Details of Drug Off-Target (DOT)

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

• DOT Name: Triokinase/FMN cyclase (TKFC)
• Synonyms: Bifunctional ATP-dependent dihydroxyacetone kinase/FAD-AMP lyase (cyclizing)
• Gene Name: TKFC
• Related Disease:
  Sengers syndrome
  Triokinase and FMN cyclase deficiency syndrome
• UniProt ID: TKFC_HUMAN
• EC Number: 2.7.1.28; 2.7.1.29; 4.6.1.15
• Pfam ID: PF02733 ; PF02734
• Sequence:
  MTSKKLVNSVAGCADDALAGLVACNPNLQLLQGHRVALRSDLDSLKGRVALLSGGGSGHE
  PAHAGFIGKGMLTGVIAGAVFTSPAVGSILAAIRAVAQAGTVGTLLIVKNYTGDRLNFGL
  AREQARAEGIPVEMVVIGDDSAFTVLKKAGRRGLCGTVLIHKVAGALAEAGVGLEEIAKQ
  VNVVAKAMGTLGVSLSSCSVPGSKPTFELSADEVELGLGIHGEAGVRRIKMATADEIVKL
  MLDHMTNTTNASHVPVQPGSSVVMMVNNLGGLSFLELGIIADATVRSLEGRGVKIARALV
  GTFMSALEMPGISLTLLLVDEPLLKLIDAETTAAAWPNVAAVSITGRKRSRVAPAEPQEA
  PDSTAAGGSASKRMALVLERVCSTLLGLEEHLNALDRAAGDGDCGTTHSRAARAIQEWLK
  EGPPPASPAQLLSKLSVLLLEKMGGSSGALYGLFLTAAAQPLKAKTSLPAWSAAMDAGLE
  AMQKYGKAAPGDRTMLDSLWAAGQELQAWKSPGADLLQVLTKAVKSAEAAAEATKNMEAG
  AGRASYISSARLEQPDPGAVAAAAILRAILEVLQS
• Function: Catalyzes both the phosphorylation of dihydroxyacetone and of glyceraldehyde, and the splitting of ribonucleoside diphosphate-X compounds among which FAD is the best substrate. Represses IFIH1-mediated cellular antiviral response.
• Tissue Specificity: Detected in erythrocytes (at protein level).
• KEGG Pathway:
  Fructose and mannose metabolism (hsa00051)
  Glycerolipid metabolism (hsa00561)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  RIG-I-like receptor sig.ling pathway (hsa04622)
• Reactome Pathway:
  Fructose catabolism (R-HSA-70350)
  SARS-CoV-1 activates/modulates innate immune responses (R-HSA-9692916)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  DDX58/IFIH1-mediated induction of interferon-alpha/beta (R-HSA-168928)
• BioCyc Pathway: MetaCyc:HS07615-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Sengers syndrome	DISV24KG	Supportive	Autosomal recessive	[1]
Triokinase and FMN cyclase deficiency syndrome	DISJU64N	Limited	Autosomal recessive	[2]

11 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 Triokinase/FMN cyclase (TKFC).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Triokinase/FMN cyclase (TKFC).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Triokinase/FMN cyclase (TKFC).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Triokinase/FMN cyclase (TKFC).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Triokinase/FMN cyclase (TKFC).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Triokinase/FMN cyclase (TKFC).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Triokinase/FMN cyclase (TKFC).	[9]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Triokinase/FMN cyclase (TKFC).	[10]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Triokinase/FMN cyclase (TKFC).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Triokinase/FMN cyclase (TKFC).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Triokinase/FMN cyclase (TKFC).	[12]

References

• [1] Bi-allelic Variants in TKFC Encoding Triokinase/FMN Cyclase Are Associated with Cataracts and Multisystem Disease. Am J Hum Genet. 2020 Feb 6;106(2):256-263. doi: 10.1016/j.ajhg.2020.01.005. Epub 2020 Jan 30.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] 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.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] 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.
• [10] 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.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.