Details of Drug Off-Target (DOT)

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

• DOT Name: Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial (MCCC1)
• Synonyms: MCCase subunit alpha; EC 6.4.1.4; 3-methylcrotonyl-CoA carboxylase 1; 3-methylcrotonyl-CoA carboxylase biotin-containing subunit; 3-methylcrotonyl-CoA:carbon dioxide ligase subunit alpha
• Gene Name: MCCC1
• Related Disease:
  3-methylcrotonyl-CoA carboxylase 1 deficiency
  3-methylcrotonyl-CoA carboxylase deficiency
  Alzheimer disease
  Plasmodium falciparum malaria
  Parkinson disease
  Tuberculosis
• UniProt ID: MCCA_HUMAN
• PDB ID: 2EJM
• EC Number: 6.4.1.4
• Pfam ID: PF02785 ; PF00289 ; PF00364 ; PF02786
• Sequence:
  MAAASAVSVLLVAAERNRWHRLPSLLLPPRTWVWRQRTMKYTTATGRNITKVLIANRGEI
  ACRVMRTAKKLGVQTVAVYSEADRNSMHVDMADEAYSIGPAPSQQSYLSMEKIIQVAKTS
  AAQAIHPGCGFLSENMEFAELCKQEGIIFIGPPPSAIRDMGIKSTSKSIMAAAGVPVVEG
  YHGEDQSDQCLKEHARRIGYPVMIKAVRGGGGKGMRIVRSEQEFQEQLESARREAKKSFN
  DDAMLIEKFVDTPRHVEVQVFGDHHGNAVYLFERDCSVQRRHQKIIEEAPAPGIKSEVRK
  KLGEAAVRAAKAVNYVGAGTVEFIMDSKHNFCFMEMNTRLQVEHPVTEMITGTDLVEWQL
  RIAAGEKIPLSQEEITLQGHAFEARIYAEDPSNNFMPVAGPLVHLSTPRADPSTRIETGV
  RQGDEVSVHYDPMIAKLVVWAADRQAALTKLRYSLRQYNIVGLHTNIDFLLNLSGHPEFE
  AGNVHTDFIPQHHKQLLLSRKAAAKESLCQAALGLILKEKAMTDTFTLQAHDQFSPFSSS
  SGRRLNISYTRNMTLKDGKNNVAIAVTYNHDGSYSMQIEDKTFQVLGNLYSEGDCTYLKC
  SVNGVASKAKLIILENTIYLFSKEGSIEIDIPVPKYLSSVSSQETQGGPLAPMTGTIEKV
  FVKAGDKVKAGDSLMVMIAMKMEHTIKSPKDGTVKKVFYREGAQANRHTPLVEFEEEESD
  KRESE
• Function: Biotin-attachment 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:ENSG00000078070-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
3-methylcrotonyl-CoA carboxylase 1 deficiency	DISEE5OU	Definitive	Autosomal recessive	[1]
3-methylcrotonyl-CoA carboxylase deficiency	DIS3TZW5	Definitive	Autosomal recessive	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Plasmodium falciparum malaria	DIS3Q9KF	Strong	Biomarker	[4]
Parkinson disease	DISQVHKL	moderate	Genetic Variation	[3]
Tuberculosis	DIS2YIMD	Limited	Genetic Variation	[5]

15 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 subunit alpha, mitochondrial (MCCC1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial (MCCC1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial (MCCC1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial (MCCC1).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial (MCCC1).	[10]
Marinol	DM70IK5	Approved	Marinol affects the expression of Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial (MCCC1).	[11]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial (MCCC1).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial (MCCC1).	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial (MCCC1).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial (MCCC1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial (MCCC1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial (MCCC1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial (MCCC1).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial (MCCC1).	[20]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial (MCCC1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Methylcrotonoyl-CoA carboxylase subunit alpha, mitochondrial (MCCC1).	[18]

References

• [1] 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.
• [2] 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.
• [3] Association of Parkinson's Disease GWAS-Linked Loci with Alzheimer's Disease in Han Chinese.Mol Neurobiol. 2017 Jan;54(1):308-318. doi: 10.1007/s12035-015-9649-5. Epub 2016 Jan 6.
• [4] CR1 Knops blood group alleles are not associated with severe malaria in the Gambia.Genes Immun. 2003 Jul;4(5):368-73. doi: 10.1038/sj.gene.6363980.
• [5] Knops blood group polymorphism and susceptibility to Mycobacterium tuberculosis infection.Transfusion. 2011 Nov;51(11):2462-9. doi: 10.1111/j.1537-2995.2011.03161.x. Epub 2011 May 13.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [14] 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.
• [15] 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.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [18] 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.
• [19] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.