Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLVN68B)

• DOT Name: 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2)
• Synonyms: AMPK subunit beta-2
• Gene Name: PRKAB2
• Related Disease:
  Coronary heart disease
  Non-insulin dependent diabetes
  Advanced cancer
• UniProt ID: AAKB2_HUMAN
• PDB ID: 2F15; 2V8Q; 2V92; 2V9J; 2Y8L; 2Y8Q; 2YA3; 4CFH; 4EAI; 4EAJ; 4RER; 4REW; 6B2E; 7JHG; 7JHH; 7JIJ; 7M74
• Pfam ID: PF16561 ; PF04739
• Sequence:
  MGNTTSDRVSGERHGAKAARSEGAGGHAPGKEHKIMVGSTDDPSVFSLPDSKLPGDKEFV
  SWQQDLEDSVKPTQQARPTVIRWSEGGKEVFISGSFNNWSTKIPLIKSHNDFVAILDLPE
  GEHQYKFFVDGQWVHDPSEPVVTSQLGTINNLIHVKKSDFEVFDALKLDSMESSETSCRD
  LSSSPPGPYGQEMYAFRSEERFKSPPILPPHLLQVILNKDTNISCDPALLPEPNHVMLNH
  LYALSIKDSVMVLSATHRYKKKYVTTLLYKPI
• Function: Non-catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Beta non-catalytic subunit acts as a scaffold on which the AMPK complex assembles, via its C-terminus that bridges alpha (PRKAA1 or PRKAA2) and gamma subunits (PRKAG1, PRKAG2 or PRKAG3).
• KEGG Pathway:
  FoxO sig.ling pathway (hsa04068)
  AMPK sig.ling pathway (hsa04152)
  Longevity regulating pathway (hsa04211)
  Longevity regulating pathway - multiple species (hsa04213)
  Apelin sig.ling pathway (hsa04371)
  Tight junction (hsa04530)
  Circadian rhythm (hsa04710)
  Thermogenesis (hsa04714)
  Insulin sig.ling pathway (hsa04910)
  Adipocytokine sig.ling pathway (hsa04920)
  Oxytocin sig.ling pathway (hsa04921)
  Glucagon sig.ling pathway (hsa04922)
  Insulin resistance (hsa04931)
  Non-alcoholic fatty liver disease (hsa04932)
  Alcoholic liver disease (hsa04936)
  Hypertrophic cardiomyopathy (hsa05410)
• Reactome Pathway:
  Macroautophagy (R-HSA-1632852)
  AMPK inhibits chREBP transcriptional activation activity (R-HSA-163680)
  Carnitine metabolism (R-HSA-200425)
  Activation of PPARGC1A (PGC-1alpha) by phosphorylation (R-HSA-2151209)
  Energy dependent regulation of mTOR by LKB1-AMPK (R-HSA-380972)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  Lipophagy (R-HSA-9613354)
  Activation of AMPK downstream of NMDARs (R-HSA-9619483)
  Translocation of SLC2A4 (GLUT4) to the plasma membrane (R-HSA-1445148)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary heart disease	DIS5OIP1	Strong	Biomarker	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[3]

23 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 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[7]
Menadione	DMSJDTY	Approved	Menadione affects the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[9]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[12]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[13]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[7]
Ifosfamide	DMCT3I8	Approved	Ifosfamide affects the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[7]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[7]
Ibuprofen	DM8VCBE	Approved	Ibuprofen decreases the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[7]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil decreases the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[7]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[14]
PEITC	DMOMN31	Phase 2	PEITC increases the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of 5'-AMP-activated protein kinase subunit beta-2 (PRKAB2).	[19]

References

• [1] Nutrient sensing pathway genes expression dysregulated in patients with T2DM and coronary artery disease.Diabetes Res Clin Pract. 2019 May;151:39-45. doi: 10.1016/j.diabres.2019.03.036. Epub 2019 Mar 30.
• [2] Haplotype structures and large-scale association testing of the 5' AMP-activated protein kinase genes PRKAA2, PRKAB1, and PRKAB2 [corrected] with type 2 diabetes.Diabetes. 2006 Mar;55(3):849-55. doi: 10.2337/diabetes.55.03.06.db05-1418.
• [3] AMP-activated protein kinase: a cellular energy sensor that comes in 12 flavours.FEBS J. 2016 Aug;283(16):2987-3001. doi: 10.1111/febs.13698. Epub 2016 Mar 24.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [8] 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.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] 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.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [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] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [15] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [16] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] 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.
• [19] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.