Details of Drug Off-Target (DOT)

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

• DOT Name: Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2)
• Synonyms: MCCase subunit beta; EC 6.4.1.4; 3-methylcrotonyl-CoA carboxylase 2; 3-methylcrotonyl-CoA carboxylase non-biotin-containing subunit; 3-methylcrotonyl-CoA:carbon dioxide ligase subunit beta
• Gene Name: MCCC2
• Related Disease:
  3-methylcrotonyl-CoA carboxylase 1 deficiency
  3-methylcrotonyl-CoA carboxylase 2 deficiency
  3-methylcrotonyl-CoA carboxylase deficiency
  Myocardial infarction
  Propionic acidemia
  Prostate cancer
  Prostate carcinoma
  Schizoaffective disorder
  Breast cancer
  Breast carcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
• UniProt ID: MCCB_HUMAN
• EC Number: 6.4.1.4
• Pfam ID: PF01039
• Sequence:
  MWAVLRLALRPCARASPAGPRAYHGDSVASLGTQPDLGSALYQENYKQMKALVNQLHERV
  EHIKLGGGEKARALHISRGKLLPRERIDNLIDPGSPFLELSQFAGYQLYDNEEVPGGGII
  TGIGRVSGVECMIIANDATVKGGAYYPVTVKKQLRAQEIAMQNRLPCIYLVDSGGAYLPR
  QADVFPDRDHFGRTFYNQAIMSSKNIAQIAVVMGSCTAGGAYVPAMADENIIVRKQGTIF
  LAGPPLVKAATGEEVSAEDLGGADLHCRKSGVSDHWALDDHHALHLTRKVVRNLNYQKKL
  DVTIEPSEEPLFPADELYGIVGANLKRSFDVREVIARIVDGSRFTEFKAFYGDTLVTGFA
  RIFGYPVGIVGNNGVLFSESAKKGTHFVQLCCQRNIPLLFLQNITGFMVGREYEAEGIAK
  DGAKMVAAVACAQVPKITLIIGGSYGAGNYGMCGRAYSPRFLYIWPNARISVMGGEQAAN
  VLATITKDQRAREGKQFSSADEAALKEPIIKKFEEEGNPYYSSARVWDDGIIDPADTRLV
  LGLSFSAALNAPIEKTDFGIFRM
• Function: Carboxyltransferase subunit of the 3-methylcrotonyl-CoA carboxylase, an enzyme that catalyzes the conversion of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA, a critical step for leucine and isovaleric acid catabolism.
• KEGG Pathway:
  Valine, leucine and isoleucine degradation (hsa00280)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective HLCS causes multiple carboxylase deficiency (R-HSA-3371599)
  Branched-chain amino acid catabolism (R-HSA-70895)
  Biotin transport and metabolism (R-HSA-196780)
• BioCyc Pathway: MetaCyc:ENSG00000131844-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
3-methylcrotonyl-CoA carboxylase 1 deficiency	DISEE5OU	Definitive	Biomarker	[1]
3-methylcrotonyl-CoA carboxylase 2 deficiency	DIS8I8K6	Definitive	Autosomal recessive	[2]
3-methylcrotonyl-CoA carboxylase deficiency	DIS3TZW5	Definitive	Autosomal recessive	[3]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[4]
Propionic acidemia	DIS56N48	Strong	Genetic Variation	[5]
Prostate cancer	DISF190Y	moderate	Altered Expression	[6]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[6]
Schizoaffective disorder	DISLBW6B	Disputed	Biomarker	[7]
Breast cancer	DIS7DPX1	Limited	Biomarker	[8]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[8]
Lung cancer	DISCM4YA	Limited	Biomarker	[9]
Lung carcinoma	DISTR26C	Limited	Biomarker	[9]
Neoplasm	DISZKGEW	Limited	Altered Expression	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[24]

17 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 Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[16]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[17]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[18]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[19]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[21]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[25]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[18]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial (MCCC2).	[23]

References

• [1] 3-Methylcrotonyl-CoA carboxylase deficiency: Mutational spectrum derived from comprehensive newborn screening.Gene. 2016 Dec 15;594(2):203-210. doi: 10.1016/j.gene.2016.09.003. Epub 2016 Sep 4.
• [2] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations.Atherosclerosis. 2011 Mar;215(1):145-52. doi: 10.1016/j.atherosclerosis.2010.12.005. Epub 2010 Dec 15.
• [5] Kinetic characterization of mutations found in propionic acidemia and methylcrotonylglycinuria: evidence for cooperativity in biotin carboxylase.J Biol Chem. 2004 Apr 16;279(16):15772-8. doi: 10.1074/jbc.M311982200. Epub 2004 Feb 11.
• [6] Modulation of androgen receptor signaling in hormonal therapy-resistant prostate cancer cell lines.PLoS One. 2011;6(8):e23144. doi: 10.1371/journal.pone.0023144. Epub 2011 Aug 4.
• [7] What does the Managing Emotions branch of the MSCEIT add to the MATRICS consensus cognitive battery?.Schizophr Res. 2018 Jul;197:414-420. doi: 10.1016/j.schres.2018.02.018. Epub 2018 Feb 24.
• [8] Methylcrotonoyl-CoA carboxylase 2 overexpression predicts an unfavorable prognosis and promotes cell proliferation in breast cancer.Biomark Med. 2019 Apr;13(6):427-436. doi: 10.2217/bmm-2018-0475. Epub 2019 Mar 21.
• [9] Streptomyces artemisiae MCCB 248 isolated from Arctic fjord sediments has unique PKS and NRPS biosynthetic genes and produces potential new anticancer natural products.3 Biotech. 2017 May;7(1):32. doi: 10.1007/s13205-017-0610-3. Epub 2017 Apr 11.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [15] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [16] 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.
• [17] 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.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] 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.
• [20] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [23] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [24] 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.
• [25] 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.
• [26] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [27] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [28] 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.