Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7TNF0L)

• DOT Name: 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1)
• Synonyms: AMPK subunit alpha-1; EC 2.7.11.1; Acetyl-CoA carboxylase kinase; ACACA kinase; Hydroxymethylglutaryl-CoA reductase kinase; HMGCR kinase; EC 2.7.11.31; Tau-protein kinase PRKAA1; EC 2.7.11.26
• Gene Name: PRKAA1
• Related Disease:
  Glioblastoma multiforme
  Alzheimer disease
  Aplasia cutis congenita
  Arteriosclerosis
  Atherosclerosis
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Cardiac failure
  Cholestasis
  Colon cancer
  Colorectal carcinoma
  Congestive heart failure
  Corpus callosum, agenesis of
  Epithelial ovarian cancer
  Gastric neoplasm
  Glioma
  Hepatocellular carcinoma
  Hereditary diffuse gastric adenocarcinoma
  High blood pressure
  Hyperglycemia
  Hyperlipidemia
  Liver cancer
  Lung cancer
  Lung carcinoma
  Melanoma
  Metabolic disorder
  Non-alcoholic fatty liver disease
  Non-small-cell lung cancer
  Osteoarthritis
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Pulmonary fibrosis
  Schizophrenia
  Urinary bladder cancer
  Urinary bladder neoplasm
  Acute myelogenous leukaemia
  Diabetic kidney disease
  Adult glioblastoma
  Clear cell renal carcinoma
  Colon carcinoma
  Non-insulin dependent diabetes
  Precancerous condition
  Renal cell carcinoma
  Triple negative breast cancer
• UniProt ID: AAPK1_HUMAN
• PDB ID: 4RED; 4RER; 4REW; 5EZV; 6C9F; 6C9G; 6C9H; 6C9J; 7JHG; 7JHH; 7JIJ; 7M74
• EC Number: 2.7.11.1; 2.7.11.26; 2.7.11.31
• Pfam ID: PF16579 ; PF21147 ; PF00069
• Sequence:
  MRRLSSWRKMATAEKQKHDGRVKIGHYILGDTLGVGTFGKVKVGKHELTGHKVAVKILNR
  QKIRSLDVVGKIRREIQNLKLFRHPHIIKLYQVISTPSDIFMVMEYVSGGELFDYICKNG
  RLDEKESRRLFQQILSGVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNMMSDGEF
  LRTSCGSPNYAAPEVISGRLYAGPEVDIWSSGVILYALLCGTLPFDDDHVPTLFKKICDG
  IFYTPQYLNPSVISLLKHMLQVDPMKRATIKDIREHEWFKQDLPKYLFPEDPSYSSTMID
  DEALKEVCEKFECSEEEVLSCLYNRNHQDPLAVAYHLIIDNRRIMNEAKDFYLATSPPDS
  FLDDHHLTRPHPERVPFLVAETPRARHTLDELNPQKSKHQGVRKAKWHLGIRSQSRPNDI
  MAEVCRAIKQLDYEWKVVNPYYLRVRRKNPVTSTYSKMSLQLYQVDSRTYLLDFRSIDDE
  ITEAKSGTATPQRSGSVSNYRSCQRSDSDAEAQGKSSEVSLTSSVTSLDSSPVDLTPRPG
  SHTIEFFEMCANLIKILAQ
• Function: 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. Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively. Promotes lipolysis of lipid droplets by mediating phosphorylation of isoform 1 of CHKA (CHKalpha2). Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160. Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription. Acts as a key regulator of cell growth and proliferation by phosphorylating FNIP1, TSC2, RPTOR, WDR24 and ATG1/ULK1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. Also phosphorylates and inhibits GATOR2 subunit WDR24 in response to nutrient limitation, leading to suppress glucose-mediated mTORC1 activation. In response to energetic stress, phosphorylates FNIP1, inactivating the non-canonical mTORC1 signaling, thereby promoting nuclear translocation of TFEB and TFE3, and inducing transcription of lysosomal or autophagy genes. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1. In that process also activates WDR45/WIPI4. Phosphorylates CASP6, thereby preventing its autoprocessing and subsequent activation. In response to nutrient limitation, phosphorylates transcription factor FOXO3 promoting FOXO3 mitochondrial import. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it. Also has tau-protein kinase activity: in response to amyloid beta A4 protein (APP) exposure, activated by CAMKK2, leading to phosphorylation of MAPT/TAU; however the relevance of such data remains unclear in vivo. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1. Regulates hepatic lipogenesis. Activated via SIRT3, represses sterol regulatory element-binding protein (SREBP) transcriptional activities and ATP-consuming lipogenesis to restore cellular energy balance.
• KEGG Pathway:
  FoxO sig.ling pathway (hsa04068)
  Autophagy - animal (hsa04140)
  mTOR sig.ling pathway (hsa04150)
  PI3K-Akt sig.ling pathway (hsa04151)
  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)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  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)
  Activation of AMPK downstream of NMDARs (R-HSA-9619483)
  Macroautophagy (R-HSA-1632852)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioblastoma multiforme	DISK8246	Definitive	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Aplasia cutis congenita	DISMDAYM	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	[6]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[7]
Cardiac failure	DISDC067	Strong	Biomarker	[8]
Cholestasis	DISDJJWE	Strong	Altered Expression	[9]
Colon cancer	DISVC52G	Strong	Altered Expression	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[11]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[8]
Corpus callosum, agenesis of	DISO9P40	Strong	Biomarker	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[12]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[13]
Glioma	DIS5RPEH	Strong	Biomarker	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[15]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[13]
High blood pressure	DISY2OHH	Strong	Biomarker	[16]
Hyperglycemia	DIS0BZB5	Strong	Biomarker	[17]
Hyperlipidemia	DIS61J3S	Strong	Altered Expression	[18]
Liver cancer	DISDE4BI	Strong	Biomarker	[7]
Lung cancer	DISCM4YA	Strong	Altered Expression	[6]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[6]
Melanoma	DIS1RRCY	Strong	Biomarker	[19]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[20]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[21]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[22]
Osteoarthritis	DIS05URM	Strong	Biomarker	[23]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[12]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[12]
Prostate cancer	DISF190Y	Strong	Biomarker	[24]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[24]
Pulmonary fibrosis	DISQKVLA	Strong	Altered Expression	[25]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[26]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[5]
Acute myelogenous leukaemia	DISCSPTN	moderate	Biomarker	[27]
Diabetic kidney disease	DISJMWEY	Disputed	Biomarker	[28]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[1]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[29]
Colon carcinoma	DISJYKUO	Limited	Altered Expression	[10]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[30]
Precancerous condition	DISV06FL	Limited	Biomarker	[31]
Renal cell carcinoma	DISQZ2X8	Limited	Biomarker	[29]
Triple negative breast cancer	DISAMG6N	Limited	Altered Expression	[32]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fenofibrate	DMFKXDY	Approved	5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1) decreases the response to substance of Fenofibrate.	[61]
Afimoxifene	DMFORDT	Phase 2	5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1) decreases the response to substance of Afimoxifene.	[62]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hexadecanoic acid	DMWUXDZ	Investigative	5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1) increases the oxidation of Hexadecanoic acid.	[63]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[33]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[34]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[35]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[36]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[37]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[38]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[40]
Aspirin	DM672AH	Approved	Aspirin increases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[43]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[44]
Atorvastatin	DMF28YC	Phase 3 Trial	Atorvastatin increases the activity of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[48]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[51]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[56]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[57]
Dorsomorphin	DMKYXJW	Investigative	Dorsomorphin decreases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[59]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[39]
Testosterone	DM7HUNW	Approved	Testosterone increases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[41]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[42]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[45]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[46]
Curcumin	DMQPH29	Phase 3	Curcumin increases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[47]
Acadesine	DM1RMF5	Phase 3	Acadesine increases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[42]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[49]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[50]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[52]
Tetrandrine	DMAOJBX	Phase 1	Tetrandrine affects the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[53]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[54]
Taxifolin	DMQJSF9	Preclinical	Taxifolin decreases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[55]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[54]
(E)-4-(3,5-dimethoxystyryl)phenol	DMYXI2V	Investigative	(E)-4-(3,5-dimethoxystyryl)phenol increases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[58]
Ginsenoside Re	DM46FVD	Investigative	Ginsenoside Re increases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[60]
schisandrin A	DMWQ480	Investigative	schisandrin A decreases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1).	[55]

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