Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC3RUN9)

• DOT Name: Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2)
• Synonyms: HMG-CoA synthase; EC 2.3.3.10; 3-hydroxy-3-methylglutaryl coenzyme A synthase
• Gene Name: HMGCS2
• Related Disease: 3-hydroxy-3-methylglutaryl-CoA synthase deficiency
• UniProt ID: HMCS2_HUMAN
• PDB ID: 2WYA
• EC Number: 2.3.3.10
• Pfam ID: PF08540 ; PF01154
• Sequence:
  MQRLLTPVKRILQLTRAVQETSLTPARLLPVAHQRFSTASAVPLAKTDTWPKDVGILALE
  VYFPAQYVDQTDLEKYNNVEAGKYTVGLGQTRMGFCSVQEDINSLCLTVVQRLMERIQLP
  WDSVGRLEVGTETIIDKSKAVKTVLMELFQDSGNTDIEGIDTTNACYGGTASLFNAANWM
  ESSSWDGRYAMVVCGDIAVYPSGNARPTGGAGAVAMLIGPKAPLALERGLRGTHMENVYD
  FYKPNLASEYPIVDGKLSIQCYLRALDRCYTSYRKKIQNQWKQAGSDRPFTLDDLQYMIF
  HTPFCKMVQKSLARLMFNDFLSASSDTQTSLYKGLEAFGGLKLEDTYTNKDLDKALLKAS
  QDMFDKKTKASLYLSTHNGNMYTSSLYGCLASLLSHHSAQELAGSRIGAFSYGSGLAASF
  FSFRVSQDAAPGSPLDKLVSSTSDLPKRLASRKCVSPEEFTEIMNQREQFYHKVNFSPPG
  DTNSLFPGTWYLERVDEQHRRKYARRPV
• Function: Catalyzes the first irreversible step in ketogenesis, condensing acetyl-CoA to acetoacetyl-CoA to form HMG-CoA, which is converted by HMG-CoA reductase (HMGCR) into mevalonate.
• Tissue Specificity: Expression in liver is 200-fold higher than in any other tissue. Low expression in colon, kidney, testis, and pancreas. Very low expression in heart and skeletal muscle . Not detected in brain .; [Isoform 3]: Highest expression detected in heart and skeletal muscle.
• KEGG Pathway:
  Valine, leucine and isoleucine degradation (hsa00280)
  Butanoate metabolism (hsa00650)
  Terpenoid backbone biosynthesis (hsa00900)
  Metabolic pathways (hsa01100)
  PPAR sig.ling pathway (hsa03320)
• Reactome Pathway:
  Synthesis of Ketone Bodies (R-HSA-77111)
  PPARA activates gene expression (R-HSA-1989781)
• BioCyc Pathway: MetaCyc:HS05836-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
3-hydroxy-3-methylglutaryl-CoA synthase deficiency	DISIIU6G	Definitive	Autosomal recessive	[1]

15 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 synthase, mitochondrial (HMGCS2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2).	[3]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2).	[5]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2).	[6]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2).	[7]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2).	[8]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2).	[9]
Chenodiol	DMQ8JIK	Approved	Chenodiol decreases the expression of Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2).	[14]
PIRINIXIC ACID	DM82Y75	Preclinical	PIRINIXIC ACID increases the expression of Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2).	[15]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2).	[16]

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 Hydroxymethylglutaryl-CoA synthase, mitochondrial (HMGCS2).	[13]

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] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [6] 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.
• [7] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [8] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [9] Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Arch Toxicol. 2013 Jun;87(6):1103-13. doi: 10.1007/s00204-013-1018-4. Epub 2013 Feb 10.
• [10] Chenodeoxycholic acid significantly impacts the expression of miRNAs and genes involved in lipid, bile acid and drug metabolism in human hepatocytes. Life Sci. 2016 Jul 1;156:47-56.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] 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.
• [14] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [15] Activation of human nuclear receptors by perfluoroalkylated substances (PFAS). Toxicol In Vitro. 2020 Feb;62:104700. doi: 10.1016/j.tiv.2019.104700. Epub 2019 Oct 30.
• [16] System analysis of cross-talk between nuclear receptors reveals an opposite regulation of the cell cycle by LXR and FXR in human HepaRG liver cells. PLoS One. 2019 Aug 22;14(8):e0220894. doi: 10.1371/journal.pone.0220894. eCollection 2019.