Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8VKBXX)

• DOT Name: Methylglutaconyl-CoA hydratase, mitochondrial (AUH)
• Synonyms: 3-MG-CoA hydratase; EC 4.2.1.18; AU-specific RNA-binding enoyl-CoA hydratase; AU-binding protein/enoyl-CoA hydratase; Itaconyl-CoA hydratase; EC 4.2.1.56
• Gene Name: AUH
• Related Disease:
  3-methylglutaconic aciduria type 1
  Metabolic disorder
  3-methylglutaconic aciduria
  Dystonia
  3-hydroxy-3-methylglutaryl-CoA synthase deficiency
  Amelocerebrohypohidrotic syndrome
  Ehlers-Danlos syndrome, kyphoscoliotic and deafness type
  HSD10 mitochondrial disease
  Isobutyryl-CoA dehydrogenase deficiency
  Short chain acyl-CoA dehydrogenase deficiency
  Smith-Lemli-Opitz syndrome
• UniProt ID: AUHM_HUMAN
• PDB ID: 1HZD; 2ZQQ; 2ZQR
• EC Number: 4.2.1.18; 4.2.1.56
• Pfam ID: PF00378
• Sequence:
  MAAAVAAAPGALGSLHAGGARLVAACSAWLCPGLRLPGSLAGRRAGPAIWAQGWVPAAGG
  PAPKRGYSSEMKTEDELRVRHLEEENRGIVVLGINRAYGKNSLSKNLIKMLSKAVDALKS
  DKKVRTIIIRSEVPGIFCAGADLKERAKMSSSEVGPFVSKIRAVINDIANLPVPTIAAID
  GLALGGGLELALACDIRVAASSAKMGLVETKLAIIPGGGGTQRLPRAIGMSLAKELIFSA
  RVLDGKEAKAVGLISHVLEQNQEGDAAYRKALDLAREFLPQGPVAMRVAKLAINQGMEVD
  LVTGLAIEEACYAQTIPTKDRLEGLLAFKEKRPPRYKGE
• Function: Catalyzes the fifth step in the leucine degradation pathway, the reversible hydration of 3-methylglutaconyl-CoA (3-MG-CoA) to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). Can catalyze the reverse reaction but at a much lower rate in vitro. HMG-CoA is then quickly degraded by another enzyme (such as HMG-CoA lyase) to give acetyl-CoA and acetoacetate. Uses other substrates such as (2E)-glutaconyl-CoA efficiently in vitro, and to a lesser extent 3-methylcrotonyl-CoA (3-methyl-(2E)-butenoyl-CoA), crotonyl-CoA ((2E)-butenoyl-CoA) and 3-hydroxybutanoyl-CoA (the missing carboxylate reduces affinity to the active site). Originally it was identified as an RNA-binding protein as it binds to AU-rich elements (AREs) in vitro. AREs direct rapid RNA degradation and mRNA deadenylation. Might have itaconyl-CoA hydratase activity, converting itaconyl-CoA into citramalyl-CoA in the C5-dicarboxylate catabolism pathway. The C5-dicarboxylate catabolism pathway is required to detoxify itaconate, an antimicrobial metabolite and immunomodulator produced by macrophages during certain infections, that can act as a vitamin B12-poisoning metabolite.
• KEGG Pathway:
  Valine, leucine and isoleucine degradation (hsa00280)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Branched-chain amino acid catabolism (R-HSA-70895)
• BioCyc Pathway: MetaCyc:HS07490-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
3-methylglutaconic aciduria type 1	DISOWG8Z	Definitive	Autosomal recessive	[1]
Metabolic disorder	DIS71G5H	Definitive	Genetic Variation	[2]
3-methylglutaconic aciduria	DIS8G1WP	Strong	Biomarker	[3]
Dystonia	DISJLFGW	Strong	Biomarker	[4]
3-hydroxy-3-methylglutaryl-CoA synthase deficiency	DISIIU6G	Limited	Biomarker	[3]
Amelocerebrohypohidrotic syndrome	DIS0DATV	Limited	Biomarker	[3]
Ehlers-Danlos syndrome, kyphoscoliotic and deafness type	DISA74TB	Limited	Biomarker	[3]
HSD10 mitochondrial disease	DISCJYFW	Limited	Biomarker	[3]
Isobutyryl-CoA dehydrogenase deficiency	DIS9ORX6	Limited	Biomarker	[3]
Short chain acyl-CoA dehydrogenase deficiency	DISDDRPY	Limited	Biomarker	[3]
Smith-Lemli-Opitz syndrome	DISX9ZUA	Limited	Biomarker	[3]

12 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 Methylglutaconyl-CoA hydratase, mitochondrial (AUH).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Methylglutaconyl-CoA hydratase, mitochondrial (AUH).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Methylglutaconyl-CoA hydratase, mitochondrial (AUH).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Methylglutaconyl-CoA hydratase, mitochondrial (AUH).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Methylglutaconyl-CoA hydratase, mitochondrial (AUH).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Methylglutaconyl-CoA hydratase, mitochondrial (AUH).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Methylglutaconyl-CoA hydratase, mitochondrial (AUH).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Methylglutaconyl-CoA hydratase, mitochondrial (AUH).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Methylglutaconyl-CoA hydratase, mitochondrial (AUH).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Methylglutaconyl-CoA hydratase, mitochondrial (AUH).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Methylglutaconyl-CoA hydratase, mitochondrial (AUH).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Methylglutaconyl-CoA hydratase, mitochondrial (AUH).	[16]

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] Biochemical characterization of human 3-methylglutaconyl-CoA hydratase and its role in leucine metabolism.FEBS J. 2006 May;273(9):2012-22. doi: 10.1111/j.1742-4658.2006.05218.x.
• [3] Genotype-based databases for variants causing rare diseases.Gene. 2014 Oct 15;550(1):136-40. doi: 10.1016/j.gene.2014.08.016. Epub 2014 Aug 8.
• [4] 3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy. Neurology. 2010 Sep 21;75(12):1079-83. doi: 10.1212/WNL.0b013e3181f39a8a.
• [5] 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.
• [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] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [9] 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.
• [10] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [11] 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.
• [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] 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.
• [14] 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.
• [15] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.