Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTHX4NB)

• DOT Name: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1 (PFKFB1)
• Synonyms: 6PF-2-K/Fru-2,6-P2ase 1; PFK/FBPase 1; 6PF-2-K/Fru-2,6-P2ase liver isozyme
• Gene Name: PFKFB1
• Related Disease:
  Gastric neoplasm
  Hyperinsulinemia
  Neoplasm
• UniProt ID: F261_HUMAN
• PDB ID: 1K6M
• EC Number: 2.7.1.105; 3.1.3.46
• Pfam ID: PF01591 ; PF00300
• Sequence:
  MSPEMGELTQTRLQKIWIPHSSGSSRLQRRRGSSIPQFTNSPTMVIMVGLPARGKTYIST
  KLTRYLNWIGTPTKVFNLGQYRREAVSYKNYEFFLPDNMEALQIRKQCALAALKDVHNYL
  SHEEGHVAVFDATNTTRERRSLILQFAKEHGYKVFFIESICNDPGIIAENIRQVKLGSPD
  YIDCDREKVLEDFLKRIECYEVNYQPLDEELDSHLSYIKIFDVGTRYMVNRVQDHIQSRT
  VYYLMNIHVTPRSIYLCRHGESELNIRGRIGGDSGLSVRGKQYAYALANFIQSQGISSLK
  VWTSHMKRTIQTAEALGVPYEQWKALNEIDAGVCEEMTYEEIQEHYPEEFALRDQDKYRY
  RYPKGESYEDLVQRLEPVIMELERQENVLVICHQAVMRCLLAYFLDKSSDELPYLKCPLH
  TVLKLTPVAYGCKVESIYLNVEAVNTHREKPENVDITREPEEALDTVPAHY
• Function: Synthesis and degradation of fructose 2,6-bisphosphate.
• Tissue Specificity: Liver.
• KEGG Pathway:
  Fructose and mannose metabolism (hsa00051)
  Metabolic pathways (hsa01100)
  AMPK sig.ling pathway (hsa04152)
  Glucagon sig.ling pathway (hsa04922)
• Reactome Pathway:
  PP2A-mediated dephosphorylation of key metabolic factors (R-HSA-163767)
  Regulation of glycolysis by fructose 2,6-bisphosphate metabolism (R-HSA-9634600)
  PKA-mediated phosphorylation of key metabolic factors (R-HSA-163358)
• BioCyc Pathway: MetaCyc:HS08310-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric neoplasm	DISOKN4Y	Strong	Altered Expression	[1]
Hyperinsulinemia	DISIDWT6	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Limited	Biomarker	[3]

10 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 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1 (PFKFB1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1 (PFKFB1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1 (PFKFB1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1 (PFKFB1).	[5]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1 (PFKFB1).	[7]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1 (PFKFB1).	[8]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1 (PFKFB1).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1 (PFKFB1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1 (PFKFB1).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1 (PFKFB1).	[11]

References

• [1] Hypoxic regulation of PFKFB-3 and PFKFB-4 gene expression in gastric and pancreatic cancer cell lines and expression of PFKFB genes in gastric cancers.Acta Biochim Pol. 2006;53(4):789-99. Epub 2006 Dec 4.
• [2] Effect of starvation on gene expression of regulatory enzymes of glycolysis/gluconeogenesis in genetically obese (fa/fa) Zucker rats.Int J Obes Relat Metab Disord. 1998 Jul;22(7):667-72. doi: 10.1038/sj.ijo.0800645.
• [3] 6-Phosphofructo-2-kinase (pfkfb3) gene promoter contains hypoxia-inducible factor-1 binding sites necessary for transactivation in response to hypoxia.J Biol Chem. 2004 Dec 17;279(51):53562-70. doi: 10.1074/jbc.M406096200. Epub 2004 Oct 5.
• [4] 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.
• [5] 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.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] 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.
• [8] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [9] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.