Details of Drug Off-Target (DOT)

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

• DOT Name: kinase isozyme 3, mitochondrial (PDK3)
• Synonyms: EC 2.7.11.2; Pyruvate dehydrogenase kinase isoform 3
• Gene Name: PDK3
• Related Disease: Charcot-Marie-Tooth disease X-linked dominant 6
• UniProt ID: PDK3_HUMAN
• PDB ID: 1Y8N; 1Y8O; 1Y8P; 2PNR; 2Q8I
• EC Number: 2.7.11.2
• Pfam ID: PF10436 ; PF02518
• Sequence:
  MRLFRWLLKQPVPKQIERYSRFSPSPLSIKQFLDFGRDNACEKTSYMFLRKELPVRLANT
  MREVNLLPDNLLNRPSVGLVQSWYMQSFLELLEYENKSPEDPQVLDNFLQVLIKVRNRHN
  DVVPTMAQGVIEYKEKFGFDPFISTNIQYFLDRFYTNRISFRMLINQHTLLFGGDTNPVH
  PKHIGSIDPTCNVADVVKDAYETAKMLCEQYYLVAPELEVEEFNAKAPDKPIQVVYVPSH
  LFHMLFELFKNSMRATVELYEDRKEGYPAVKTLVTLGKEDLSIKISDLGGGVPLRKIDRL
  FNYMYSTAPRPSLEPTRAAPLAGFGYGLPISRLYARYFQGDLKLYSMEGVGTDAVIYLKA
  LSSESFERLPVFNKSAWRHYKTTPEADDWSNPSSEPRDASKYKAKQ
• Function: Inhibits pyruvate dehydrogenase activity by phosphorylation of the E1 subunit PDHA1, and thereby regulates glucose metabolism and aerobic respiration. Can also phosphorylate PDHA2. Decreases glucose utilization and increases fat metabolism in response to prolonged fasting, and as adaptation to a high-fat diet. Plays a role in glucose homeostasis and in maintaining normal blood glucose levels in function of nutrient levels and under starvation. Plays a role in the generation of reactive oxygen species.
• Tissue Specificity: Expressed in heart, skeletal muscle, spinal cord, as well as fetal and adult brain.
• KEGG Pathway: Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Signaling by Retinoic Acid (R-HSA-5362517)
  Regulation of pyruvate dehydrogenase (PDH) complex (R-HSA-204174)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot-Marie-Tooth disease X-linked dominant 6	DIS00ET9	Definitive	X-linked	[1]

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 kinase isozyme 3, mitochondrial (PDK3).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of kinase isozyme 3, mitochondrial (PDK3).	[12]

14 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 kinase isozyme 3, mitochondrial (PDK3).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of kinase isozyme 3, mitochondrial (PDK3).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of kinase isozyme 3, mitochondrial (PDK3).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of kinase isozyme 3, mitochondrial (PDK3).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of kinase isozyme 3, mitochondrial (PDK3).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of kinase isozyme 3, mitochondrial (PDK3).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of kinase isozyme 3, mitochondrial (PDK3).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of kinase isozyme 3, mitochondrial (PDK3).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of kinase isozyme 3, mitochondrial (PDK3).	[10]
Tramadol	DMRQD04	Approved	Tramadol increases the expression of kinase isozyme 3, mitochondrial (PDK3).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of kinase isozyme 3, mitochondrial (PDK3).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of kinase isozyme 3, mitochondrial (PDK3).	[14]
AZD-7545	DMU6L4I	Terminated	AZD-7545 increases the activity of kinase isozyme 3, mitochondrial (PDK3).	[15]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of kinase isozyme 3, mitochondrial (PDK3).	[16]

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] 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] 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.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] 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.
• [10] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [11] Comparative study of the neurotoxicological effects of tramadol and tapentadol in SH-SY5Y cells. Toxicology. 2016 Jun 1;359-360:1-10. doi: 10.1016/j.tox.2016.06.010. Epub 2016 Jun 15.
• [12] 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.
• [13] 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.
• [14] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [15] VER-246608, a novel pan-isoform ATP competitive inhibitor of pyruvate dehydrogenase kinase, disrupts Warburg metabolism and induces context-dependent cytostasis in cancer cells. Oncotarget. 2014 Dec 30;5(24):12862-76. doi: 10.18632/oncotarget.2656.
• [16] 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.