Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX9HZT5)

• DOT Name: Formimidoyltransferase-cyclodeaminase (FTCD)
• Synonyms: Formiminotransferase-cyclodeaminase; FTCD; LCHC1
• Gene Name: FTCD
• Related Disease:
  Formiminoglutamic aciduria
  Age-related macular degeneration
  Autoimmune hepatitis
  Hepatocellular carcinoma
  Nicotine dependence
  Burkitt lymphoma
  Neoplasm
• UniProt ID: FTCD_HUMAN
• EC Number: 2.1.2.5; 4.3.1.4
• Pfam ID: PF02971 ; PF04961 ; PF07837
• Sequence:
  MSQLVECVPNFSEGKNQEVIDAISGAITQTPGCVLLDVDAGPSTNRTVYTFVGPPECVVE
  GALNAARVASRLIDMSRHQGEHPRMGALDVCPFIPVRGVSVDECVLCAQAFGQRLAEELD
  VPVYLYGEAARMDSRRTLPAIRAGEYEALPKKLQQADWAPDFGPSSFVPSWGATATGARK
  FLIAFNINLLGTKEQAHRIALNLREQGRGKDQPGRLKKVQGIGWYLDEKNLAQVSTNLLD
  FEVTALHTVYEETCREAQELSLPVVGSQLVGLVPLKALLDAAAFYCEKENLFILEEEQRI
  RLVVSRLGLDSLCPFSPKERIIEYLVPERGPERGLGSKSLRAFVGEVGARSAAPGGGSVA
  AAAAAMGAALGSMVGLMTYGRRQFQSLDTTMRRLIPPFREASAKLTTLVDADAEAFTAYL
  EAMRLPKNTPEEKDRRTAALQEGLRRAVSVPLTLAETVASLWPALQELARCGNLACRSDL
  QVAAKALEMGVFGAYFNVLINLRDITDEAFKDQIHHRVSSLLQEAKTQAALVLDCLETRQ
  E
• Function: Folate-dependent enzyme, that displays both transferase and deaminase activity. Serves to channel one-carbon units from formiminoglutamate to the folate pool; Binds and promotes bundling of vimentin filaments originating from the Golgi.
• KEGG Pathway:
  Histidine metabolism (hsa00340)
  One carbon pool by folate (hsa00670)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Histidine catabolism (R-HSA-70921)
• BioCyc Pathway: MetaCyc:HS08479-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
Formiminoglutamic aciduria	DISKR1WR	Definitive	Autosomal recessive	[1]
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[2]
Autoimmune hepatitis	DISOX03Q	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Nicotine dependence	DISZD9W7	Strong	Altered Expression	[5]
Burkitt lymphoma	DIS9D5XU	moderate	Biomarker	[6]
Neoplasm	DISZKGEW	moderate	Altered Expression	[4]

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 Formimidoyltransferase-cyclodeaminase (FTCD).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Formimidoyltransferase-cyclodeaminase (FTCD).	[14]

8 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 Formimidoyltransferase-cyclodeaminase (FTCD).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Formimidoyltransferase-cyclodeaminase (FTCD).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Formimidoyltransferase-cyclodeaminase (FTCD).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Formimidoyltransferase-cyclodeaminase (FTCD).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Formimidoyltransferase-cyclodeaminase (FTCD).	[12]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Formimidoyltransferase-cyclodeaminase (FTCD).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Formimidoyltransferase-cyclodeaminase (FTCD).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Formimidoyltransferase-cyclodeaminase (FTCD).	[15]

References

• [1] The molecular basis of glutamate formiminotransferase deficiency. Hum Mutat. 2003 Jul;22(1):67-73. doi: 10.1002/humu.10236.
• [2] Assessment of Novel Genome-Wide Significant Gene Loci and Lesion Growth in Geographic Atrophy Secondary to Age-Related Macular Degeneration.JAMA Ophthalmol. 2019 Aug 1;137(8):867-876. doi: 10.1001/jamaophthalmol.2019.1318.
• [3] The induction of autoimmune hepatitis in the human leucocyte antigen-DR4 non-obese diabetic mice autoimmune hepatitis mouse model.Clin Exp Immunol. 2016 Nov;186(2):164-176. doi: 10.1111/cei.12843. Epub 2016 Aug 23.
• [4] Formiminotransferase Cyclodeaminase Suppresses Hepatocellular Carcinoma by Modulating Cell Apoptosis, DNA Damage, and Phosphatidylinositol 3-Kinases (PI3K)/Akt Signaling Pathway.Med Sci Monit. 2019 Jun 16;25:4474-4484. doi: 10.12659/MSM.916202.
• [5] Nicotine Dependence, Nicotine Metabolism, and the Extent of Compensation in Response to Reduced Nicotine Content Cigarettes.Nicotine Tob Res. 2015 Sep;17(9):1167-72. doi: 10.1093/ntr/ntu337. Epub 2015 Jan 2.
• [6] The genetic landscape of mutations in Burkitt lymphoma.Nat Genet. 2012 Dec;44(12):1321-5. doi: 10.1038/ng.2468. Epub 2012 Nov 11.
• [7] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [13] Anti-proliferative and gene expression actions of resveratrol in breast cancer cells in vitro. Oncotarget. 2014 Dec 30;5(24):12891-907.
• [14] 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.
• [15] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.