Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRO9RII)

• DOT Name: Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL)
• Synonyms: HL; HMG-CoA lyase; EC 4.1.3.4; 3-hydroxy-3-methylglutarate-CoA lyase
• Gene Name: HMGCL
• Related Disease:
  3-hydroxy-3-methylglutaric aciduria
  Hyperlipidemia due to hepatic triglyceride lipase deficiency
  Intellectual disability
  Mitochondrial disease
  Melanoma
  Neoplasm
  Hypoglycemia
• UniProt ID: HMGCL_HUMAN
• PDB ID: 2CW6; 3MP3; 3MP4; 3MP5
• EC Number: 4.1.3.4
• Pfam ID: PF00682
• Sequence:
  MAAMRKALPRRLVGLASLRAVSTSSMGTLPKRVKIVEVGPRDGLQNEKNIVSTPVKIKLI
  DMLSEAGLSVIETTSFVSPKWVPQMGDHTEVLKGIQKFPGINYPVLTPNLKGFEAAVAAG
  AKEVVIFGAASELFTKKNINCSIEESFQRFDAILKAAQSANISVRGYVSCALGCPYEGKI
  SPAKVAEVTKKFYSMGCYEISLGDTIGVGTPGIMKDMLSAVMQEVPLAALAVHCHDTYGQ
  ALANTLMALQMGVSVVDSSVAGLGGCPYAQGASGNLATEDLVYMLEGLGIHTGVNLQKLL
  EAGNFICQALNRKTSSKVAQATCKL
• Function: Mitochondrial 3-hydroxymethyl-3-methylglutaryl-CoA lyase that catalyzes a cation-dependent cleavage of (S)-3-hydroxy-3-methylglutaryl-CoA into acetyl-CoA and acetoacetate, a key step in ketogenesis. Terminal step in leucine catabolism. Ketone bodies (beta-hydroxybutyrate, acetoacetate and acetone) are essential as an alternative source of energy to glucose, as lipid precursors and as regulators of metabolism.
• Tissue Specificity: Highest expression in liver. Expressed in pancreas, kidney, intestine, testis, fibroblasts and lymphoblasts. Very low expression in brain and skeletal muscle. The relative expression of isoform 2 (at mRNA level) is highest in heart (30%), skeletal muscle (22%), and brain (14%).
• KEGG Pathway:
  Valine, leucine and isoleucine degradation (hsa00280)
  Butanoate metabolism (hsa00650)
  Metabolic pathways (hsa01100)
  Peroxisome (hsa04146)
• Reactome Pathway:
  Peroxisomal protein import (R-HSA-9033241)
  Synthesis of Ketone Bodies (R-HSA-77111)
• BioCyc Pathway: MetaCyc:HS04116-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
3-hydroxy-3-methylglutaric aciduria	DISOWT9U	Definitive	Autosomal recessive	[1]
Hyperlipidemia due to hepatic triglyceride lipase deficiency	DISA68R2	Strong	Biomarker	[2]
Intellectual disability	DISMBNXP	Strong	Biomarker	[3]
Mitochondrial disease	DISKAHA3	Strong	Genetic Variation	[4]
Melanoma	DIS1RRCY	moderate	Genetic Variation	[5]
Neoplasm	DISZKGEW	moderate	Genetic Variation	[5]
Hypoglycemia	DISRCKR7	Limited	Biomarker	[6]

16 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL).	[13]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL).	[14]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL).	[15]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL).	[16]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL).	[19]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Hydroxymethylglutaryl-CoA lyase, mitochondrial (HMGCL).	[22]

References

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• [2] 3-Hydroxy-3-Methylglutaric Acid Impairs Redox and Energy Homeostasis, Mitochondrial Dynamics, and Endoplasmic Reticulum-Mitochondria Crosstalk in Rat Brain.Neurotox Res. 2020 Feb;37(2):314-325. doi: 10.1007/s12640-019-00122-x. Epub 2019 Nov 13.
• [3] Molecular and clinical analysis of Japanese patients with 3-hydroxy-3-methylglutaryl CoA lyase (HL) deficiency.Hum Genet. 2000 Oct;107(4):320-6. doi: 10.1007/s004390000363.
• [4] Molecular analysis of Taiwanese patients with 3-hydroxy-3-methylglutaryl CoA lyase deficiency.Clin Chim Acta. 2009 Mar;401(1-2):33-6. doi: 10.1016/j.cca.2008.11.004. Epub 2008 Nov 12.
• [5] Metabolic Rewiring by Oncogenic BRAF V600E Links Ketogenesis Pathway to BRAF-MEK1 Signaling.Mol Cell. 2015 Aug 6;59(3):345-358. doi: 10.1016/j.molcel.2015.05.037. Epub 2015 Jul 2.
• [6] Application of multiplex ligation-dependent probe amplification, and identification of a heterozygous Alu-associated deletion and a uniparental disomy of chromosome 1 in two patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.Int J Mol Med. 2015 Jun;35(6):1554-60. doi: 10.3892/ijmm.2015.2184. Epub 2015 Apr 14.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [9] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [13] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [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] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [16] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [17] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [18] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [19] 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.
• [20] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [21] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.