Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9SQ5PU)

• DOT Name: 3-hydroxy-3-methylglutaryl-CoA lyase, cytoplasmic (HMGCLL1)
• Synonyms: EC 4.1.3.4; 3-hydroxy-3-methylglutaryl-CoA lyase-like protein 1; HMGCL-like 1; Endoplasmic reticulum 3-hydroxy-3-methylglutaryl-CoA lyase; er-cHL
• Gene Name: HMGCLL1
• UniProt ID: HMGC2_HUMAN
• EC Number: 4.1.3.4
• Pfam ID: PF00682
• Sequence:
  MGNVPSAVKHCLSYQQLLREHLWIGDSVAGALDPAQTSLLTNLHCFQPDVSGFSVSLAGT
  VACIHWETSQLSGLPEFVKIVEVGPRDGLQNEKVIVPTDIKIEFINRLSQTGLSVIEVTS
  FVSSRWVPQMADHTEVMKGIHQYPGVRYPVLTPNLQGFHHAVAAGATEISVFGAASESFS
  KKNINCSIEESMGKFEEVVKSARHMNIPARGYVSCALGCPYEGSITPQKVTEVSKRLYGM
  GCYEISLGDTIGVGTPGSMKRMLESVMKEIPPGALAVHCHDTYGQALANILTALQMGINV
  VDSAVSGLGGCPYAKGASGNVATEDLIYMLNGLGLNTGVNLYKVMEAGDFICKAVNKTTN
  SKVAQASFNA
• Function: Non-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, the products of which support energy production in nonhepatic animal tissues.
• KEGG Pathway:
  Valine, leucine and isoleucine degradation (hsa00280)
  Butanoate metabolism (hsa00650)
  Metabolic pathways (hsa01100)
  Peroxisome (hsa04146)
• Reactome Pathway: Synthesis of Ketone Bodies (R-HSA-77111)

Molecular Interaction Atlas (MIA) of This DOT

7 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 3-hydroxy-3-methylglutaryl-CoA lyase, cytoplasmic (HMGCLL1).	[1]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of 3-hydroxy-3-methylglutaryl-CoA lyase, cytoplasmic (HMGCLL1).	[2]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of 3-hydroxy-3-methylglutaryl-CoA lyase, cytoplasmic (HMGCLL1).	[3]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of 3-hydroxy-3-methylglutaryl-CoA lyase, cytoplasmic (HMGCLL1).	[4]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of 3-hydroxy-3-methylglutaryl-CoA lyase, cytoplasmic (HMGCLL1).	[3]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 3-hydroxy-3-methylglutaryl-CoA lyase, cytoplasmic (HMGCLL1).	[6]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of 3-hydroxy-3-methylglutaryl-CoA lyase, cytoplasmic (HMGCLL1).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 3-hydroxy-3-methylglutaryl-CoA lyase, cytoplasmic (HMGCLL1).	[5]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [3] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [4] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [5] 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.
• [6] 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.
• [7] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.