Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW00PRY)

• DOT Name: 5'-AMP-activated protein kinase subunit gamma-1 (PRKAG1)
• Synonyms: AMPK gamma1; AMPK subunit gamma-1; AMPKg
• Gene Name: PRKAG1
• Related Disease: Neoplasm
• UniProt ID: AAKG1_HUMAN
• PDB ID: 2UV4; 2UV5; 2UV6; 2UV7; 4CFE; 4CFF; 4RER; 4REW; 4ZHX; 5EZV; 5ISO; 6B1U; 6B2E; 6C9F; 6C9G; 6C9H; 6C9J; 7JHG; 7JHH; 7JIJ; 7M74; 7MYJ
• Pfam ID: PF00571
• Sequence:
  METVISSDSSPAVENEHPQETPESNNSVYTSFMKSHRCYDLIPTSSKLVVFDTSLQVKKA
  FFALVTNGVRAAPLWDSKKQSFVGMLTITDFINILHRYYKSALVQIYELEEHKIETWREV
  YLQDSFKPLVCISPNASLFDAVSSLIRNKIHRLPVIDPESGNTLYILTHKRILKFLKLFI
  TEFPKPEFMSKSLEELQIGTYANIAMVRTTTPVYVALGIFVQHRVSALPVVDEKGRVVDI
  YSKFDVINLAAEKTYNNLDVSVTKALQHRSHYFEGVLKCYLHETLETIINRLVEAEVHRL
  VVVDENDVVKGIVSLSDILQALVLTGGEKKP
• Function: AMP/ATP-binding 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. Gamma non-catalytic subunit mediates binding to AMP, ADP and ATP, leading to activate or inhibit AMPK: AMP-binding results in allosteric activation of alpha catalytic subunit (PRKAA1 or PRKAA2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. ADP also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. ATP promotes dephosphorylation of catalytic subunit, rendering the AMPK enzyme inactive.
• 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

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 5'-AMP-activated protein kinase subunit gamma-1 (PRKAG1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 5'-AMP-activated protein kinase subunit gamma-1 (PRKAG1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of 5'-AMP-activated protein kinase subunit gamma-1 (PRKAG1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 5'-AMP-activated protein kinase subunit gamma-1 (PRKAG1).	[5]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of 5'-AMP-activated protein kinase subunit gamma-1 (PRKAG1).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of 5'-AMP-activated protein kinase subunit gamma-1 (PRKAG1).	[8]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of 5'-AMP-activated protein kinase subunit gamma-1 (PRKAG1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 5'-AMP-activated protein kinase subunit gamma-1 (PRKAG1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of 5'-AMP-activated protein kinase subunit gamma-1 (PRKAG1).	[6]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of 5'-AMP-activated protein kinase subunit gamma-1 (PRKAG1).	[10]

References

• [1] AMPK variant, a candidate of novel predictor for chemotherapy in metastatic colorectal cancer: A meta-analysis using TRIBE, MAVERICC and FIRE3.Int J Cancer. 2019 Oct 15;145(8):2082-2090. doi: 10.1002/ijc.32261. Epub 2019 Mar 26.
• [2] 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.
• [3] 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.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [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] 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.
• [8] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [9] 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.
• [10] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [11] 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.