Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHTAM54)

• DOT Name: 5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2)
• Synonyms: AMPK gamma2; AMPK subunit gamma-2; H91620p
• Gene Name: PRKAG2
• Related Disease:
  Cardiomyopathy
  Chromosomal disorder
  Chronic renal failure
  Hypertrophic cardiomyopathy
  Hypertrophic cardiomyopathy 6
  PRKAG2-related cardiomyopathy
  Anemia
  Arrhythmogenic right ventricular cardiomyopathy
  Atopic dermatitis
  Atrial fibrillation
  Atrioventricular block
  Autism spectrum disorder
  Cardiac disease
  Cardiac failure
  Cardiovascular disease
  Congestive heart failure
  Danon disease
  Disorder of glycogen metabolism
  Fabry disease
  Glycogen storage disease type II
  Gout
  Hepatocellular carcinoma
  Lethal congenital glycogen storage disease of heart
  Non-insulin dependent diabetes
  Obesity
  Open-angle glaucoma
  Stroke
  Type-1/2 diabetes
  Wolff-Parkinson-White syndrome
  Cardiac arrest
  High blood pressure
  Pancreatic cancer
  Ventricular fibrillation
  Advanced cancer
  Arrhythmia
  Breast cancer
  Breast carcinoma
  Chronic kidney disease
  Chronic obstructive pulmonary disease
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Familial hypertrophic cardiomyopathy
  Myopathy
  Proliferative diabetic retinopathy
  Rectal carcinoma
  Rectal neoplasm
• UniProt ID: AAKG2_HUMAN
• Pfam ID: PF00571
• Sequence:
  MGSAVMDTKKKKDVSSPGGSGGKKNASQKRRSLRVHIPDLSSFAMPLLDGDLEGSGKHSS
  RKVDSPFGPGSPSKGFFSRGPQPRPSSPMSAPVRPKTSPGSPKTVFPFSYQESPPRSPRR
  MSFSGIFRSSSKESSPNSNPATSPGGIRFFSRSRKTSGLSSSPSTPTQVTKQHTFPLESY
  KHEPERLENRIYASSSPPDTGQRFCPSSFQSPTRPPLASPTHYAPSKAAALAAALGPAEA
  GMLEKLEFEDEAVEDSESGVYMRFMRSHKCYDIVPTSSKLVVFDTTLQVKKAFFALVANG
  VRAAPLWESKKQSFVGMLTITDFINILHRYYKSPMVQIYELEEHKIETWRELYLQETFKP
  LVNISPDASLFDAVYSLIKNKIHRLPVIDPISGNALYILTHKRILKFLQLFMSDMPKPAF
  MKQNLDELGIGTYHNIAFIHPDTPIIKALNIFVERRISALPVVDESGKVVDIYSKFDVIN
  LAAEKTYNNLDITVTQALQHRSQYFEGVVKCNKLEILETIVDRIVRAEVHRLVVVNEADS
  IVGIISLSDILQALILTPAGAKQKETETE
• 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.
• Tissue Specificity: Isoform B is ubiquitously expressed except in liver and thymus. The highest level is detected in heart with abundant expression in placenta and testis.
• 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

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiomyopathy	DISUPZRG	Definitive	Genetic Variation	[1]
Chromosomal disorder	DISM5BB5	Definitive	Genetic Variation	[2]
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[3]
Hypertrophic cardiomyopathy	DISQG2AI	Definitive	Autosomal dominant	[4]
Hypertrophic cardiomyopathy 6	DIS52OBL	Definitive	Autosomal dominant	[5]
PRKAG2-related cardiomyopathy	DIS5DQIA	Definitive	Autosomal dominant	[4]
Anemia	DISTVL0C	Strong	Genetic Variation	[6]
Arrhythmogenic right ventricular cardiomyopathy	DIS3V2BE	Strong	Genetic Variation	[7]
Atopic dermatitis	DISTCP41	Strong	Genetic Variation	[8]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[9]
Atrioventricular block	DIS8YLE6	Strong	Genetic Variation	[10]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[11]
Cardiac disease	DISVO1I5	Strong	Genetic Variation	[12]
Cardiac failure	DISDC067	Strong	Genetic Variation	[13]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[14]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[13]
Danon disease	DIS45YLU	Strong	Genetic Variation	[15]
Disorder of glycogen metabolism	DISYGNOB	Strong	Genetic Variation	[16]
Fabry disease	DISUUQJF	Strong	Genetic Variation	[17]
Glycogen storage disease type II	DISXZPBC	Strong	Genetic Variation	[18]
Gout	DISHC0U7	Strong	Genetic Variation	[19]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[20]
Lethal congenital glycogen storage disease of heart	DIS322OY	Strong	Autosomal dominant	[21]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[22]
Obesity	DIS47Y1K	Strong	Posttranslational Modification	[23]
Open-angle glaucoma	DISSZEE8	Strong	Genetic Variation	[24]
Stroke	DISX6UHX	Strong	Altered Expression	[14]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[25]
Wolff-Parkinson-White syndrome	DISW4TQ8	Strong	Autosomal dominant	[21]
Cardiac arrest	DIS9DIA4	moderate	Genetic Variation	[26]
High blood pressure	DISY2OHH	moderate	Altered Expression	[14]
Pancreatic cancer	DISJC981	moderate	Genetic Variation	[27]
Ventricular fibrillation	DIS7IN76	moderate	Genetic Variation	[26]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[28]
Arrhythmia	DISFF2NI	Limited	Genetic Variation	[29]
Breast cancer	DIS7DPX1	Limited	Genetic Variation	[30]
Breast carcinoma	DIS2UE88	Limited	Genetic Variation	[30]
Chronic kidney disease	DISW82R7	Limited	Genetic Variation	[31]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Posttranslational Modification	[32]
Colon cancer	DISVC52G	Limited	Genetic Variation	[28]
Colon carcinoma	DISJYKUO	Limited	Genetic Variation	[28]
Colonic neoplasm	DISSZ04P	Limited	Genetic Variation	[28]
Familial hypertrophic cardiomyopathy	DISQ89HN	Limited	Genetic Variation	[33]
Myopathy	DISOWG27	Limited	Biomarker	[34]
Proliferative diabetic retinopathy	DISQZ13G	Limited	Genetic Variation	[35]
Rectal carcinoma	DIS8FRR7	Limited	Biomarker	[28]
Rectal neoplasm	DISB4UZ0	Limited	Genetic Variation	[28]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Uric acid	DMA1MKT	Investigative	5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2) affects the abundance of Uric acid.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of 5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2).	[36]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2).	[37]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2).	[38]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2).	[39]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of 5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2).	[40]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2).	[41]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of 5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2).	[43]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of 5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2).	[44]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of 5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2).	[45]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of 5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2).	[46]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of 5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2).	[47]
HMPL-004	DM29XGY	Phase 3	HMPL-004 increases the expression of 5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2).	[48]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl affects the expression of 5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2).	[48]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of 5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2).	[48]
2-tert-butylbenzene-1,4-diol	DMNXI1E	Investigative	2-tert-butylbenzene-1,4-diol decreases the expression of 5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2).	[48]

3 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-2 (PRKAG2).	[42]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2).	[49]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of 5'-AMP-activated protein kinase subunit gamma-2 (PRKAG2).	[50]

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