Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA8L0TN)

• DOT Name: Succinate--hydroxymethylglutarate CoA-transferase (SUGCT)
• Synonyms: EC 2.8.3.13; Dermal papilla-derived protein 13; SuccinylCoA:glutarate-CoA transferase
• Gene Name: SUGCT
• Related Disease:
  Advanced cancer
  Familial prostate carcinoma
  Glutaric acidemia type 3
  Glutaric aciduria
  Herpes simplex infection
  Melanoma
  Pancreatic cancer
  Pancreatic tumour
  Prostate cancer, hereditary, 1
  Prostate carcinoma
  Tuberculosis
  Neuroblastoma
• UniProt ID: SUCHY_HUMAN
• EC Number: 2.8.3.13
• Pfam ID: PF02515
• Sequence:
  MLATLARVAALRRTCLFSGRGGGRGLWTGRPQSDMNNIKPLEGVKILDLTRVLAGPFATM
  NLGDLGAEVIKVERPGAGDDTRTWGPPFVGTESTYYLSVNRNKKSIAVNIKDPKGVKIIK
  ELAAVCDVFVENYVPGKLSAMGLGYEDIDEIAPHIIYCSITGYGQTGPISQRAGYDAVAS
  AVSGLMHITGPENGDPVRPGVAMTDLATGLYAYGAIMAGLIQKYKTGKGLFIDCNLLSSQ
  VACLSHIAANYLIGQKEAKRWGTAHGSIVPYQAFKTKDGYIVVGAGNNQQFATVCKILDL
  PELIDNSKYKTNHLRVHNRKELIKILSERFEEELTSKWLYLFEGSGVPYGPINNMKNVFA
  EPQVLHNGLVMEMEHPTVGKISVPGPAVRYSKFKMSEARPPPLLGQHTTHILKEVLRYDD
  RAIGELLSAGVVDQHETH
• Function: Catalyzes the succinyl-CoA-dependent conversion of glutarate to glutaryl-CoA. Can use different dicarboxylic acids as CoA acceptors, the preferred ones are glutarate, succinate, adipate, and 3-hydroxymethylglutarate.
• Tissue Specificity: Highly expressed in kidney. Intermediate expression in liver, skeletal muscle and pancreas. Little to no expression detected in other tissues examined.
• BioCyc Pathway: MetaCyc:ENSG00000175600-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[1]
Familial prostate carcinoma	DISL9KNO	Strong	Biomarker	[2]
Glutaric acidemia type 3	DIS86G88	Strong	Autosomal recessive	[3]
Glutaric aciduria	DISGE8NR	Strong	Genetic Variation	[4]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[5]
Melanoma	DIS1RRCY	Strong	Biomarker	[5]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[6]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[7]
Prostate cancer, hereditary, 1	DISE2P4L	Strong	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[2]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[8]
Neuroblastoma	DISVZBI4	Disputed	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Succinate--hydroxymethylglutarate CoA-transferase (SUGCT).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Succinate--hydroxymethylglutarate CoA-transferase (SUGCT).	[18]

11 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 Succinate--hydroxymethylglutarate CoA-transferase (SUGCT).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Succinate--hydroxymethylglutarate CoA-transferase (SUGCT).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Succinate--hydroxymethylglutarate CoA-transferase (SUGCT).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Succinate--hydroxymethylglutarate CoA-transferase (SUGCT).	[14]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Succinate--hydroxymethylglutarate CoA-transferase (SUGCT).	[15]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Succinate--hydroxymethylglutarate CoA-transferase (SUGCT).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Succinate--hydroxymethylglutarate CoA-transferase (SUGCT).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Succinate--hydroxymethylglutarate CoA-transferase (SUGCT).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Succinate--hydroxymethylglutarate CoA-transferase (SUGCT).	[19]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Succinate--hydroxymethylglutarate CoA-transferase (SUGCT).	[20]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Succinate--hydroxymethylglutarate CoA-transferase (SUGCT).	[21]

References

• [1] Synthesis, crystal structure and antiproliferative mechanisms of 2-acetylpyridine-thiosemicarbazones Ga(III) with a greater selectivity against tumor cells.J Inorg Biochem. 2017 Dec;177:110-117. doi: 10.1016/j.jinorgbio.2017.09.012. Epub 2017 Sep 19.
• [2] Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.Nat Genet. 2018 Jul;50(7):928-936. doi: 10.1038/s41588-018-0142-8. Epub 2018 Jun 11.
• [3] Genetic mapping of glutaric aciduria, type 3, to chromosome 7 and identification of mutations in c7orf10. Am J Hum Genet. 2008 Nov;83(5):604-9. doi: 10.1016/j.ajhg.2008.09.018.
• [4] Novel contiguous gene deletion in peruvian girl with Trichothiodystrophy type 4 and glutaric aciduria type 3.Eur J Med Genet. 2018 Jul;61(7):388-392. doi: 10.1016/j.ejmg.2018.02.004. Epub 2018 Feb 5.
• [5] Deletion of the varicella-zoster virus large subunit of ribonucleotide reductase impairs growth of virus in vitro.J Virol. 1994 May;68(5):3317-23. doi: 10.1128/JVI.68.5.3317-3323.1994.
• [6] Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer.Nat Commun. 2018 Feb 8;9(1):556. doi: 10.1038/s41467-018-02942-5.
• [7] Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer.Nat Genet. 2015 Aug;47(8):911-6. doi: 10.1038/ng.3341. Epub 2015 Jun 22.
• [8] Ga(III) Nanoparticles Inhibit Growth of both Mycobacterium tuberculosis and HIV and Release of Interleukin-6 (IL-6) and IL-8 in Coinfected Macrophages.Antimicrob Agents Chemother. 2017 Mar 24;61(4):e02505-16. doi: 10.1128/AAC.02505-16. Print 2017 Apr.
• [9] Unveiling Ga(III) phthalocyanine-a different photosensitizer in neuroblastoma cellular model.J Cell Mol Med. 2019 Feb;23(2):1086-1094. doi: 10.1111/jcmm.14009. Epub 2018 Nov 19.
• [10] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [11] 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.
• [12] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [21] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.