Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVHGAT7)

• DOT Name: ATP-dependent 6-phosphofructokinase, liver type (PFKL)
• Synonyms: ATP-PFK; PFK-L; EC 2.7.1.11; 6-phosphofructokinase type B; Phosphofructo-1-kinase isozyme B; PFK-B; Phosphohexokinase
• Gene Name: PFKL
• Related Disease:
  Bipolar disorder
  Lafora disease
  Hepatocellular carcinoma
  Tetralogy of fallot
  Unverricht-Lundborg syndrome
  Ventricular septal defect
  Mood disorder
• UniProt ID: PFKAL_HUMAN
• PDB ID: 7LW1
• EC Number: 2.7.1.11
• Pfam ID: PF00365
• Sequence:
  MAAVDLEKLRASGAGKAIGVLTSGGDAQGMNAAVRAVTRMGIYVGAKVFLIYEGYEGLVE
  GGENIKQANWLSVSNIIQLGGTIIGSARCKAFTTREGRRAAAYNLVQHGITNLCVIGGDG
  SLTGANIFRSEWGSLLEELVAEGKISETTARTYSHLNIAGLVGSIDNDFCGTDMTIGTDS
  ALHRIMEVIDAITTTAQSHQRTFVLEVMGRHCGYLALVSALASGADWLFIPEAPPEDGWE
  NFMCERLGETRSRGSRLNIIIIAEGAIDRNGKPISSSYVKDLVVQRLGFDTRVTVLGHVQ
  RGGTPSAFDRILSSKMGMEAVMALLEATPDTPACVVTLSGNQSVRLPLMECVQMTKEVQK
  AMDDKRFDEATQLRGGSFENNWNIYKLLAHQKPPKEKSNFSLAILNVGAPAAGMNAAVRS
  AVRTGISHGHTVYVVHDGFEGLAKGQVQEVGWHDVAGWLGRGGSMLGTKRTLPKGQLESI
  VENIRIYGIHALLVVGGFEAYEGVLQLVEARGRYEELCIVMCVIPATISNNVPGTDFSLG
  SDTAVNAAMESCDRIKQSASGTKRRVFIVETMGGYCGYLATVTGIAVGADAAYVFEDPFN
  IHDLKVNVEHMTEKMKTDIQRGLVLRNEKCHDYYTTEFLYNLYSSEGKGVFDCRTNVLGH
  LQQGGAPTPFDRNYGTKLGVKAMLWLSEKLREVYRKGRVFANAPDSACVIGLKKKAVAFS
  PVTELKKDTDFEHRMPREQWWLSLRLMLKMLAQYRISMAAYVSGELEHVTRRTLSMDKGF
• Function: Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis. Negatively regulates the phagocyte oxidative burst in response to bacterial infection by controlling cellular NADPH biosynthesis and NADPH oxidase-derived reactive oxygen species. Upon macrophage activation, drives the metabolic switch toward glycolysis, thus preventing glucose turnover that produces NADPH via pentose phosphate pathway.
• KEGG Pathway:
  Glycolysis / Gluconeogenesis (hsa00010)
  Pentose phosphate pathway (hsa00030)
  Fructose and mannose metabolism (hsa00051)
  Galactose metabolism (hsa00052)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  Biosynthesis of amino acids (hsa01230)
  R. degradation (hsa03018)
  HIF-1 sig.ling pathway (hsa04066)
  AMPK sig.ling pathway (hsa04152)
  Thyroid hormone sig.ling pathway (hsa04919)
  Glucagon sig.ling pathway (hsa04922)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  Glycolysis (R-HSA-70171)
  Neutrophil degranulation (R-HSA-6798695)
• BioCyc Pathway: MetaCyc:HS06881-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
Bipolar disorder	DISAM7J2	Definitive	Genetic Variation	[1]
Lafora disease	DIS83JHH	Definitive	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Tetralogy of fallot	DISMHFNW	Strong	Biomarker	[4]
Unverricht-Lundborg syndrome	DISG4WLX	Strong	Genetic Variation	[5]
Ventricular septal defect	DISICO41	Strong	Biomarker	[4]
Mood disorder	DISLVMWO	moderate	Biomarker	[6]

13 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 ATP-dependent 6-phosphofructokinase, liver type (PFKL).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ATP-dependent 6-phosphofructokinase, liver type (PFKL).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ATP-dependent 6-phosphofructokinase, liver type (PFKL).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ATP-dependent 6-phosphofructokinase, liver type (PFKL).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATP-dependent 6-phosphofructokinase, liver type (PFKL).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of ATP-dependent 6-phosphofructokinase, liver type (PFKL).	[12]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of ATP-dependent 6-phosphofructokinase, liver type (PFKL).	[13]
Penfluridol	DMG1DTE	Approved	Penfluridol decreases the activity of ATP-dependent 6-phosphofructokinase, liver type (PFKL).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of ATP-dependent 6-phosphofructokinase, liver type (PFKL).	[12]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of ATP-dependent 6-phosphofructokinase, liver type (PFKL).	[17]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of ATP-dependent 6-phosphofructokinase, liver type (PFKL).	[18]
PP-242	DM2348V	Investigative	PP-242 increases the expression of ATP-dependent 6-phosphofructokinase, liver type (PFKL).	[19]
Benzoquinone	DMNBA0G	Investigative	Benzoquinone increases the expression of ATP-dependent 6-phosphofructokinase, liver type (PFKL).	[20]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of ATP-dependent 6-phosphofructokinase, liver type (PFKL).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of ATP-dependent 6-phosphofructokinase, liver type (PFKL).	[16]

References

• [1] A follow-up linkage study supports evidence for a bipolar affective disorder locus on chromosome 21q22.Am J Med Genet. 2001 Mar 8;105(2):189-94. doi: 10.1002/ajmg.1195.
• [2] Lafora disease is not linked to the Unverricht-Lundborg locus.Am J Med Genet. 1995 Feb 27;60(1):80-4. doi: 10.1002/ajmg.1320600114.
• [3] (125)I suppressed the Warburg effect viaregulating miR-338/PFKL axis in hepatocellular carcinoma.Biomed Pharmacother. 2019 Nov;119:109402. doi: 10.1016/j.biopha.2019.109402. Epub 2019 Sep 9.
• [4] Down syndrome congenital heart disease: a narrowed region and a candidate gene.Genet Med. 2001 Mar-Apr;3(2):91-101. doi: 10.1097/00125817-200103000-00002.
• [5] Identification of mutations in cystatin B, the gene responsible for the Unverricht-Lundborg type of progressive myoclonus epilepsy (EPM1). Am J Hum Genet. 1997 Feb;60(2):342-51.
• [6] Linkage study between manic-depressive illness and chromosome 21.Am J Med Genet. 1996 Apr 9;67(2):218-24. doi: 10.1002/(SICI)1096-8628(19960409)67:2<218::AID-AJMG15>3.0.CO;2-M.
• [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] 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.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [14] Targeting PFKL with penfluridol inhibits glycolysis and suppresses esophageal cancer tumorigenesis in an AMPK/FOXO3a/BIM-dependent manner. Acta Pharm Sin B. 2022 Mar;12(3):1271-1287. doi: 10.1016/j.apsb.2021.09.007. Epub 2021 Sep 11.
• [15] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [16] 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.
• [17] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [18] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.
• [19] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.
• [20] Overexpression of HIF-1a could partially protect K562 cells from 1,4-benzoquinone induced toxicity by inhibiting ROS, apoptosis and enhancing glycolysis. Toxicol In Vitro. 2019 Mar;55:18-23. doi: 10.1016/j.tiv.2018.11.005. Epub 2018 Nov 15.