Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTJP3GM)

• DOT Name: Methylmalonyl-CoA epimerase, mitochondrial (MCEE)
• Synonyms: EC 5.1.99.1; DL-methylmalonyl-CoA racemase
• Gene Name: MCEE
• Related Disease:
  Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency
  Dopa-responsive dystonia due to sepiapterin reductase deficiency
  Methylmalonic acidemia
  Pneumonia
• UniProt ID: MCEE_HUMAN
• PDB ID: 3RMU; 6QH4
• EC Number: 5.1.99.1
• Pfam ID: PF13669
• Sequence:
  MARVLKAAAANAVGLFSRLQAPIPTVRASSTSQPLDQVTGSVWNLGRLNHVAIAVPDLEK
  AAAFYKNILGAQVSEAVPLPEHGVSVVFVNLGNTKMELLHPLGRDSPIAGFLQKNKAGGM
  HHICIEVDNINAAVMDLKKKKIRSLSEEVKIGAHGKPVIFLHPKDCGGVLVELEQA
• Function: Methylmalonyl-CoA epimerase involved in propionyl-CoA metabolism.
• KEGG Pathway:
  Valine, leucine and isoleucine degradation (hsa00280)
  Glyoxylate and dicarboxylate metabolism (hsa00630)
  Propanoate metabolism (hsa00640)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
• Reactome Pathway: Propionyl-CoA catabolism (R-HSA-71032)
• BioCyc Pathway: MetaCyc:HS13124-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency	DIS2GC8D	Definitive	Autosomal recessive	[1]
Dopa-responsive dystonia due to sepiapterin reductase deficiency	DISZ8S4R	Strong	Biomarker	[2]
Methylmalonic acidemia	DISHY8VB	moderate	Genetic Variation	[3]
Pneumonia	DIS8EF3M	Disputed	Biomarker	[4]

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 Methylmalonyl-CoA epimerase, mitochondrial (MCEE).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Methylmalonyl-CoA epimerase, mitochondrial (MCEE).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Methylmalonyl-CoA epimerase, mitochondrial (MCEE).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Methylmalonyl-CoA epimerase, mitochondrial (MCEE).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Methylmalonyl-CoA epimerase, mitochondrial (MCEE).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Methylmalonyl-CoA epimerase, mitochondrial (MCEE).	[10]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Methylmalonyl-CoA epimerase, mitochondrial (MCEE).	[11]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Methylmalonyl-CoA epimerase, mitochondrial (MCEE).	[13]
Linalool	DMGZQ5P	Investigative	Linalool decreases the expression of Methylmalonyl-CoA epimerase, mitochondrial (MCEE).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Methylmalonyl-CoA epimerase, mitochondrial (MCEE).	[12]

References

• [1] 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.
• [2] Methylmalonyl-CoA Epimerase Deficiency Mimicking Propionic Aciduria.Int J Mol Sci. 2017 Nov 1;18(11):2294. doi: 10.3390/ijms18112294.
• [3] Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency.Biochim Biophys Acta Mol Basis Dis. 2019 Jun 1;1865(6):1265-1272. doi: 10.1016/j.bbadis.2019.01.021. Epub 2019 Jan 22.
• [4] National, regional, and state-level burden of Streptococcus pneumoniae and Haemophilus influenzae type b disease in children in India: modelled estimates for 2000-15.Lancet Glob Health. 2019 Jun;7(6):e735-e747. doi: 10.1016/S2214-109X(19)30081-6.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.
• [10] 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.
• [11] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [12] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [13] 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.
• [14] Linalool is a PPARalpha ligand that reduces plasma TG levels and rewires the hepatic transcriptome and plasma metabolome. J Lipid Res. 2014 Jun;55(6):1098-110.