Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM436F9)

• DOT Name: kinase isozyme 2, mitochondrial (PDK2)
• Synonyms: EC 2.7.11.2; Pyruvate dehydrogenase kinase isoform 2; PDH kinase 2; PDKII
• Gene Name: PDK2
• UniProt ID: PDK2_HUMAN
• PDB ID: 2BTZ; 2BU2; 2BU5; 2BU6; 2BU7; 2BU8; 4MP2; 4MP7; 4MPC; 4MPE; 4MPN; 4V25; 4V26; 5J6A; 5J71; 5M4K; 5M4M; 5M4N; 5M4P; 6LIL; 6LIN; 6LIO; 6TMP; 6TMQ; 6TMZ; 6TN0; 6TN2; 7EA0; 7EAS; 7EBH; 7VBU; 7VBV; 7VBX
• EC Number: 2.7.11.2
• Pfam ID: PF10436 ; PF02518
• Sequence:
  MRWVWALLKNASLAGAPKYIEHFSKFSPSPLSMKQFLDFGSSNACEKTSFTFLRQELPVR
  LANIMKEINLLPDRVLSTPSVQLVQSWYVQSLLDIMEFLDKDPEDHRTLSQFTDALVTIR
  NRHNDVVPTMAQGVLEYKDTYGDDPVSNQNIQYFLDRFYLSRISIRMLINQHTLIFDGST
  NPAHPKHIGSIDPNCNVSEVVKDAYDMAKLLCDKYYMASPDLEIQEINAANSKQPIHMVY
  VPSHLYHMLFELFKNAMRATVESHESSLILPPIKVMVALGEEDLSIKMSDRGGGVPLRKI
  ERLFSYMYSTAPTPQPGTGGTPLAGFGYGLPISRLYAKYFQGDLQLFSMEGFGTDAVIYL
  KALSTDSVERLPVYNKSAWRHYQTIQEAGDWCVPSTEPKNTSTYRVS
• Function: Kinase that plays a key role in the regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism. Mediates cellular responses to insulin. Plays an important role in maintaining normal blood glucose levels and in metabolic adaptation to nutrient availability. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. Plays a role in the regulation of cell proliferation and in resistance to apoptosis under oxidative stress. Plays a role in p53/TP53-mediated apoptosis.
• Tissue Specificity: Expressed in many tissues, with the highest level in heart and skeletal muscle, intermediate levels in brain, kidney, pancreas and liver, and low levels in placenta and lung.
• 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

13 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 2, mitochondrial (PDK2).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of kinase isozyme 2, mitochondrial (PDK2).	[2]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of kinase isozyme 2, mitochondrial (PDK2).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of kinase isozyme 2, mitochondrial (PDK2).	[4]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of kinase isozyme 2, mitochondrial (PDK2).	[5]
Marinol	DM70IK5	Approved	Marinol increases the expression of kinase isozyme 2, mitochondrial (PDK2).	[6]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of kinase isozyme 2, mitochondrial (PDK2).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of kinase isozyme 2, mitochondrial (PDK2).	[8]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of kinase isozyme 2, mitochondrial (PDK2).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of kinase isozyme 2, mitochondrial (PDK2).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of kinase isozyme 2, mitochondrial (PDK2).	[12]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of kinase isozyme 2, mitochondrial (PDK2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of kinase isozyme 2, mitochondrial (PDK2).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of kinase isozyme 2, mitochondrial (PDK2).	[10]

References

• [1] 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.
• [2] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [3] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [4] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [5] Gene induction and apoptosis in human hepatocellular carci-noma cells SMMC-7721 exposed to 5-aza-2'-deoxycytidine. Chin Med J (Engl). 2007 Sep 20;120(18):1626-31.
• [6] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [7] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [10] 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.
• [11] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [12] 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.
• [13] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [14] 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.