. doi: 10.1136/annrheumdis-2013-204591. Epub 2014 Feb 14.
• [6] Theranostic Application of a Novel G-Quadruplex-Forming DNA Aptamer Targeting Malate Synthase of Mycobacterium tuberculosis.Mol Ther Nucleic Acids. 2019 Dec 6;18:661-672. doi: 10.1016/j.omtn.2019.09.026. Epub 2019 Oct 4.
• [7] Prognostic impact of karyotype and immunologic phenotype in 125 adult patients with de novo AML.Cancer Genet Cytogenet. 1992 Jul 1;61(1):14-25. doi: 10.1016/0165-4608(92)90364-e.
• [8] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [9] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [10] 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.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Characterisation of cisplatin-induced transcriptomics responses in primary mouse hepatocytes, HepG2 cells and mouse embryonic stem cells shows conservation of regulating transcription factor networks. Mutagenesis. 2014 Jan;29(1):17-26.
• [14] 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.
• [15] 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.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [19] 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.
• [20] Mapping genes that contribute to daunorubicin-induced cytotoxicity. Cancer Res. 2007 Jun 1;67(11):5425-33. doi: 10.1158/0008-5472.CAN-06-4431.