Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1QY9JM)

• DOT Name: ATP-dependent 6-phosphofructokinase, muscle type (PFKM)
• Synonyms: ATP-PFK; PFK-M; EC 2.7.1.11; 6-phosphofructokinase type A; Phosphofructo-1-kinase isozyme A; PFK-A; Phosphohexokinase
• Gene Name: PFKM
• Related Disease:
  Glioblastoma multiforme
  Glycogen storage disease VII
  Adenocarcinoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Hepatocellular carcinoma
  Hyperglycemia
  Liver cancer
  Myocardial ischemia
  Neoplasm
  Non-insulin dependent diabetes
  Renal tubular acidosis
  Schizophrenia
  Urinary tract infection
  Adult glioblastoma
  Inherited fatty acid metabolism disorder
  Myopathy
  Pancreatic cancer
  Purine metabolism disease
  Tuberculosis
  Disorder of glycogen metabolism
• UniProt ID: PFKAM_HUMAN
• PDB ID: 4OMT
• EC Number: 2.7.1.11
• Pfam ID: PF00365
• Sequence:
  MTHEEHHAAKTLGIGKAIAVLTSGGDAQGMNAAVRAVVRVGIFTGARVFFVHEGYQGLVD
  GGDHIKEATWESVSMMLQLGGTVIGSARCKDFREREGRLRAAYNLVKRGITNLCVIGGDG
  SLTGADTFRSEWSDLLSDLQKAGKITDEEATKSSYLNIVGLVGSIDNDFCGTDMTIGTDS
  ALHRIMEIVDAITTTAQSHQRTFVLEVMGRHCGYLALVTSLSCGADWVFIPECPPDDDWE
  EHLCRRLSETRTRGSRLNIIIVAEGAIDKNGKPITSEDIKNLVVKRLGYDTRVTVLGHVQ
  RGGTPSAFDRILGSRMGVEAVMALLEGTPDTPACVVSLSGNQAVRLPLMECVQVTKDVTK
  AMDEKKFDEALKLRGRSFMNNWEVYKLLAHVRPPVSKSGSHTVAVMNVGAPAAGMNAAVR
  STVRIGLIQGNRVLVVHDGFEGLAKGQIEEAGWSYVGGWTGQGGSKLGTKRTLPKKSFEQ
  ISANITKFNIQGLVIIGGFEAYTGGLELMEGRKQFDELCIPFVVIPATVSNNVPGSDFSV
  GADTALNTICTTCDRIKQSAAGTKRRVFIIETMGGYCGYLATMAGLAAGADAAYIFEEPF
  TIRDLQANVEHLVQKMKTTVKRGLVLRNEKCNENYTTDFIFNLYSEEGKGIFDSRKNVLG
  HMQQGGSPTPFDRNFATKMGAKAMNWMSGKIKESYRNGRIFANTPDSGCVLGMRKRALVF
  QPVAELKDQTDFEHRIPKEQWWLKLRPILKILAKYEIDLDTSDHAHLEHITRKRSGEAAV
• Function: Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis.
• 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)
• BioCyc Pathway: MetaCyc:HS07832-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioblastoma multiforme	DISK8246	Definitive	Altered Expression	[1]
Glycogen storage disease VII	DISWZUF2	Definitive	Autosomal recessive	[2]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Carcinoma	DISH9F1N	Strong	Biomarker	[6]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Hyperglycemia	DIS0BZB5	Strong	Altered Expression	[8]
Liver cancer	DISDE4BI	Strong	Biomarker	[7]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[10]
Renal tubular acidosis	DISE1NDR	Strong	Genetic Variation	[11]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[12]
Urinary tract infection	DISMT6UV	Strong	Genetic Variation	[13]
Adult glioblastoma	DISVP4LU	moderate	Altered Expression	[1]
Inherited fatty acid metabolism disorder	DISOT51Y	moderate	Biomarker	[14]
Myopathy	DISOWG27	moderate	Genetic Variation	[15]
Pancreatic cancer	DISJC981	moderate	Biomarker	[16]
Purine metabolism disease	DIS4B865	moderate	Biomarker	[14]
Tuberculosis	DIS2YIMD	Disputed	Biomarker	[17]
Disorder of glycogen metabolism	DISYGNOB	Limited	CausalMutation	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of ATP-dependent 6-phosphofructokinase, muscle type (PFKM).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ATP-dependent 6-phosphofructokinase, muscle type (PFKM).	[28]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of ATP-dependent 6-phosphofructokinase, muscle type (PFKM).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP-dependent 6-phosphofructokinase, muscle type (PFKM).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of ATP-dependent 6-phosphofructokinase, muscle type (PFKM).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATP-dependent 6-phosphofructokinase, muscle type (PFKM).	[22]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of ATP-dependent 6-phosphofructokinase, muscle type (PFKM).	[23]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of ATP-dependent 6-phosphofructokinase, muscle type (PFKM).	[24]
Imatinib	DM7RJXL	Approved	Imatinib decreases the expression of ATP-dependent 6-phosphofructokinase, muscle type (PFKM).	[25]
Clotrimazole	DMMFCIH	Approved	Clotrimazole decreases the expression of ATP-dependent 6-phosphofructokinase, muscle type (PFKM).	[25]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the activity of ATP-dependent 6-phosphofructokinase, muscle type (PFKM).	[26]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the expression of ATP-dependent 6-phosphofructokinase, muscle type (PFKM).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ATP-dependent 6-phosphofructokinase, muscle type (PFKM).	[30]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the expression of ATP-dependent 6-phosphofructokinase, muscle type (PFKM).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ATP-dependent 6-phosphofructokinase, muscle type (PFKM).	[32]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of ATP-dependent 6-phosphofructokinase, muscle type (PFKM).	[33]
CH-223191	DMMJZYC	Investigative	CH-223191 increases the expression of ATP-dependent 6-phosphofructokinase, muscle type (PFKM).	[34]
Alpha-naphthoflavone	DMELOIQ	Investigative	Alpha-naphthoflavone increases the expression of ATP-dependent 6-phosphofructokinase, muscle type (PFKM).	[34]

References

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• [8] Metformin counteracts glucose-dependent lipogenesis and impairs transdeamination in the liver of gilthead sea bream ( Sparus aurata).Am J Physiol Regul Integr Comp Physiol. 2019 Mar 1;316(3):R265-R273. doi: 10.1152/ajpregu.00216.2018. Epub 2019 Jan 16.
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• [10] Insulin resistance and impaired insulin secretion due to phosphofructo-1-kinase-deficiency in humans.J Mol Med (Berl). 1999 Jan;77(1):96-103. doi: 10.1007/s001090050311.
• [11] Human H+ATPase a4 subunit mutations causing renal tubular acidosis reveal a role for interaction with phosphofructokinase-1.Am J Physiol Renal Physiol. 2008 Oct;295(4):F950-8. doi: 10.1152/ajprenal.90258.2008. Epub 2008 Jul 16.
• [12] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [13] Flexible Metabolism and Suppression of Latent Enzymes Are Important for Escherichia coli Adaptation to Diverse Environments within the Host.J Bacteriol. 2019 Jul 24;201(16):e00181-19. doi: 10.1128/JB.00181-19. Print 2019 Aug 15.
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• [15] Nonsense mutation in the phosphofructokinase muscle subunit gene associated with retention of intron 10 in one of the isolated transcripts in Ashkenazi Jewish patients with Tarui disease.Proc Natl Acad Sci U S A. 1995 Oct 24;92(22):10322-6. doi: 10.1073/pnas.92.22.10322.
• [16] MiR-135 suppresses glycolysis and promotes pancreatic cancer cell adaptation to metabolic stress by targeting phosphofructokinase-1.Nat Commun. 2019 Feb 18;10(1):809. doi: 10.1038/s41467-019-08759-0.
• [17] Characterization of phosphofructokinase activity in Mycobacterium tuberculosis reveals that a functional glycolytic carbon flow is necessary to limit the accumulation of toxic metabolic intermediates under hypoxia.PLoS One. 2013;8(2):e56037. doi: 10.1371/journal.pone.0056037. Epub 2013 Feb 7.
• [18] Deficiency of phosphofructo-1-kinase/muscle subtype in humans impairs insulin secretion and causes insulin resistance.J Clin Invest. 1997 Dec 1;100(11):2833-41. doi: 10.1172/JCI119831.
• [19] 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.
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• [21] 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.
• [22] 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.
• [23] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [24] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [25] Combination of imatinib and clotrimazole enhances cell growth inhibition in T47D breast cancer cells. Chem Biol Interact. 2015 May 25;233:147-56. doi: 10.1016/j.cbi.2015.03.028. Epub 2015 Apr 8.
• [26] Resveratrol decreases breast cancer cell viability and glucose metabolism by inhibiting 6-phosphofructo-1-kinase. Biochimie. 2013 Jun;95(6):1336-43. doi: 10.1016/j.biochi.2013.02.013. Epub 2013 Feb 27.
• [27] Synthetic oleanane triterpenoid derivative CDDO-Me disrupts cellular bioenergetics to suppress pancreatic ductal adenocarcinoma via targeting SLC1A5. J Biochem Mol Toxicol. 2022 Nov;36(11):e23192. doi: 10.1002/jbt.23192. Epub 2022 Aug 5.
• [28] 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.
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• [31] Dose-dependent effects of caffeine in human Sertoli cells metabolism and oxidative profile: relevance for male fertility. Toxicology. 2015 Feb 3;328:12-20. doi: 10.1016/j.tox.2014.12.003. Epub 2014 Dec 5.
• [32] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [33] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [34] 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated production of reactive oxygen species is an essential step in the mechanism of action to accelerate human keratinocyte differentiation. Toxicol Sci. 2013 Mar;132(1):235-49.