Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTTM1QI)

• DOT Name: Pyruvate kinase PKLR (PKLR)
• Synonyms: EC 2.7.1.40; Pyruvate kinase 1; Pyruvate kinase isozymes L/R; R-type/L-type pyruvate kinase; Red cell/liver pyruvate kinase
• Gene Name: PKLR
• Related Disease:
  Pyruvate kinase deficiency
  Pyruvate kinase hyperactivity
• UniProt ID: KPYR_HUMAN
• PDB ID: 2VGB ; 2VGF ; 2VGG ; 2VGI ; 4IMA ; 4IP7 ; 5SC8 ; 5SC9 ; 5SCA ; 5SCB ; 5SCC ; 5SCD ; 5SCE ; 5SCF ; 5SCG ; 5SCH ; 5SCI ; 5SCJ ; 5SCK ; 5SCL ; 5SDT ; 6NN4 ; 6NN5 ; 6NN7 ; 6NN8 ; 7FRV ; 7FRW ; 7FRX ; 7FRY ; 7FRZ ; 7FS0 ; 7FS1 ; 7FS2 ; 7FS3 ; 7FS4 ; 7FS5 ; 7FS6 ; 7FS7 ; 7FS8 ; 7FS9 ; 7FSA ; 7FSB ; 7FSC ; 7FSD ; 7QDN ; 7QZU
• EC Number: 2.7.1.40
• Pfam ID: PF00224 ; PF02887
• Sequence:
  MSIQENISSLQLRSWVSKSQRDLAKSILIGAPGGPAGYLRRASVAQLTQELGTAFFQQQQ
  LPAAMADTFLEHLCLLDIDSEPVAARSTSIIATIGPASRSVERLKEMIKAGMNIARLNFS
  HGSHEYHAESIANVREAVESFAGSPLSYRPVAIALDTKGPEIRTGILQGGPESEVELVKG
  SQVLVTVDPAFRTRGNANTVWVDYPNIVRVVPVGGRIYIDDGLISLVVQKIGPEGLVTQV
  ENGGVLGSRKGVNLPGAQVDLPGLSEQDVRDLRFGVEHGVDIVFASFVRKASDVAAVRAA
  LGPEGHGIKIISKIENHEGVKRFDEILEVSDGIMVARGDLGIEIPAEKVFLAQKMMIGRC
  NLAGKPVVCATQMLESMITKPRPTRAETSDVANAVLDGADCIMLSGETAKGNFPVEAVKM
  QHAIAREAEAAVYHRQLFEELRRAAPLSRDPTEVTAIGAVEAAFKCCAAAIIVLTTTGRS
  AQLLSRYRPRAAVIAVTRSAQAARQVHLCRGVFPLLYREPPEAIWADDVDRRVQFGIESG
  KLRGFLRVGDLVIVVTGWRPGSGYTNIMRVLSIS
• Function: Pyruvate kinase that catalyzes the conversion of phosphoenolpyruvate to pyruvate with the synthesis of ATP, and which plays a key role in glycolysis.
• KEGG Pathway:
  Glycolysis / Gluconeogenesis (hsa00010)
  Pyruvate metabolism (hsa00620)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  Biosynthesis of amino acids (hsa01230)
  Insulin sig.ling pathway (hsa04910)
  Type II diabetes mellitus (hsa04930)
  Non-alcoholic fatty liver disease (hsa04932)
  Maturity onset diabetes of the young (hsa04950)
• Reactome Pathway:
  (Name not found)
  Glycolysis (R-HSA-70171)
• BioCyc Pathway: MetaCyc:HS07088-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
Pyruvate kinase deficiency	DIS3LZ44	Definitive	Autosomal recessive	[1]
Pyruvate kinase hyperactivity	DIS36JFX	Limited	Autosomal dominant	[2]

2 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 Pyruvate kinase PKLR (PKLR).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Pyruvate kinase PKLR (PKLR).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Pyruvate kinase PKLR (PKLR).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Pyruvate kinase PKLR (PKLR).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Pyruvate kinase PKLR (PKLR).	[4]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Pyruvate kinase PKLR (PKLR).	[7]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Pyruvate kinase PKLR (PKLR).	[8]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Pyruvate kinase PKLR (PKLR).	[8]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Pyruvate kinase PKLR (PKLR).	[9]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Pyruvate kinase PKLR (PKLR).	[8]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Pyruvate kinase PKLR (PKLR).	[10]
Bosentan	DMIOGBU	Approved	Bosentan affects the expression of Pyruvate kinase PKLR (PKLR).	[11]
Aluminium	DM6ECN9	Approved	Aluminium increases the activity of Pyruvate kinase PKLR (PKLR).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Pyruvate kinase PKLR (PKLR).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Pyruvate kinase PKLR (PKLR).	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Pyruvate kinase PKLR (PKLR).	[14]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Pyruvate kinase PKLR (PKLR).	[15]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Modulation of Malaria Phenotypes by Pyruvate Kinase (PKLR) Variants in a Thai Population. PLoS One. 2015 Dec 14;10(12):e0144555. doi: 10.1371/journal.pone.0144555. eCollection 2015.
• [3] 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.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] 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.
• [8] 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.
• [9] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [10] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [11] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [12] Aluminum toxicity triggers the nuclear translocation of HIF-1alpha and promotes anaerobiosis in hepatocytes. Toxicol In Vitro. 2007 Feb;21(1):16-24. doi: 10.1016/j.tiv.2006.07.013. Epub 2006 Aug 5.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [15] Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression. J Biol Chem. 2016 Jul 15;291(29):15378-87. doi: 10.1074/jbc.M116.715151. Epub 2016 May 25.