Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1OG4QZ)

• DOT Name: 5'-AMP-activated protein kinase subunit beta-1 (PRKAB1)
• Synonyms: AMPK subunit beta-1; AMPKb
• Gene Name: PRKAB1
• Related Disease:
  Glioblastoma multiforme
  Advanced cancer
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Cardiac failure
  Colon cancer
  Colorectal carcinoma
  Congestive heart failure
  Epithelial ovarian cancer
  Gastric cancer
  Gastric neoplasm
  Hepatocellular carcinoma
  Hereditary diffuse gastric adenocarcinoma
  High blood pressure
  Hyperglycemia
  Hyperlipidemia
  Liver cancer
  Lung cancer
  Lung carcinoma
  Metabolic disorder
  Myocardial infarction
  Non-alcoholic fatty liver disease
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Osteoarthritis
  Ovarian cancer
  Ovarian neoplasm
  Parkinson disease
  Prostate carcinoma
  Pulmonary fibrosis
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Acute myelogenous leukaemia
  Aplasia cutis congenita
  Corpus callosum, agenesis of
  Glioma
  Diabetic kidney disease
  Melanoma
  Adult glioblastoma
  Clear cell renal carcinoma
  Colon carcinoma
  Prostate cancer
  Renal cell carcinoma
  Triple negative breast cancer
• UniProt ID: AAKB1_HUMAN
• PDB ID: 4CFE; 4CFF; 4ZHX; 5EZV; 5ISO; 6B1U; 6C9F; 6C9G; 6C9H; 6C9J; 7MYJ
• Pfam ID: PF16561 ; PF04739
• Sequence:
  MGNTSSERAALERHGGHKTPRRDSSGGTKDGDRPKILMDSPEDADLFHSEEIKAPEKEEF
  LAWQHDLEVNDKAPAQARPTVFRWTGGGKEVYLSGSFNNWSKLPLTRSHNNFVAILDLPE
  GEHQYKFFVDGQWTHDPSEPIVTSQLGTVNNIIQVKKTDFEVFDALMVDSQKCSDVSELS
  SSPPGPYHQEPYVCKPEERFRAPPILPPHLLQVILNKDTGISCDPALLPEPNHVMLNHLY
  ALSIKDGVMVLSATHRYKKKYVTTLLYKPI
• 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)
  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

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioblastoma multiforme	DISK8246	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[4]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[4]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[6]
Cardiac failure	DISDC067	Strong	Biomarker	[7]
Colon cancer	DISVC52G	Strong	Altered Expression	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[9]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[10]
Gastric cancer	DISXGOUK	Strong	Biomarker	[11]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[13]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[12]
High blood pressure	DISY2OHH	Strong	Biomarker	[14]
Hyperglycemia	DIS0BZB5	Strong	Biomarker	[15]
Hyperlipidemia	DIS61J3S	Strong	Altered Expression	[16]
Liver cancer	DISDE4BI	Strong	Biomarker	[6]
Lung cancer	DISCM4YA	Strong	Altered Expression	[2]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[2]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[17]
Myocardial infarction	DIS655KI	Strong	Altered Expression	[7]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[18]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[19]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[20]
Osteoarthritis	DIS05URM	Strong	Biomarker	[21]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[10]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[10]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[22]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[23]
Pulmonary fibrosis	DISQKVLA	Strong	Altered Expression	[24]
Stomach cancer	DISKIJSX	Strong	Biomarker	[11]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[5]
Acute myelogenous leukaemia	DISCSPTN	moderate	Biomarker	[25]
Aplasia cutis congenita	DISMDAYM	moderate	Biomarker	[26]
Corpus callosum, agenesis of	DISO9P40	moderate	Biomarker	[26]
Glioma	DIS5RPEH	moderate	Biomarker	[27]
Diabetic kidney disease	DISJMWEY	Disputed	Biomarker	[28]
Melanoma	DIS1RRCY	Disputed	Biomarker	[29]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[1]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[30]
Colon carcinoma	DISJYKUO	Limited	Altered Expression	[8]
Prostate cancer	DISF190Y	Limited	Biomarker	[23]
Renal cell carcinoma	DISQZ2X8	Limited	Biomarker	[30]
Triple negative breast cancer	DISAMG6N	Limited	Altered Expression	[31]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Deoxycholic acid	DM3GYAL	Approved	5'-AMP-activated protein kinase subunit beta-1 (PRKAB1) decreases the response to substance of Deoxycholic acid.	[44]

16 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 5'-AMP-activated protein kinase subunit beta-1 (PRKAB1).	[32]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 5'-AMP-activated protein kinase subunit beta-1 (PRKAB1).	[33]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of 5'-AMP-activated protein kinase subunit beta-1 (PRKAB1).	[34]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of 5'-AMP-activated protein kinase subunit beta-1 (PRKAB1).	[35]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of 5'-AMP-activated protein kinase subunit beta-1 (PRKAB1).	[36]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of 5'-AMP-activated protein kinase subunit beta-1 (PRKAB1).	[37]
Ifosfamide	DMCT3I8	Approved	Ifosfamide affects the expression of 5'-AMP-activated protein kinase subunit beta-1 (PRKAB1).	[32]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of 5'-AMP-activated protein kinase subunit beta-1 (PRKAB1).	[32]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of 5'-AMP-activated protein kinase subunit beta-1 (PRKAB1).	[37]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea increases the expression of 5'-AMP-activated protein kinase subunit beta-1 (PRKAB1).	[37]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of 5'-AMP-activated protein kinase subunit beta-1 (PRKAB1).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of 5'-AMP-activated protein kinase subunit beta-1 (PRKAB1).	[39]
Dioscin	DM5H2W9	Preclinical	Dioscin increases the expression of 5'-AMP-activated protein kinase subunit beta-1 (PRKAB1).	[41]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 5'-AMP-activated protein kinase subunit beta-1 (PRKAB1).	[42]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of 5'-AMP-activated protein kinase subunit beta-1 (PRKAB1).	[36]
Morin	DM2OGZ5	Investigative	Morin decreases the expression of 5'-AMP-activated protein kinase subunit beta-1 (PRKAB1).	[43]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the phosphorylation of 5'-AMP-activated protein kinase subunit beta-1 (PRKAB1).	[38]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of 5'-AMP-activated protein kinase subunit beta-1 (PRKAB1).	[40]

References

• [1] DNA-PKcs is activated under nutrient starvation and activates Akt, MST1, FoxO3a, and NDR1.Biochem Biophys Res Commun. 2020 Jan 15;521(3):668-673. doi: 10.1016/j.bbrc.2019.10.133. Epub 2019 Nov 1.
• [2] Ouabain impairs cancer metabolism and activates AMPK-Src signaling pathway in human cancer cell lines.Acta Pharmacol Sin. 2020 Jan;41(1):110-118. doi: 10.1038/s41401-019-0290-0. Epub 2019 Sep 12.
• [3] Profiling of differentially expressed circular RNAs in peripheral blood mononuclear cells from Alzheimer's disease patients.Metab Brain Dis. 2020 Jan;35(1):201-213. doi: 10.1007/s11011-019-00497-y. Epub 2019 Dec 13.
• [4] AMPK Subunits Harbor Largely Nonoverlapping Genetic Determinants for Body Fat Mass, Glucose Metabolism, and Cholesterol Metabolism.J Clin Endocrinol Metab. 2020 Jan 1;105(1):dgz020. doi: 10.1210/clinem/dgz020.
• [5] BET inhibitor JQ1 suppresses cell proliferation via inducing autophagy and activating LKB1/AMPK in bladder cancer cells.Cancer Med. 2019 Aug;8(10):4792-4805. doi: 10.1002/cam4.2385. Epub 2019 Jun 28.
• [6] LATS2 overexpression attenuates the therapeutic resistance of liver cancer HepG2 cells to sorafenib-mediated death via inhibiting the AMPK-Mfn2 signaling pathway.Cancer Cell Int. 2019 Mar 18;19:60. doi: 10.1186/s12935-019-0778-1. eCollection 2019.
• [7] BDNF contributes to the skeletal muscle anti-atrophic effect of exercise training through AMPK-PGC1 signaling in heart failure mice.Arch Med Sci. 2019 Jan;15(1):214-222. doi: 10.5114/aoms.2018.81037. Epub 2018 Dec 30.
• [8] A Functional Signature Ontology (FUSION) screen detects an AMPK inhibitor with selective toxicity toward human colon tumor cells.Sci Rep. 2018 Feb 28;8(1):3770. doi: 10.1038/s41598-018-22090-6.
• [9] DT-13 inhibited the proliferation of colorectal cancer via glycolytic metabolism and AMPK/mTOR signaling pathway.Phytomedicine. 2019 Feb 15;54:120-131. doi: 10.1016/j.phymed.2018.09.003. Epub 2018 Sep 14.
• [10] Inhibition of mitochondrial translation as a therapeutic strategy for human ovarian cancer to overcome chemoresistance.Biochem Biophys Res Commun. 2019 Feb 5;509(2):373-378. doi: 10.1016/j.bbrc.2018.12.127. Epub 2018 Dec 25.
• [11] Adrenergic modulation of AMPKdependent autophagy by chronic stress enhances cell proliferation and survival in gastric cancer.Int J Oncol. 2019 May;54(5):1625-1638. doi: 10.3892/ijo.2019.4753. Epub 2019 Mar 18.
• [12] A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.PLoS One. 2011 Feb 18;6(2):e16694. doi: 10.1371/journal.pone.0016694.
• [13] Metabolism-induced tumor activator 1 (MITA1), an Energy Stress-Inducible Long Noncoding RNA, Promotes Hepatocellular Carcinoma Metastasis.Hepatology. 2019 Jul;70(1):215-230. doi: 10.1002/hep.30602. Epub 2019 Apr 26.
• [14] Metformin prevents vascular damage in hypertension through the AMPK/ER stress pathway.Hypertens Res. 2019 Jul;42(7):960-969. doi: 10.1038/s41440-019-0212-z. Epub 2019 Jan 21.
• [15] Pharmacological AMPK activation induces transcriptional responses congruent to exercise in skeletal and cardiac muscle, adipose tissues and liver.PLoS One. 2019 Feb 27;14(2):e0211568. doi: 10.1371/journal.pone.0211568. eCollection 2019.
• [16] Gamma-glutamyl carboxylated Gas6 mediates the beneficial effect of vitamin K on lowering hyperlipidemia via regulating the AMPK/SREBP1/PPAR signaling cascade of lipid metabolism.J Nutr Biochem. 2019 Aug;70:174-184. doi: 10.1016/j.jnutbio.2019.05.006. Epub 2019 May 25.
• [17] Effects of AMPK on Apoptosis and Energy Metabolism of Gastric Smooth Muscle Cells in Rats with Diabetic Gastroparesis.Cell Biochem Biophys. 2019 Jun;77(2):165-177. doi: 10.1007/s12013-019-00870-9. Epub 2019 Apr 9.
• [18] L-Carnitine counteracts in vitro fructose-induced hepatic steatosis through targeting oxidative stress markers.J Endocrinol Invest. 2020 Apr;43(4):493-503. doi: 10.1007/s40618-019-01134-2. Epub 2019 Nov 8.
• [19] Flavonoids extracted from mulberry (Morus alba L.) leaf improve skeletal muscle mitochondrial function by activating AMPK in type 2 diabetes.J Ethnopharmacol. 2020 Feb 10;248:112326. doi: 10.1016/j.jep.2019.112326. Epub 2019 Oct 19.
• [20] Circular RNA circHIPK3 modulates autophagy via MIR124-3p-STAT3-PRKAA/AMPK signaling in STK11 mutant lung cancer.Autophagy. 2020 Apr;16(4):659-671. doi: 10.1080/15548627.2019.1634945. Epub 2019 Jun 28.
• [21] 15-Lipoxygenase-1 in osteoblasts promotes TGF-1 expression via inhibiting autophagy in human osteoarthritis.Biomed Pharmacother. 2020 Jan;121:109548. doi: 10.1016/j.biopha.2019.109548. Epub 2019 Nov 5.
• [22] Cypermethrin Activates Autophagosome Formation Albeit Inhibits Autophagy Owing to Poor Lysosome Quality: Relevance to Parkinson's Disease.Neurotox Res. 2018 Feb;33(2):377-387. doi: 10.1007/s12640-017-9800-3. Epub 2017 Aug 24.
• [23] The human oncogene SCL/TAL1 interrupting locus (STIL) promotes tumor growth through MAPK/ERK, PI3K/Akt and AMPK pathways in prostate cancer.Gene. 2019 Feb 20;686:220-227. doi: 10.1016/j.gene.2018.11.048. Epub 2018 Nov 16.
• [24] Wedelolactone Attenuates Pulmonary Fibrosis Partly Through Activating AMPK and Regulating Raf-MAPKs Signaling Pathway.Front Pharmacol. 2019 Mar 5;10:151. doi: 10.3389/fphar.2019.00151. eCollection 2019.
• [25] LncRNA LINP1 regulates acute myeloid leukemia progression via HNF4/AMPK/WNT5A signaling pathway.Hematol Oncol. 2019 Oct;37(4):474-482. doi: 10.1002/hon.2651. Epub 2019 Aug 5.
• [26] Pyridostigmine alleviates cardiac dysfunction via improving mitochondrial cristae shape in a mouse model of metabolic syndrome.Free Radic Biol Med. 2019 Apr;134:119-132. doi: 10.1016/j.freeradbiomed.2019.01.011. Epub 2019 Jan 10.
• [27] Baicalein Induces Autophagy and Apoptosis through AMPK Pathway in Human Glioma Cells.Am J Chin Med. 2019;47(6):1405-1418. doi: 10.1142/S0192415X19500721. Epub 2019 Sep 5.
• [28] 4-O-methylhonokiol ameliorates type 2 diabetes-induced nephropathy in mice likely by activation of AMPK-mediated fatty acid oxidation and Nrf2-mediated anti-oxidative stress.Toxicol Appl Pharmacol. 2019 May 1;370:93-105. doi: 10.1016/j.taap.2019.03.007. Epub 2019 Mar 12.
• [29] Panduratin A induces protective autophagy in melanoma via the AMPK and mTOR pathway.Phytomedicine. 2018 Mar 15;42:144-151. doi: 10.1016/j.phymed.2018.03.027. Epub 2018 Mar 15.
• [30] Activation of AMPK by metformin promotes renal cancer cell proliferation under glucose deprivation through its interaction with PKM2.Int J Biol Sci. 2019 Jan 1;15(3):617-627. doi: 10.7150/ijbs.29689. eCollection 2019.
• [31] AMP-activated protein kinase: a potential therapeutic target for triple-negative breast cancer.Breast Cancer Res. 2019 Feb 21;21(1):29. doi: 10.1186/s13058-019-1107-2.
• [32] 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.
• [33] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [34] p53 hypersensitivity is the predominant mechanism of the unique responsiveness of testicular germ cell tumor (TGCT) cells to cisplatin. PLoS One. 2011 Apr 21;6(4):e19198. doi: 10.1371/journal.pone.0019198.
• [35] 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.
• [36] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [37] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [38] AMPK-dependent signaling modulates the suppression of invasion and migration by fenofibrate in CAL 27 oral cancer cells through NF-B pathway. Environ Toxicol. 2016 Jul;31(7):866-76. doi: 10.1002/tox.22097. Epub 2014 Dec 24.
• [39] 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.
• [40] 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.
• [41] Molecular mechanism and inhibitory targets of dioscin in HepG2 cells. Food Chem Toxicol. 2018 Oct;120:143-154.
• [42] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [43] Molecular mechanism of anti-cancerous potential of Morin extracted from mulberry in Hela cells. Food Chem Toxicol. 2018 Feb;112:466-475. doi: 10.1016/j.fct.2017.07.002. Epub 2017 Jul 6.
• [44] Development and molecular characterization of HCT-116 cell lines resistant to the tumor promoter and multiple stress-inducer, deoxycholate. Carcinogenesis. 2002 Dec;23(12):2063-80. doi: 10.1093/carcin/23.12.2063.