Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU1KZPV)

• DOT Name: 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2)
• Synonyms: AMPK subunit alpha-2; EC 2.7.11.1; Acetyl-CoA carboxylase kinase; ACACA kinase; Hydroxymethylglutaryl-CoA reductase kinase; HMGCR kinase; EC 2.7.11.31
• Gene Name: PRKAA2
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Aplasia cutis congenita
  Arteriosclerosis
  Atherosclerosis
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Cardiac failure
  Cardiomyopathy
  Colon cancer
  Colorectal carcinoma
  Congestive heart failure
  Corpus callosum, agenesis of
  Diabetic kidney disease
  Epithelial ovarian cancer
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Hyperglycemia
  Hyperlipidemia
  Idiopathic cardiomyopathy
  Liver cancer
  Lung cancer
  Lung carcinoma
  Metabolic disorder
  Metastatic malignant neoplasm
  Non-alcoholic fatty liver disease
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Osteoarthritis
  Ovarian cancer
  Ovarian neoplasm
  Prostate carcinoma
  Pulmonary fibrosis
  Stomach cancer
  Stroke
  Urinary bladder cancer
  Urinary bladder neoplasm
  Acute myelogenous leukaemia
  Colon carcinoma
  High blood pressure
  Melanoma
  Adult glioblastoma
  Prostate cancer
  Triple negative breast cancer
• UniProt ID: AAPK2_HUMAN
• PDB ID: 2H6D; 2LTU; 2YZA; 3AQV; 4CFE; 4CFF; 4ZHX; 5EZV; 5ISO; 6B1U; 6B2E; 6BX6; 7MYJ
• EC Number: 2.7.11.1; 2.7.11.31
• Pfam ID: PF16579 ; PF21147 ; PF00069
• Sequence:
  MAEKQKHDGRVKIGHYVLGDTLGVGTFGKVKIGEHQLTGHKVAVKILNRQKIRSLDVVGK
  IKREIQNLKLFRHPHIIKLYQVISTPTDFFMVMEYVSGGELFDYICKHGRVEEMEARRLF
  QQILSAVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNMMSDGEFLRTSCGSPNYA
  APEVISGRLYAGPEVDIWSCGVILYALLCGTLPFDDEHVPTLFKKIRGGVFYIPEYLNRS
  VATLLMHMLQVDPLKRATIKDIREHEWFKQDLPSYLFPEDPSYDANVIDDEAVKEVCEKF
  ECTESEVMNSLYSGDPQDQLAVAYHLIIDNRRIMNQASEFYLASSPPSGSFMDDSAMHIP
  PGLKPHPERMPPLIADSPKARCPLDALNTTKPKSLAVKKAKWHLGIRSQSKPYDIMAEVY
  RAMKQLDFEWKVVNAYHLRVRRKNPVTGNYVKMSLQLYLVDNRSYLLDFKSIDDEVVEQR
  SGSSTPQRSCSAAGLHRPRSSFDSTTAESHSLSGSLTGSLTGSTLSSVSPRLGSHTMDFF
  EMCASLITTLAR
• 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. Involved in insulin receptor/INSR internalization. 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. 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 acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1. Plays an important role in the differential regulation of pro-autophagy (composed of PIK3C3, BECN1, PIK3R4 and UVRAG or ATG14) and non-autophagy (composed of PIK3C3, BECN1 and PIK3R4) complexes, in response to glucose starvation. Can inhibit the non-autophagy complex by phosphorylating PIK3C3 and can activate the pro-autophagy complex by phosphorylating BECN1. Upon glucose starvation, promotes ARF6 activation in a kinase-independent manner leading to cell migration. Upon glucose deprivation mediates the phosphorylation of ACSS2 at 'Ser-659', which exposes the nuclear localization signal of ACSS2, required for its interaction with KPNA1 and nuclear translocation.
• 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:
  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)
  Nuclear events mediated by NFE2L2 (R-HSA-9759194)
  Translocation of SLC2A4 (GLUT4) to the plasma membrane (R-HSA-1445148)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[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	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[6]
Cardiac failure	DISDC067	Strong	Biomarker	[7]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[8]
Colon cancer	DISVC52G	Strong	Biomarker	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[7]
Corpus callosum, agenesis of	DISO9P40	Strong	Biomarker	[3]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[12]
Gastric cancer	DISXGOUK	Strong	Biomarker	[13]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[14]
Glioma	DIS5RPEH	Strong	Biomarker	[15]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[16]
Hyperglycemia	DIS0BZB5	Strong	Biomarker	[8]
Hyperlipidemia	DIS61J3S	Strong	Altered Expression	[17]
Idiopathic cardiomyopathy	DISUGBZL	Strong	Biomarker	[18]
Liver cancer	DISDE4BI	Strong	Biomarker	[6]
Lung cancer	DISCM4YA	Strong	Altered Expression	[1]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[1]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[19]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[20]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[21]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[22]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[23]
Osteoarthritis	DIS05URM	Strong	Biomarker	[24]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[12]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[12]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[25]
Pulmonary fibrosis	DISQKVLA	Strong	Altered Expression	[26]
Stomach cancer	DISKIJSX	Strong	Biomarker	[13]
Stroke	DISX6UHX	Strong	Therapeutic	[27]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[5]
Acute myelogenous leukaemia	DISCSPTN	moderate	Biomarker	[28]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[9]
High blood pressure	DISY2OHH	moderate	Biomarker	[29]
Melanoma	DIS1RRCY	Disputed	Biomarker	[30]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[14]
Prostate cancer	DISF190Y	Limited	Biomarker	[25]
Triple negative breast cancer	DISAMG6N	Limited	Altered Expression	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2) affects the response to substance of Temozolomide.	[50]
DTI-015	DMXZRW0	Approved	5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2) affects the response to substance of DTI-015.	[50]

11 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 catalytic subunit alpha-2 (PRKAA2).	[32]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2).	[33]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2).	[34]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2).	[35]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2).	[36]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2).	[37]
Vitamin B3	DMQVRZH	Approved	Vitamin B3 increases the activity of 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2).	[39]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2).	[40]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2).	[47]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2).	[48]
Dibutyl phthalate	DMEDGKO	Investigative	Dibutyl phthalate increases the expression of 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2).	[49]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Capsaicin	DMGMF6V	Approved	Capsaicin increases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2).	[38]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2).	[41]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2).	[42]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2).	[43]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2).	[44]
Taxifolin	DMQJSF9	Preclinical	Taxifolin decreases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2).	[45]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2).	[46]
schisandrin A	DMWQ480	Investigative	schisandrin A decreases the phosphorylation of 5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2).	[45]

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