Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT77IYIS)

• DOT Name: Riboflavin kinase (RFK)
• Synonyms: EC 2.7.1.26; ATP:riboflavin 5'-phosphotransferase; Flavokinase
• Gene Name: RFK
• Related Disease:
  Prostate cancer
  Prostate neoplasm
• UniProt ID: RIFK_HUMAN
• PDB ID: 1NB0; 1NB9; 1P4M; 1Q9S
• EC Number: 2.7.1.26
• Pfam ID: PF01687
• Sequence:
  MRHLPYFCRGQVVRGFGRGSKQLGIPTANFPEQVVDNLPADISTGIYYGWASVGSGDVHK
  MVVSIGWNPYYKNTKKSMETHIMHTFKEDFYGEILNVAIVGYLRPEKNFDSLESLISAIQ
  GDIEEAKKRLELPEHLKIKEDNFFQVSKSKIMNGH
• Function: Catalyzes the phosphorylation of riboflavin (vitamin B2) to form flavin-mononucleotide (FMN), hence rate-limiting enzyme in the synthesis of FAD. Essential for TNF-induced reactive oxygen species (ROS) production. Through its interaction with both TNFRSF1A and CYBA, physically and functionally couples TNFRSF1A to NADPH oxidase. TNF-activation of RFK may enhance the incorporation of FAD in NADPH oxidase, a critical step for the assembly and activation of NADPH oxidase.
• Tissue Specificity: Detected in brain, placenta and urinary bladder.
• KEGG Pathway:
  Riboflavin metabolism (hsa00740)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Vitamin B2 (riboflavin) metabolism (R-HSA-196843)
• BioCyc Pathway: MetaCyc:HS05938-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
Prostate cancer	DISF190Y	Strong	Biomarker	[1]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[1]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Riboflavin kinase (RFK) decreases the response to substance of Cisplatin.	[1]
Hydrogen peroxide	DM1NG5W	Approved	Riboflavin kinase (RFK) decreases the response to substance of Hydrogen peroxide.	[1]
Diamide	DMOCQ9J	Investigative	Riboflavin kinase (RFK) decreases the response to substance of Diamide.	[1]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Glutathione	DMAHMT9	Approved	Riboflavin kinase (RFK) increases the abundance of Glutathione.	[1]
Flavin-Adenine Dinucleotide	DM5S4GK	Investigative	Riboflavin kinase (RFK) increases the abundance of Flavin-Adenine Dinucleotide.	[1]

1 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 Riboflavin kinase (RFK).	[2]

9 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Riboflavin kinase (RFK).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Riboflavin kinase (RFK).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Riboflavin kinase (RFK).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Riboflavin kinase (RFK).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Riboflavin kinase (RFK).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Riboflavin kinase (RFK).	[8]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Riboflavin kinase (RFK).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Riboflavin kinase (RFK).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Riboflavin kinase (RFK).	[8]

References

• [1] Involvement of riboflavin kinase expression in cellular sensitivity against cisplatin. Int J Oncol. 2011 Apr;38(4):893-902. doi: 10.3892/ijo.2011.938. Epub 2011 Feb 9.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [10] 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.
• [11] Involvement of riboflavin kinase expression in cellular sensitivity against cisplatin. Int J Oncol. 2011 Apr;38(4):893-902. doi: 10.3892/ijo.2011.938. Epub 2011 Feb 9.