PRKAA1

Summary

PRKAA1 (protein kinase AMP-activated catalytic subunit alpha 1, HGNC:9376) is a protein-coding gene on chromosome 5p13.1, encoding 5’-AMP-activated protein kinase catalytic subunit alpha-1 (Q13131). Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism.

The protein encoded by this gene belongs to the ser/thr protein kinase family. It is the catalytic subunit of the 5’-prime-AMP-activated protein kinase (AMPK). AMPK is a cellular energy sensor conserved in all eukaryotic cells. The kinase activity of AMPK is activated by the stimuli that increase the cellular AMP/ATP ratio. AMPK regulates the activities of a number of key metabolic enzymes through phosphorylation. It protects cells from stresses that cause ATP depletion by switching off ATP-consuming biosynthetic pathways. Alternatively spliced transcript variants encoding distinct isoforms have been observed.

Source: NCBI Gene 5562 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 53 total
• Druggable target: yes — 46 molecules with ChEMBL bioactivity
• Transcription factor: yes — 13 downstream targets (CollecTRI)
• MANE Select transcript: NM_006251

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9376
Approved symbol	PRKAA1
Name	protein kinase AMP-activated catalytic subunit alpha 1
Location	5p13.1
Locus type	gene with protein product
Status	Approved
Aliases	AMPKa1
Ensembl gene	ENSG00000132356
Ensembl biotype	protein_coding
OMIM	602739
Entrez	5562

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 retained_intron, 3 protein_coding

ENST00000296800, ENST00000354209, ENST00000397006, ENST00000397128, ENST00000505783, ENST00000506652, ENST00000509874, ENST00000511248, ENST00000513152

RefSeq mRNA: 8 — MANE Select: NM_006251 NM_001355028, NM_001355029, NM_001355034, NM_001355035, NM_001355036, NM_001355037, NM_006251, NM_206907

CCDS: CCDS3932, CCDS3933

Canonical transcript exons

ENST00000397128 — 9 exons

Exon	Start	End
ENSE00000903754	40764514	40764640
ENSE00001135348	40764752	40765238
ENSE00001305125	40759389	40763022
ENSE00001892100	40798063	40798374
ENSE00003484220	40767466	40767690
ENSE00003497407	40777445	40777586
ENSE00003520553	40775410	40775503
ENSE00003553386	40771719	40771863
ENSE00003681543	40769416	40769503

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 97.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.6110 / max 421.0361, expressed in 1810 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
61448	30.5254	1808
61449	0.0724	9
61450	0.0132	5

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	97.18	gold quality
sperm	CL:0000019	96.39	gold quality
rectum	UBERON:0001052	96.00	gold quality
gall bladder	UBERON:0002110	95.67	gold quality
mucosa of stomach	UBERON:0001199	95.19	gold quality
adrenal tissue	UBERON:0018303	94.92	gold quality
male germ cell	CL:0000015	94.69	gold quality
stromal cell of endometrium	CL:0002255	94.68	gold quality
colonic epithelium	UBERON:0000397	93.85	gold quality
popliteal artery	UBERON:0002250	93.47	gold quality
tibial artery	UBERON:0007610	93.47	gold quality
artery	UBERON:0001637	93.17	gold quality
body of pancreas	UBERON:0001150	93.13	gold quality
descending thoracic aorta	UBERON:0002345	93.11	gold quality
islet of Langerhans	UBERON:0000006	93.08	gold quality
left testis	UBERON:0004533	92.96	gold quality
monocyte	CL:0000576	92.89	gold quality
minor salivary gland	UBERON:0001830	92.86	gold quality
aorta	UBERON:0000947	92.76	gold quality
tendon	UBERON:0000043	92.73	gold quality
left coronary artery	UBERON:0001626	92.66	gold quality
left uterine tube	UBERON:0001303	92.61	gold quality
right testis	UBERON:0004534	92.59	gold quality
right lobe of liver	UBERON:0001114	92.58	gold quality
right lung	UBERON:0002167	92.46	gold quality
mononuclear cell	CL:0000842	92.45	gold quality
leukocyte	CL:0000738	92.26	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.22	gold quality
metanephros cortex	UBERON:0010533	92.07	gold quality
right coronary artery	UBERON:0001625	91.99	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.50

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

13 targets.

Target	Regulation
CDKN1A	Repression
CPT1C	Activation
CYCS	Activation
EIF4E	Repression
EIF4G1	Repression
FLCN	Activation
FNIP1	Activation
G6PC1	Repression
HDAC6	Repression
NAMPT	Activation
SCD	Repression
SLC2A4	Activation
UCP3	Activation

Upstream regulators (CollecTRI, top): AR, CEBPB, CREBZF, FOXO3, HMGA1, NFE2L2, NFKB, NR0B2, NR1H3, NR1I3, NR5A2, NRF1, PPARA, SP1, STAT3, TBXT, USF1

miRNA regulators (miRDB)

274 targeting PRKAA1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754

Literature-anchored findings (GeneRIF, showing 40)

• Role of AMPK in tolerance to glucose starvation in cell lines (PMID:12091379)
• Trained human skeletal muscle has increased alpha(1)-AMPK protein levels and blunted AMPK activation during exercise. (PMID:12391032)
• AMPK activation is linked with reductions in cAMP-mediated epithelial chloride flux and may be a contributing factor to the hyporesponsiveness seen under conditions of chronic inflammation. (PMID:12869384)
• IGF-1 induces AMPK-alpha subunit phosphorylation via an ATM-dependent and LKB1-independent pathway (PMID:15485651)
• These are the first data to show an effect of AMPK on cell movement, and suggest a fundamental role for energy deficiency in regulating cellular behaviour. (PMID:16405649)
• The data provide novel insight into the subunit composition of the epithelial CFTR/AMPK/NDPK complex, such that: CFTR interacts specifically with AMPK alpha1, gamma2 and NDPK-A and not NDPK-B or AMPK gamma1. (PMID:16466905)
• interaction between Leu-328 and Val-298 plays an important role in AMPK alpha autoinhibitory function (PMID:17088252)
• Data show that overexpression of AMPK mediated by the adenovirus can induce LX2 cell apoptosis. (PMID:17584647)
• alpha2 But not alpha1 AMP-activated protein kinase mediates oxidative stress-induced inhibition of retinal pigment epithelium cell phagocytosis of photoreceptor outer segments (PMID:18195011)
• Ultrasound increased COX-2 expression in osteoblasts via the LKB1/AMPKalpha1/p38/IKKalphabeta and NF-kappaB signaling pathway. (PMID:18276112)
• rosiglitazone is able to acutely stimulate NO synthesis in cultured endothelial cells by an AMP-activated protein kinase-dependent mechanism, likely to be mediated by LKB1 (PMID:18303014)
• repeated, high-intensity exercise that leads to clinically relevant immunosuppression may do so via AMPK inactivation within immune cells (PMID:18347656)
• The dynamic of AMPK activity was consistent with a prosurvival role during chronic hypoxia. (PMID:18359290)
• AMPK alpha2 activity, AMPK alpha2 Thr172 phosphorylation, and ACC-beta Ser222 phosphorylation were increased immediately after exercise. These increases had all returned to basal levels at 3 and 24 h after exercise. (PMID:18614941)
• Results demonstrate that AMPK-alpha1 and AMPK-alpha2 activity and fuel selection in skeletal muscle in response to exercise can be manipulated by diet and/or the interactive effects of diet and exercise training. (PMID:18801964)
• although the molecular mechanism underlying AMPK activation via the forskolin stimulation is unclear, the tight junction formation induced by forskolin is likely to be mediated by the AMPK pathway in trophoblasts (PMID:18950855)
• AMPK activation partially contributes to the cytotoxic effect of curcumin in ovarian cancer cells (PMID:19020741)
• D-xylose derivatives stimulate muscle glucose uptake by activating AMP-activated protein kinase alpha (PMID:19049348)
• AMP-activated protein kinase alpha-1 subunit is a potent counterregulator of inflammatory signaling pathways in macrophages. (PMID:19050283)
• Adiponectin-induced growth inhibition is significantly attenuated when AMPK level is reduced using small interfering RNA, indicating that AMPK is involved in mediating the antiproliferative action of this adipokine. (PMID:19138981)
• TRAIL-induced AMPK activation depends on transforming growth factor-beta-activating kinase 1 (TAK1) and TAK1-binding subunit 2. (PMID:19197243)
• AMP-activated protein kinase inhibits alkaline pH- and PKA-induced apical vacuolar H+-ATPase accumulation in epididymal clear cells. (PMID:19211918)
• Thus AMPKalpha1 in HUVECs regulates both their mitochondrial content and their antioxidant defences. (PMID:19442239)
• AMPK inhibits myoblast differentiation through a PGC-1alpha-dependent mechanism. (PMID:19491292)
• Results suggest that fatty acids and ER stress reduce AdipoR2 protein and pAMPK levels. (PMID:19502591)
• the active form of the alpha-catalytic AMPK subunit (P-AMPKalphaThr172)transiently associates with several mitotic structures including centrosomes, spindle poles, the central spindle midzone and the midbody throughout all of the mitotic stages and cytokinesis. (PMID:19556893)
• Data show that kidney bean husk extract exhibited antitumor effects accompanied by the increase in p-AMPK and p-Acc as well as antitumor proteins p53 and p21. (PMID:19723093)
• Results indicate that AMPK is crucial in apoptosis induced by curcumin and further that the pAkt-AMPK-COX-2 cascade or AMPK-pAkt-COX-2 pathway is important in cell proliferation and apoptosis in colon cancer cells. (PMID:19723094)
• Results indicate that the liberation of excessive ROS might be the upstream signal of the AMPK-COX-2 signaling pathway (PMID:19723101)
• Findings suggest that both COX-2 stimulators (TPA and H(2)O(2)) might have differential effects on COX-2 and AMPK regulation and further apoptotic regulation. (PMID:19723105)
• These results indicate that AMP-activated protein kinase supports the NGF-induced viability of human HeLa cells to glucose starvation. (PMID:19728147)
• Epigallocatechin gallate decreases ET-1 expression and secretion from endothelial cells, in part, via Akt- and AMPK-stimulated FOXO1 regulation of the ET-1 promoter. (PMID:19887561)
• Autophagy promoted via troglitazone is correlated with AMPKalpha activation and independent of PPARgamma activation and EGFR transactivation. (PMID:19923924)
• Data show a novel mechanism for the sensitization to DR-induced apoptosis linking glucose metabolism to Mcl-1 downexpression, and provide a rationale for the combined use of DR ligands with AMPK activators or mTOR inhibitors in the treatment of cancers. (PMID:19966861)
• AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism (PMID:20080969)
• Results show taht RSV triggered autophagic cell death in CML cells via both JNK-mediated p62 overexpression and AMPK activation. (PMID:20103647)
• Exercise-induced decreases in intracellular reactive oxygen species and AMPK phosphorylation constitute evidence supporting a role for ROS in controlling AMPK, and hence immune function, in the context of exercise-induced immunosuppression. (PMID:20167678)
• Sprint exercise 60 min after glucose ingestion elicits an immediate Ser485-AMPKalpha1/Ser491-AMPKalpha2 phosphorylation. (PMID:20217115)
• Hypoxia-induced peroxisome proliferator-activated receptor gamma coactivator (PGC-1alpha) expression is associated with activation of AMPK in patients with tetralogy of Fallot. (PMID:20368732)
• AMPK negatively regulates lipid-induced inflammation, which acts through SIRT1, thereby contributing to the protection against obesity, inflammation, and insulin resistance (PMID:20421294)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	prkaa1	ENSDARG00000060596
mus_musculus	Prkaa1	ENSMUSG00000050697
rattus_norvegicus	Prkaa1	ENSRNOG00000012799
drosophila_melanogaster	Snrk	FBGN0033915
drosophila_melanogaster	Nuak	FBGN0262617
caenorhabditis_elegans		WBGENE00012638
caenorhabditis_elegans	ZK524.4	WBGENE00013994
caenorhabditis_elegans	tag-344	WBGENE00015230
caenorhabditis_elegans		WBGENE00044388

Paralogs (17): NUAK1 (ENSG00000074590), TSSK4 (ENSG00000139908), HUNK (ENSG00000142149), SIK1 (ENSG00000142178), BRSK1 (ENSG00000160469), SIK3 (ENSG00000160584), PRKAA2 (ENSG00000162409), TSSK3 (ENSG00000162526), NUAK2 (ENSG00000163545), SNRK (ENSG00000163788), MELK (ENSG00000165304), SIK2 (ENSG00000170145), BRSK2 (ENSG00000174672), NIM1K (ENSG00000177453), TSSK6 (ENSG00000178093), TSSK2 (ENSG00000206203), TSSK1B (ENSG00000212122)

Protein

Protein identifiers

5’-AMP-activated protein kinase catalytic subunit alpha-1 — Q13131 (reviewed: Q13131)

Alternative names: Acetyl-CoA carboxylase kinase, Hydroxymethylglutaryl-CoA reductase kinase, Tau-protein kinase PRKAA1

All UniProt accessions (2): Q13131, Q96E92

UniProt curated annotations — full annotation on UniProt →

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, it 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. Upon stress, regulates mitochondrial fragmentation through phosphorylation of MTFR1L. Phosphorylates ALDH7A1 in response to cellular stress, such as hypoxia or ferroptotic stress, promoting ALDH7A1 recruitment to membranes.

Subunit / interactions. AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2. Interacts with LACC1; this interaction may regulate macrophage autophagic flux. (Microbial infection) Interacts with Dengue type 2 virus non-structural protein 1; this interaction promotes the AMPK/ERK/mTOR signaling pathway to induce autophagy.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Ubiquitinated. Phosphorylated at Thr-183 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Also phosphorylated at Thr-183 by CAMKK2; triggered by a rise in intracellular calcium ions, without detectable changes in the AMP/ATP ratio. CAMKK1 can also phosphorylate Thr-183, but at a much lower level. Dephosphorylated by protein phosphatase 2A and 2C (PP2A and PP2C). Phosphorylated by ULK1 and ULK2; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1, ULK2 and AMPK. Dephosphorylated by PPM1A and PPM1B. Glycosylated; O-GlcNAcylated by OGT, promoting the AMP-activated protein kinase (AMPK) activity.

Activity regulation. Activated by phosphorylation on Thr-183. Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing phosphorylation on Thr-183. AMP-binding to gamma subunit also sustains activity by preventing dephosphorylation of Thr-183. ADP also stimulates Thr-183 phosphorylation, without stimulating already phosphorylated AMPK. ATP promotes dephosphorylation of Thr-183, rendering the enzyme inactive. Under physiological conditions AMPK mainly exists in its inactive form in complex with ATP, which is much more abundant than AMP. Inhibited by modified adenosine monophosphate (AMP) N(6)-methyl-AMP (m6AMP), N(6),N(6)-dimethyl-AMP (m6,6AMP) and N(6)-isopentenyl-AMP (i6AMP). AMPK is activated by antihyperglycemic drug metformin, a drug prescribed to patients with type 2 diabetes: in vivo, metformin seems to mainly inhibit liver gluconeogenesis. However, metformin can be used to activate AMPK in muscle and other cells in culture or ex vivo. Selectively inhibited by compound C (6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine. Activated by resveratrol, a natural polyphenol present in red wine, and S17834, a synthetic polyphenol.

Domain organisation. The AIS (autoinhibitory sequence) region shows some sequence similarity with the ubiquitin-associated domains and represses kinase activity.

Similarity. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13131-1	1	yes
Q13131-2	2

RefSeq proteins (8): NP_001341957, NP_001341958, NP_001341963, NP_001341964, NP_001341965, NP_001341966, NP_006242, NP_996790 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR028375	KA1/Ssp2_C	Homologous_superfamily
IPR028797	PRKAA1_UBA	Domain
IPR032270	AMPK_C	Domain
IPR039137	AMPKA1_C	Domain
IPR049020	PRKAA1/2_AID	Domain

Pfam: PF00069, PF16579, PF21147

Enzyme classification (BRENDA):

• EC 2.7.11.1 — non-specific serine/threonine protein kinase (BRENDA: 71 organisms, 682 substrates, 228 inhibitors, 23 Km, 6 kcat entries)
• EC 2.7.11.31 — [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase (BRENDA: 25 organisms, 266 substrates, 134 inhibitors, 51 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

27 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.02–0.4168	15
ATP	0.0007–0.64	11
BIOTIN-GGHMRSAMSGLHLVKRR-NH2	0.0267–0.1214	6
ACETYL-COA CARBOXYLASE	—	4
KKRAARATSNVFA	0.013–0.045	3
PAH1 PHOSPHATIDATE PHOSPHATASE	0.0002	2
RRRLSSLRA	0.0036–0.0037	2
HMGSAMSGLHLVKRR	0.573–2.316	2
HMHSAMSGLHLVKRR	0.118–0.428	2
HMKSAMSGLHLVKRR	0.111–0.133	2
HMRSAGSGLHLVKRR	0.069–0.07	2
HMRSAMSGLHGVKRR	0.013–0.096	2
HMRSAMSGLHLGKRR	0.038–0.042	2
HMRSAMSGLHLVKRR	0.0498–0.091	2
HMRSAMTGLHGVKRR	0.034–0.065	2

Catalyzed reactions (Rhea), 6 shown:

• L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein] + ADP + H(+) (RHEA:12801)
• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-seryl-[acetyl-CoA carboxylase] + ATP = O-phospho-L-seryl-[acetyl-CoA carboxylase] + ADP + H(+) (RHEA:20333)
• L-seryl-[3-hydroxy-3-methylglutaryl-coenzyme A reductase] + ATP = O-phospho-L-seryl-[3-hydroxy-3-methylglutaryl-coenzyme A reductase] + ADP + H(+) (RHEA:23172)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)
• L-threonyl-[tau protein] + ATP = O-phospho-L-threonyl-[tau protein] + ADP + H(+) (RHEA:53904)

UniProt features (80 total): helix 20, modified residue 17, strand 17, turn 7, sequence conflict 6, region of interest 2, sequence variant 2, compositionally biased region 2, binding site 2, chain 1, domain 1, splice variant 1, mutagenesis site 1, active site 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
6C9H	X-RAY DIFFRACTION	2.65
6C9G	X-RAY DIFFRACTION	2.7
6C9F	X-RAY DIFFRACTION	2.92
4RED	X-RAY DIFFRACTION	2.95
5EZV	X-RAY DIFFRACTION	2.99
6C9J	X-RAY DIFFRACTION	3.05
7JHG	ELECTRON MICROSCOPY	3.47
7JHH	ELECTRON MICROSCOPY	3.92
7M74	ELECTRON MICROSCOPY	3.93
4RER	X-RAY DIFFRACTION	4.05
4REW	X-RAY DIFFRACTION	4.58
7JIJ	X-RAY DIFFRACTION	5.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13131-F1	80.08	0.51

Antibody-complex structures (SAbDab): 3 — 7JHG, 7JHH, 7M74

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 150 (proton acceptor)

Ligand- & substrate-binding residues (2): 33–41; 56

Post-translational modifications (17): 183, 269, 355, 356, 360, 368, 382, 397, 467, 486, 488, 490, 496, 508, 524, 527, 32

Mutagenesis-validated functional residues (1):

Position	Phenotype
307	activates the kinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

19 pathways

ID	Pathway
R-HSA-1632852	Macroautophagy
R-HSA-380972	Energy dependent regulation of mTOR by LKB1-AMPK
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation
R-HSA-9619483	Activation of AMPK downstream of NMDARs
R-HSA-9931269	AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-162582	Signal Transduction
R-HSA-165159	MTOR signalling
R-HSA-212436	Generic Transcription Pathway
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-438064	Post NMDA receptor activation events
R-HSA-442755	Activation of NMDA receptors and postsynaptic events
R-HSA-5633007	Regulation of TP53 Activity
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-9612973	Autophagy

MSigDB gene sets: 0 (showing top):

GO Biological Process (99): response to hypoxia (GO:0001666), positive regulation of T cell mediated immune response to tumor cell (GO:0002842), glucose metabolic process (GO:0006006), fatty acid biosynthetic process (GO:0006633), cholesterol biosynthetic process (GO:0006695), autophagy (GO:0006914), signal transduction (GO:0007165), positive regulation of cell population proliferation (GO:0008284), lipid biosynthetic process (GO:0008610), cellular response to starvation (GO:0009267), response to UV (GO:0009411), cold acclimation (GO:0009631), response to gamma radiation (GO:0010332), positive regulation of autophagy (GO:0010508), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), response to activity (GO:0014823), Wnt signaling pathway (GO:0016055), fatty acid oxidation (GO:0019395), response to caffeine (GO:0031000), cellular response to nutrient levels (GO:0031669), negative regulation of TOR signaling (GO:0032007), cellular response to stress (GO:0033554), cellular response to oxidative stress (GO:0034599), cellular response to glucose starvation (GO:0042149), glucose homeostasis (GO:0042593), regulation of circadian rhythm (GO:0042752), negative regulation of apoptotic process (GO:0043066), regulation of vascular permeability (GO:0043114), response to estrogen (GO:0043627), positive regulation of cholesterol biosynthetic process (GO:0045542), positive regulation of glycolytic process (GO:0045821), positive regulation of DNA-templated transcription (GO:0045893), negative regulation of glucosylceramide biosynthetic process (GO:0046318), negative regulation of insulin receptor signaling pathway (GO:0046627), rhythmic process (GO:0048511), positive regulation of skeletal muscle tissue development (GO:0048643), positive regulation of T cell activation (GO:0050870), negative regulation of lipid catabolic process (GO:0050995), fatty acid homeostasis (GO:0055089)

GO Molecular Function (17): chromatin binding (GO:0003682), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), AMP-activated protein kinase activity (GO:0004679), cAMP-dependent protein kinase activity (GO:0004691), ATP binding (GO:0005524), protein-containing complex binding (GO:0044877), metal ion binding (GO:0046872), [hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity (GO:0047322), tau protein binding (GO:0048156), tau-protein kinase activity (GO:0050321), protein serine kinase activity (GO:0106310), histone H2BS36 kinase activity (GO:0140823), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (14): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), cilium (GO:0005929), apical plasma membrane (GO:0016324), nuclear speck (GO:0016607), axon (GO:0030424), dendrite (GO:0030425), nucleotide-activated protein kinase complex (GO:0031588), ciliary basal body (GO:0036064), neuronal cell body (GO:0043025), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Transcriptional Regulation by TP53	2
Autophagy	1
MTOR signalling	1
Regulation of TP53 Activity	1
Post NMDA receptor activation events	1
Regulation of PD-L1(CD274) Post-translational modification	1
Transmission across Chemical Synapses	1
Neuronal System	1
Signal Transduction	1
RNA Polymerase II Transcription	1
Generic Transcription Pathway	1
Activation of NMDA receptors and postsynaptic events	1
Neurotransmitter receptors and postsynaptic signal transmission	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein serine/threonine kinase activity	4
cellular anatomical structure	4
binding	3
fatty acid metabolic process	2
gene expression	2
regulation of gene expression	2
protein kinase activity	2
neuron projection	2
response to stress	1
response to decreased oxygen levels	1
T cell mediated immune response to tumor cell	1
positive regulation of T cell mediated immunity	1
positive regulation of immune response to tumor cell	1
regulation of T cell mediated immune response to tumor cell	1
hexose metabolic process	1
lipid biosynthetic process	1
monocarboxylic acid biosynthetic process	1
cholesterol metabolic process	1
sterol biosynthetic process	1
secondary alcohol biosynthetic process	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
lipid metabolic process	1
biosynthetic process	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
response to light stimulus	1
response to cold	1
response to ionizing radiation	1
autophagy	1

Protein interactions and networks

STRING

2966 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRKAA1	PRKAB1	Q9Y478	980
PRKAA1	PRKAG1	P54619	970
PRKAA1	PRKAB2	O43741	937
PRKAA1	PRKAG2	Q9UGJ0	884
PRKAA1	PRKAG3	Q9UGI9	860
PRKAA1	PRKAA2	P54646	748
PRKAA1	FNIP1	Q8TF40	705
PRKAA1	MTOR	P42345	698
PRKAA1	FLCN	Q8NFG4	694
PRKAA1	ACACA	Q13085	675
PRKAA1	INS	P01308	566
PRKAA1	FNIP2	Q9P278	553
PRKAA1	HRH1	P35367	547
PRKAA1	HRH2	P25021	544
PRKAA1	SIRT1	Q96EB6	542

IntAct

279 interactions, top by confidence:

A	B	Type	Score
PRKAA1	PRKAB2	psi-mi:“MI:0914”(association)	0.950
PRKAA1	PRKAB2	psi-mi:“MI:0915”(physical association)	0.950
PRKAB2	PRKAA1	psi-mi:“MI:0915”(physical association)	0.950
PRKAG1	PRKAA1	psi-mi:“MI:0915”(physical association)	0.940
PRKAA1	PRKAG1	psi-mi:“MI:0915”(physical association)	0.940
PRKAA1	PRKAG1	psi-mi:“MI:0914”(association)	0.940
PRKAG1	PRKAA1	psi-mi:“MI:0914”(association)	0.940
PRKAG1	PRKAB2	psi-mi:“MI:0914”(association)	0.940
PRKAB1	PRKAG1	psi-mi:“MI:0914”(association)	0.920
PRKAG2	PRKAB2	psi-mi:“MI:0914”(association)	0.730
PNMA5	PRKAA1	psi-mi:“MI:0915”(physical association)	0.670
ROPN1	PRKAA1	psi-mi:“MI:0915”(physical association)	0.670
PRKAA1	ABI2	psi-mi:“MI:0915”(physical association)	0.670
PRKAA1	PNMA5	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (472): PRKAA1 (Affinity Capture-Western), ACACA (Biochemical Activity), PRKAA1 (Affinity Capture-Western), Trp53 (Biochemical Activity), PRKAB1 (Two-hybrid), PRKAA1 (Two-hybrid), PRKAA1 (Reconstituted Complex), PRKAB1 (Reconstituted Complex), PRKAG1 (Reconstituted Complex), PRKAA1 (Reconstituted Complex), PRKAB1 (Reconstituted Complex), PRKAG1 (Reconstituted Complex), PRKAA1 (Affinity Capture-Western), PRKAA1 (Affinity Capture-Western), PRKAA1 (Two-hybrid)

ESM2 similar proteins: A1Z9X0, A8WUG4, A8XWC4, F1M7Y5, O13310, O19111, O74536, O97627, P00518, P07934, P09217, P13286, P23443, P26817, P26818, P26819, P31325, P34722, P35626, P41743, P54645, P54646, P67998, P67999, P83099, Q02111, Q02956, Q04759, Q05513, Q09137, Q12706, Q13131, Q16816, Q19266, Q21734, Q28948, Q2KJ16, Q3UYH7, Q5EG47, Q5R4K9

Diamond homologs: A0AUV4, A1A5Q6, A2KF29, A2XFF4, A8WYE4, B2DD29, B7XHR6, B8BBT7, C0HKC8, C0HKC9, F1QGZ6, O08678, O08679, O22932, O22971, O65554, O74536, O94168, P27448, P52497, P54645, P54646, P57059, P92958, Q00372, Q02723, Q03141, Q05512, Q09137, Q0D4B2, Q0JI49, Q13131, Q19469, Q28948, Q2QY53, Q2RAX3, Q2V452, Q38997, Q54DF2, Q54TA3

SIGNOR signaling

153 interactions.

A	Effect	B	Mechanism
PRKAA1	“down-regulates activity”	HNF4A	phosphorylation
PRKAA1	down-regulates	MLXIPL	phosphorylation
PRKAA1	down-regulates	NOS2
PRKAA1	up-regulates	KPNA2	phosphorylation
PRKAA1	up-regulates	NRF1
PRKAA1	up-regulates	TP53	phosphorylation
CAMK2B	up-regulates	PRKAA1	phosphorylation
PRKAA1	“form complex”	AMPK	binding
PRKAA1	down-regulates	ZNF692	phosphorylation
PRKAA1	“up-regulates quantity by expression”	CYCS	“transcriptional regulation”
PRKAA1	“up-regulates activity”	PPARGC1A	phosphorylation
PRKAA1	“up-regulates quantity by expression”	SLC2A4	“transcriptional regulation”
PRKAA1	“up-regulates quantity by expression”	UCP3	“transcriptional regulation”
PRKAA1	up-regulates	PRKAB1	phosphorylation
PRKAA1	up-regulates	FOXO1	phosphorylation
PRKAA1	up-regulates	FOXO4	phosphorylation
PRKAA1	up-regulates	NR0B2
PRKAA1	up-regulates	GFPT1	phosphorylation
PRKAA1	down-regulates	TBC1D1	phosphorylation
PRKAA1	down-regulates	GBF1	phosphorylation
PRKAA1	up-regulates	NOS3	phosphorylation
PRKAA1	“up-regulates quantity by stabilization”	SNAI1	phosphorylation
PRKAA1	up-regulates	SNAI1	phosphorylation
PRKAA1	down-regulates	CRTC1	phosphorylation
PRKAA1	“down-regulates activity”	RPTOR	phosphorylation
PRKAA1	“up-regulates activity”	ULK1	phosphorylation
ULK1	“down-regulates activity”	PRKAA1	phosphorylation
PRKAA1	down-regulates	NR2C2	phosphorylation
PRKAA1	“down-regulates quantity by repression”	SCD	“transcriptional regulation”
PRKAA1	down-regulates	HDAC4	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 114 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Energy dependent regulation of mTOR by LKB1-AMPK	6	40.7×	4e-07
Activation of AMPK downstream of NMDARs	6	39.4×	5e-07
MTOR signalling	7	32.0×	2e-07
Selective autophagy	6	28.8×	2e-06
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	8	26.7×	6e-08
Post NMDA receptor activation events	7	24.6×	6e-07
Activation of NMDA receptors and postsynaptic events	7	22.2×	1e-06
Regulation of TP53 Activity	8	18.3×	6e-07

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to nutrient levels	7	42.6×	2e-07
fatty acid biosynthetic process	6	27.4×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

53 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1943 predictions. Top by Δscore:

Variant	Effect	Δscore
5:40767460:TATTA:T	donor_loss	1.0000
5:40767461:ATTAC:A	donor_loss	1.0000
5:40767462:TTACC:T	donor_loss	1.0000
5:40767463:TA:T	donor_loss	1.0000
5:40767464:ACCTG:A	donor_loss	1.0000
5:40767465:C:A	donor_loss	1.0000
5:40767687:CAAT:C	acceptor_gain	1.0000
5:40769418:T:A	donor_gain	1.0000
5:40771860:CCAG:C	acceptor_gain	1.0000
5:40771861:CAG:C	acceptor_gain	1.0000
5:40771861:CAGC:C	acceptor_gain	1.0000
5:40775405:CTTA:C	donor_loss	1.0000
5:40775407:T:TA	donor_loss	1.0000
5:40775408:A:AC	donor_gain	1.0000
5:40775408:A:AG	donor_loss	1.0000
5:40775408:AC:A	donor_gain	1.0000
5:40775409:C:A	donor_loss	1.0000
5:40775409:C:CC	donor_gain	1.0000
5:40775409:CC:C	donor_gain	1.0000
5:40775409:CCCTT:C	donor_gain	1.0000
5:40775504:CT:C	acceptor_loss	1.0000
5:40777443:A:AC	donor_gain	1.0000
5:40777444:C:CC	donor_gain	1.0000
5:40777444:CAG:C	donor_gain	1.0000
5:40777582:GCCAA:G	acceptor_gain	1.0000
5:40777583:CCAA:C	acceptor_gain	1.0000
5:40777583:CCAAC:C	acceptor_gain	1.0000
5:40777584:CAA:C	acceptor_gain	1.0000
5:40777584:CAAC:C	acceptor_gain	1.0000
5:40777585:AA:A	acceptor_gain	1.0000

AlphaMissense

3703 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:40762788:A:G	L557P	1.000
5:40762800:A:G	L553P	1.000
5:40762808:A:C	C550W	1.000
5:40762809:C:T	C550Y	1.000
5:40762810:A:G	C550R	1.000
5:40762820:A:C	F546L	1.000
5:40762820:A:T	F546L	1.000
5:40762822:A:G	F546L	1.000
5:40764527:G:C	F474L	1.000
5:40764527:G:T	F474L	1.000
5:40764528:A:G	F474S	1.000
5:40764529:A:G	F474L	1.000
5:40764531:T:A	D473V	1.000
5:40764532:C:G	D473H	1.000
5:40764534:A:C	L472R	1.000
5:40764534:A:G	L472P	1.000
5:40764534:A:T	L472Q	1.000
5:40764537:A:G	L471P	1.000
5:40764562:A:C	Y463D	1.000
5:40764564:A:G	L462S	1.000
5:40764567:T:G	Q461P	1.000
5:40764570:A:G	L460P	1.000
5:40764757:A:G	W435R	1.000
5:40764757:A:T	W435R	1.000
5:40764781:C:G	A427P	1.000
5:40764801:A:T	I420N	1.000
5:40764802:T:A	I420F	1.000
5:40764821:A:C	S413R	1.000
5:40764821:A:T	S413R	1.000
5:40764823:T:G	S413R	1.000

dbSNP variants (sampled 300 via entrez): RS1000040161 (5:40786294 G>A), RS1000046191 (5:40778455 G>A), RS1000221103 (5:40759615 A>C,T), RS1000442139 (5:40759824 A>G), RS1000502457 (5:40792425 G>A), RS1000533088 (5:40770548 A>C), RS1000541474 (5:40783321 TAAA>T,TAA,TAAAA), RS1000929392 (5:40786605 C>G), RS1000970626 (5:40772854 G>A,C), RS1000995596 (5:40783556 G>A,C), RS1001026797 (5:40765470 G>C), RS1001064981 (5:40763852 G>T), RS1001075072 (5:40796163 G>A), RS1001090207 (5:40772583 C>G), RS1001272788 (5:40779874 C>T)

Disease associations

OMIM: gene MIM:602739 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001300_2	Gastric cancer	8.000000e-29
GCST002992_8	Gastric cancer	5.000000e-06
GCST003007_2	Non-cardia gastric cancer	2.000000e-23
GCST003009_1	Cardia gastric cancer	7.000000e-12
GCST003010_3	Gastric cancer	5.000000e-26
GCST003218_6	Non-cardia gastric cancer	1.000000e-10
GCST008646_2	Gastric cancer	5.000000e-12
GCST90002387_105	Immature fraction of reticulocytes	4.000000e-11
GCST90002390_128	Mean corpuscular hemoglobin	2.000000e-10
GCST90002392_626	Mean corpuscular volume	1.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (9): CHEMBL2096907 (PROTEIN COMPLEX GROUP), CHEMBL2111345 (PROTEIN COMPLEX), CHEMBL3038451 (PROTEIN COMPLEX), CHEMBL3038452 (PROTEIN COMPLEX), CHEMBL3038453 (PROTEIN COMPLEX), CHEMBL3038454 (PROTEIN COMPLEX), CHEMBL4045 (SINGLE PROTEIN), CHEMBL4106162 (PROTEIN COMPLEX), CHEMBL4106163 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

46 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 391,418 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL752	ADENOSINE PHOSPHATE	4	165,316
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL189963	PALBOCICLIB	4	13,102
CHEMBL1983268	ENTRECTINIB	4	3,510
CHEMBL2325741	CAPIVASERTIB	4	2,157
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3622821	UPADACITINIB	4	2,726
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL2105728	CRENOLANIB	3	2,167
CHEMBL3426621	RIPASUDIL	3	870
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL3544911	PREXASERTIB	2	699
CHEMBL3115681	NARAZACICLIB	2	287
CHEMBL1230165	SILMITASERTIB	2	593
CHEMBL1230609	FORETINIB	2
CHEMBL1721885	SU-014813	2
CHEMBL1967878	CENISERTIB	2
CHEMBL1980297	ILORASERTIB	2
CHEMBL362558	LY-2090314	2
CHEMBL402548	DANUSERTIB	2
CHEMBL475251	R-406	2
CHEMBL495727	AT-9283	2
CHEMBL558752	RAF-265	2
CHEMBL565612	SOTRASTAURIN	2

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs249429	PRKAA1		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — AMPK subfamily

Binding affinities (BindingDB)

312 measured of 316 human assays (316 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]benzamide	EC50	0.05 nM	US-11407768: AMPK activators
4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]benzenesulfonamide	EC50	0.09 nM	US-11407768: AMPK activators
(2R,3R,4R,5S)-6-[[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]phenyl]methylamino]hexane-1,2,3,4,5-pentol	EC50	0.1 nM	US-11407768: AMPK activators
(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[2-hydroxy-4-[[2-(2-hydroxyethoxy)ethylamino]methyl]phenyl]phenyl]-1H-benzimidazol-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	0.15 nM	US-11407768: AMPK activators
2-[[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]phenyl]methylamino]-2-(hydroxymethyl)propane-1,3-diol	EC50	0.23 nM	US-11407768: AMPK activators
4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-benzimidazol-5-yl]phenyl]-3-hydroxy-N-[2-(2-hydroxyethoxy)ethyl]benzamide	EC50	0.37 nM	US-11407768: AMPK activators
5-[2-[[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]benzoyl]amino]ethylamino]naphthalene-1-sulfonic acid	EC50	0.4 nM	US-11407768: AMPK activators
6-chloro-5-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-1H-indole-3-carboxylic acid	EC50	0.5 nM	US-9394285: Indole and indazole compounds that activate AMPK
3-[[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]benzoyl]amino]propylphosphonic acid	EC50	0.5 nM	US-11407768: AMPK activators
2-[[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-benzimidazol-5-yl]phenyl]benzoyl]amino]ethyl-trimethylazanium	EC50	0.56 nM	US-11407768: AMPK activators
(3R,3aR,6R,6aR)-6-[[5-[4-[4-[[4,4-bis(hydroxymethyl)piperidin-1-yl]methyl]phenyl]phenyl]-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	0.57 nM	US-11407768: AMPK activators
3-[[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]benzoyl]amino]propane-1-sulfonic acid	EC50	0.62 nM	US-11407768: AMPK activators
3-[[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]phenyl]methylamino]-2-hydroxypropanoic acid	EC50	0.63 nM	US-11407768: AMPK activators
4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-benzimidazol-5-yl]phenyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]benzenesulfonamide	EC50	0.63 nM	US-11407768: AMPK activators
4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-benzimidazol-5-yl]phenyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]benzamide	EC50	0.65 nM	US-11407768: AMPK activators
(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-[[4-(2-hydroxyethyl)piperazin-1-yl]methyl]phenyl]phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	0.72 nM	US-11407768: AMPK activators
US11407768, Compound 32	EC50	0.76 nM	US-11407768: AMPK activators
(2R,3R,4R,5S)-6-[[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-benzimidazol-5-yl]phenyl]phenyl]methylamino]hexane-1,2,3,4,5-pentol	EC50	0.77 nM	US-11407768: AMPK activators
(3R,3aR,6R,6aR)-6-[[5-[4-[4-[[3,3-bis(hydroxymethyl)azetidin-1-yl]methyl]phenyl]phenyl]-6-chloro-1H-benzimidazol-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	0.8 nM	US-11407768: AMPK activators
(3R,3aR,6R,6aR)-6-[[5-[4-[4-[[3,3-bis(hydroxymethyl)azetidin-1-yl]methyl]phenyl]phenyl]-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	0.81 nM	US-11407768: AMPK activators
2-[[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-benzimidazol-5-yl]phenyl]phenyl]methylamino]-2-(hydroxymethyl)propane-1,3-diol	EC50	0.84 nM	US-11407768: AMPK activators
4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-benzimidazol-5-yl]phenyl]-N-[2-(2-hydroxyethoxy)ethyl]benzamide	EC50	0.85 nM	US-11407768: AMPK activators
(3R,3aR,6R,6aR)-6-[[5-[4-[4-[[4,4-bis(hydroxymethyl)piperidin-1-yl]methyl]phenyl]phenyl]-6-chloro-1H-benzimidazol-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	0.85 nM	US-11407768: AMPK activators
2-[[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]benzoyl]amino]ethanesulfonic acid	EC50	0.86 nM	US-11407768: AMPK activators
(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]phenyl]-1H-benzimidazol-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	0.89 nM	US-11407768: AMPK activators
(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-[[4-(2-hydroxyethyl)piperazin-1-yl]methyl]phenyl]phenyl]-1H-benzimidazol-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	0.93 nM	US-11407768: AMPK activators
(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-[[2-(2-hydroxyethoxy)ethylamino]methyl]phenyl]phenyl]-1H-benzimidazol-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	0.93 nM	US-11407768: AMPK activators
(3R,3aR,6R,6aR)-6-[[5-[4-[4-[[3-(aminomethyl)azetidin-1-yl]methyl]phenyl]phenyl]-6-chloro-1H-benzimidazol-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	0.93 nM	US-11407768: AMPK activators
4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-benzimidazol-5-yl]phenyl]-N-[3-(4-aza-1-azoniabicyclo[2.2.2]octan-1-yl)propyl]benzamide	EC50	0.96 nM	US-11407768: AMPK activators
[6-chloro-5-[4-(2-hydroxyphenyl)phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]sulfanylmethyl-methylphosphinic acid	EC50	0.97 nM	US-11279702: AMPK activators
(3R)-1-[[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-benzimidazol-5-yl]phenyl]phenyl]methyl]pyrrolidin-3-ol	EC50	1.04 nM	US-11407768: AMPK activators
2-[[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-benzimidazol-5-yl]phenyl]phenyl]methylamino]propane-1,3-diol	EC50	1.08 nM	US-11407768: AMPK activators
(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-[[3-(hydroxymethyl)azetidin-1-yl]methyl]phenyl]phenyl]-1H-benzimidazol-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	1.09 nM	US-11407768: AMPK activators
4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-benzimidazol-5-yl]phenyl]-N-[2-(2-hydroxyethoxy)ethyl]-N-methylbenzamide	EC50	1.16 nM	US-11407768: AMPK activators
N-[1-[4-[6-chloro-2-[[(3R,6R)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]piperidin-4-yl]butanamide	EC50	1.2 nM	US-9187477: Azabenzimidazole derivatives
3-[[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]benzoyl]amino]-2-(4-chlorophenyl)propane-1-sulfonic acid	EC50	1.22 nM	US-11407768: AMPK activators
(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-[[2-(2-hydroxyethoxy)ethyl-methylamino]methyl]phenyl]phenyl]-1H-benzimidazol-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	1.3 nM	US-11407768: AMPK activators
(2R,3R,4R,5S)-6-[1-[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]phenyl]ethylamino]hexane-1,2,3,4,5-pentol	EC50	1.33 nM	US-11407768: AMPK activators
(3R,4S)-1-[[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-benzimidazol-5-yl]phenyl]phenyl]methyl]pyrrolidine-3,4-diol	EC50	1.36 nM	US-11407768: AMPK activators
4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-benzimidazol-5-yl]phenyl]-N-[2-(2-hydroxyethoxy)ethyl]-N-methylbenzenesulfonamide	EC50	1.38 nM	US-11407768: AMPK activators
[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]phenyl]phosphonic acid	EC50	1.4 nM	US-11407768: AMPK activators
(3S,4S)-1-[[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-benzimidazol-5-yl]phenyl]phenyl]methyl]pyrrolidine-3,4-diol	EC50	1.4 nM	US-11407768: AMPK activators
(3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-[[3-(2-hydroxyethoxymethyl)azetidin-1-yl]methyl]phenyl]phenyl]-1H-benzimidazol-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	EC50	1.46 nM	US-11407768: AMPK activators
4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-benzimidazol-5-yl]phenyl]-N-[2-(2-hydroxyethoxy)ethyl]benzenesulfonamide	EC50	1.51 nM	US-11407768: AMPK activators
2-[[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]benzoyl]-(2-amino-2-oxoethyl)amino]ethanesulfonic acid	EC50	1.61 nM	US-11407768: AMPK activators
6-chloro-5-(4-phenylphenyl)-1H-indole-3-carboxylic acid	EC50	1.7 nM	US-9394285: Indole and indazole compounds that activate AMPK
Staurosporine	KD	1.7 nM
US11407768, Compound 49	EC50	1.76 nM	US-11407768: AMPK activators
2-[[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]benzoyl]-methylamino]ethanesulfonic acid	EC50	1.78 nM	US-11407768: AMPK activators
6-chloro-5-[4-(2-hydroxyphenyl)phenyl]-2,3,3a,4,5,6,7,7a-octahydro-1H-indazole-3-carboxylic acid	EC50	1.8 nM	US-9394285: Indole and indazole compounds that activate AMPK

ChEMBL bioactivities

984 potent at pChembl≥5 of 1078 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.30	EC50	0.05	nM	CHEMBL6048763
10.05	EC50	0.09	nM	CHEMBL5810593
10.00	EC50	0.1	nM	CHEMBL5836835
9.82	EC50	0.15	nM	CHEMBL5892252
9.64	EC50	0.23	nM	CHEMBL5771550
9.50	Ki	0.3162	nM	CHEMBL1980995
9.43	EC50	0.37	nM	CHEMBL5796255
9.40	EC50	0.4	nM	CHEMBL6009640
9.34	EC50	0.46	nM	CHEMBL5783632
9.30	EC50	0.5	nM	CHEMBL3986249
9.30	EC50	0.5	nM	CHEMBL5891901
9.26	EC50	0.55	nM	CHEMBL6032116
9.25	EC50	0.56	nM	CHEMBL5775914
9.24	EC50	0.57	nM	CHEMBL5784714
9.22	EC50	0.6	nM	CHEMBL3393129
9.21	EC50	0.62	nM	CHEMBL5772530
9.20	EC50	0.63	nM	CHEMBL5894957
9.20	EC50	0.63	nM	CHEMBL5813619
9.19	EC50	0.65	nM	CHEMBL5881047
9.14	EC50	0.72	nM	CHEMBL5919560
9.12	EC50	0.76	nM	CHEMBL5825201
9.11	EC50	0.77	nM	CHEMBL5919095
9.10	EC50	0.8	nM	CHEMBL5919881
9.09	EC50	0.81	nM	CHEMBL5760186
9.08	EC50	0.84	nM	CHEMBL5992695
9.07	EC50	0.86	nM	CHEMBL5805427
9.07	EC50	0.85	nM	CHEMBL5967863
9.07	EC50	0.85	nM	CHEMBL5795930
9.05	EC50	0.89	nM	CHEMBL5770913
9.03	EC50	0.93	nM	CHEMBL5761917
9.03	EC50	0.93	nM	CHEMBL5930657
9.03	EC50	0.93	nM	CHEMBL5768406
9.02	EC50	0.96	nM	CHEMBL5983345
9.01	EC50	0.97	nM	CHEMBL5991168
9.00	EC50	1	nM	CHEMBL3393128
9.00	EC50	1	nM	CHEMBL3959081
9.00	EC50	1	nM	CHEMBL4167177
9.00	EC50	1	nM	CHEMBL5179319
9.00	EC50	1	nM	CHEMBL5181529
9.00	EC50	1	nM	CHEMBL5183763
9.00	IC50	1	nM	CHEMBL5183579
9.00	IC50	1	nM	PF-03758309
9.00	Ki	1	nM	CENISERTIB
8.98	EC50	1.04	nM	CHEMBL5754808
8.97	EC50	1.08	nM	CHEMBL5897987
8.96	EC50	1.1	nM	CHEMBL3393130
8.96	EC50	1.1	nM	CHEMBL5806531
8.96	EC50	1.09	nM	CHEMBL6058212
8.94	EC50	1.16	nM	CHEMBL5908554
8.92	EC50	1.2	nM	CHEMBL3898977

PubChem BioAssay actives

370 with measured affinity, of 3518 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
[3-[[6-chloro-5-(1-methylindol-5-yl)-1H-benzimidazol-2-yl]oxy]phenyl]phosphonic acid	1189222: Activation of human AMPK alpha1beta1gamma1	ec50	0.0006	uM
5-[[6-chloro-5-[4-(2-hydroxyphenyl)phenyl]-1H-benzimidazol-2-yl]oxy]-2-methylbenzoic acid	1189222: Activation of human AMPK alpha1beta1gamma1	ec50	0.0010	uM
N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methylthieno[3,2-d]pyrimidin-4-yl)amino]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	2167998: Inhibition of human AMPK alpha1/beta1/gamma1 in presence of ATP	ic50	0.0010	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-[(4-fluorophenyl)methyl]piperazine-1-carbonyl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0010	uM
5-[[6-chloro-5-(4-pyrrolidin-1-ylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2-methylbenzoic acid	1320682: Activation of full length human recombinant AMPK alpha1/beta1/gamma1 expressed in baculovirus infected sf21 cells using 5’-FAM-SAMS peptide substrate after 45 mins by fluorescence assay	ec50	0.0010	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-[fluoro-(4-fluorophenyl)methyl]piperidine-1-carbonyl]pyridine-2-carboxamide	1855899: Activation of AMPK in human HepG2 cells assessed as reduction in mitochondrial ATP production incubated for 1 hr	ic50	0.0010	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-[(4-fluorophenyl)methyl]-3,3-dimethylpiperazine-1-carbonyl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0010	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-[(4-methoxyphenyl)methyl]piperidine-1-carbonyl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0010	uM
(3R,3aR,6R,6aR)-6-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol	1552802: Activation of recombinant human AMPK expressed in Sf9 cells using SAMS peptide as substrate preincubated for 30 mins followed by substrate addition and measured after 60 mins by fluorescence based assay	ec50	0.0010	uM
[2-[6-chloro-5-(4-pyrrolidin-1-ylphenyl)-1H-benzimidazol-2-yl]-5-methoxyphenyl]phosphonic acid	1189222: Activation of human AMPK alpha1beta1gamma1	ec50	0.0011	uM
[5-[[6-chloro-5-(4-morpholin-4-ylphenyl)-1H-benzimidazol-2-yl]oxy]-2-methylphenyl]phosphonic acid	1320681: Activation of full length human recombinant AMPK alpha1/beta1/gamma1 expressed in baculovirus infected sf21 cells using SAMS peptide substrate after 30 mins in presence of [33P]ATP by TopCount analysis	ec50	0.0012	uM
6-chloro-5-[4-(2-hydroxyphenyl)phenyl]-1H-indole-3-carboxylic acid	1315824: Activation of recombinant human AMPK alpha1/beta1/gamma1 using Cy5-labelled SAMS as substrate assessed as protection from Thr172 residue dephosphorylation preincubated for 15 mins followed by incubation with PP2a for 60 mins measured 60 mins post okadaic acid/Cy5-labelled SAMS and ATP addition by TR-FRET assay	ec50	0.0013	uM
6-chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic acid	1398174: Activation of full-length recombinant N-terminal His-tagged human AMPKalpha1beta1gamma1 expressed in Escherichia coli BL21 cells using Cy-5 SAMS peptide as substrate preincubated for 60 mins followed by substrate addition and measured after 60 mins in presence of PP2a by TR-FRET assay	ec50	0.0019	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-fluoro-4-(4-fluorobenzoyl)piperidine-1-carbonyl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0020	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-(4-fluorobenzoyl)piperidine-1-carbonyl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0020	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-6-[4-(4-methoxybenzoyl)piperidine-1-carbonyl]pyridine-3-carboxamide	1855899: Activation of AMPK in human HepG2 cells assessed as reduction in mitochondrial ATP production incubated for 1 hr	ic50	0.0028	uM
N-[4-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]phenyl]-3-fluorophenyl]methanesulfonamide	1320693: Activation of full length human recombinant N-terminal GST-tagged AMPK alpha1/beta1/gamma1 expressed in baculovirus infected High Five cells using NH2-HMRSAMSGLHLVKRR CONH2 substrate after 60 mins by ADP-Glo kinase assay	ec50	0.0030	uM
5-[[6-chloro-5-(1-methylindol-5-yl)-1H-benzimidazol-2-yl]oxy]-2-methylbenzoic acid	1189222: Activation of human AMPK alpha1beta1gamma1	ec50	0.0030	uM
5-[4-(4-cyanophenoxy)piperidine-1-carbonyl]-N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0030	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	435148: Binding constant for AMPK-alpha1 kinase domain	kd	0.0037	uM
2-[4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1H-benzimidazol-5-yl]phenyl]benzene-1,3-diol	1320698: Activation of human recombinant AMPK alpha1/beta2/gamma1 expressed in African green monkey COS7 cells assessed as increase in biotinylated AAC (1 to 120 residues) peptide phosphorylation at Ser-79 residue measured after 60 mins by Alphascreen assay	ec50	0.0040	uM
(2R,3S,5R)-5-[[6-chloro-5-[4-(2-hydroxypropan-2-yl)phenyl]-1H-benzimidazol-2-yl]oxy]-2-(hydroxymethyl)oxan-3-ol	1320682: Activation of full length human recombinant AMPK alpha1/beta1/gamma1 expressed in baculovirus infected sf21 cells using 5’-FAM-SAMS peptide substrate after 45 mins by fluorescence assay	ec50	0.0040	uM
4-[[5-(1-cyclopropylindol-5-yl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy]cyclohexane-1-carboxylic acid	1189222: Activation of human AMPK alpha1beta1gamma1	ec50	0.0040	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-(2,4-difluorophenoxy)piperidine-1-carbonyl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0040	uM
N-[4-[[(2-hydroxy-1H-indol-3-yl)-phenylmethylidene]amino]phenyl]-N-methyl-2-(4-methylpiperazin-1-yl)acetamide	1474638: Inhibition of AMPK (unknown origin) using SAMS peptide as substrate measured after 30 mins in presence of [gamma32P]ATP by liquid scintillation counting method	ki	0.0042	uM
[4-[5-[1-[(6-methoxy-3-pyridinyl)methyl]piperidin-4-yl]-1,3,4-oxadiazol-2-yl]phenyl]-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]methanone;bis(4-methylbenzenesulfonic acid)	1666796: Activation of AMPK in human MDA-MB-435 cells measured after 2 hrs by anti-phospho-Acetyl-CoA Carboxylase (Ser79) antibody-based ELISA	ec50	0.0045	uM
N-[(1R,2S)-2-aminocyclohexyl]-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]thiophene-2-carboxamide	1637052: Inhibition of full-length recombinant human GST and His-tagged AMPK alpha1/beta1/gamma1 expressed in baculovirus expression system by LanthaScreen assay	ic50	0.0046	uM
4-[(4-methoxyphenyl)methyl]-N-[4-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazine-1-carbonyl]phenyl]piperazine-1-carboxamide	1666796: Activation of AMPK in human MDA-MB-435 cells measured after 2 hrs by anti-phospho-Acetyl-CoA Carboxylase (Ser79) antibody-based ELISA	ec50	0.0047	uM
2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-5-carboxylic acid	1474638: Inhibition of AMPK (unknown origin) using SAMS peptide as substrate measured after 30 mins in presence of [gamma32P]ATP by liquid scintillation counting method	ki	0.0049	uM
5-[4-(4-cyanobenzoyl)piperidine-1-carbonyl]-N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0050	uM
4-[(4-aminocyclohexyl)amino]-3-(1H-benzimidazol-2-yl)-1H-pyridin-2-one	1287939: Inhibition of AMPKa1 (unknown origin)	ic50	0.0055	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-[2-(4-fluorophenyl)propan-2-yl]piperazine-1-carbonyl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0060	uM
bis(N-cyclohexylcyclohexanamine);[5-(5-oxo-2H-1,2-oxazol-3-yl)furan-2-yl]phosphonic acid	580978: Activation of human AMPK after 15 mins	ec50	0.0063	uM
6-chloro-5-[6-(dimethylamino)-2-methoxy-3-pyridinyl]-1H-indole-3-carboxylic acid	1398174: Activation of full-length recombinant N-terminal His-tagged human AMPKalpha1beta1gamma1 expressed in Escherichia coli BL21 cells using Cy-5 SAMS peptide as substrate preincubated for 60 mins followed by substrate addition and measured after 60 mins in presence of PP2a by TR-FRET assay	ec50	0.0070	uM
4-[[4-(trifluoromethyl)phenyl]methyl]-N-[4-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazine-1-carbonyl]phenyl]piperazine-1-carboxamide	1666796: Activation of AMPK in human MDA-MB-435 cells measured after 2 hrs by anti-phospho-Acetyl-CoA Carboxylase (Ser79) antibody-based ELISA	ec50	0.0079	uM
4,6-difluoro-5-[4-[(2S)-oxan-2-yl]phenyl]-1H-indole-3-carboxylic acid	1398174: Activation of full-length recombinant N-terminal His-tagged human AMPKalpha1beta1gamma1 expressed in Escherichia coli BL21 cells using Cy-5 SAMS peptide as substrate preincubated for 60 mins followed by substrate addition and measured after 60 mins in presence of PP2a by TR-FRET assay	ec50	0.0080	uM
5-[[6-chloro-5-(4-phenylphenyl)-1H-benzimidazol-2-yl]oxy]-2-methylbenzoic acid	1471590: Agonist activity at human recombinant phosphorylated AMPK complex 1 alpha1/beta1/gamma1 expressed in baculovirus infected Sf21 cells assessed as phosphorylation of 5-FAM-labeled SAMS substrate preincubated for 30 mins in presence of AMPK activator followed by substrate addition measured after 60 mins	ec50	0.0080	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-(2,4-difluorobenzoyl)piperidine-1-carbonyl]pyridine-2-carboxamide	1855899: Activation of AMPK in human HepG2 cells assessed as reduction in mitochondrial ATP production incubated for 1 hr	ic50	0.0080	uM
6-chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indazole-3-carboxylic acid	1320672: Activation of full length human phosphorylated His-tagged AMPK alpha1/beta1/gamma1 expressed in Escherichia coli BL21-CodonPlus (DE3)-RIPL using SAMS peptide substrate preincubated for 15 mins followed by PP2A addition for 90 mins followed by substrate addition measured after 60 mins in presence of [33P]ATP by scintillation counting method	ec50	0.0083	uM
6-[4-(4-methoxybenzoyl)piperidine-1-carbonyl]-N-[1-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-4-yl]pyridine-3-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0090	uM
6-[4-(4-pyrrolidin-1-ylbenzoyl)piperidine-1-carbonyl]-N-[1-[[4-(trifluoromethoxy)phenyl]methyl]piperidin-4-yl]pyridine-3-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0090	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-5-carboxylate	1474638: Inhibition of AMPK (unknown origin) using SAMS peptide as substrate measured after 30 mins in presence of [gamma32P]ATP by liquid scintillation counting method	ki	0.0092	uM
4-[6-[4-(2-piperidin-1-ylethoxy)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide	1637052: Inhibition of full-length recombinant human GST and His-tagged AMPK alpha1/beta1/gamma1 expressed in baculovirus expression system by LanthaScreen assay	ic50	0.0100	uM
7-[(1S)-4-hydroxy-2,3-dihydro-1H-inden-1-yl]-5,5-dimethyl-2-[3-(pyrrolidin-1-ylmethyl)anilino]pyrrolo[2,3-d]pyrimidin-6-one	1992921: Inhibition of AMPKalpha1/2 (unknown origin)	ic50	0.0100	uM
1-[(4-methoxyphenyl)methyl]-N-[4-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazine-1-carbonyl]phenyl]piperidine-4-carboxamide;dihydrochloride	1666796: Activation of AMPK in human MDA-MB-435 cells measured after 2 hrs by anti-phospho-Acetyl-CoA Carboxylase (Ser79) antibody-based ELISA	ec50	0.0110	uM
N-[1-[(4-cyanophenyl)methyl]piperidin-4-yl]-5-[4-(4-methoxyphenoxy)piperidine-1-carbonyl]pyridine-2-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0110	uM
1-[(6-methoxy-3-pyridinyl)methyl]-N-[4-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazine-1-carbonyl]phenyl]piperidine-4-carboxamide	1666796: Activation of AMPK in human MDA-MB-435 cells measured after 2 hrs by anti-phospho-Acetyl-CoA Carboxylase (Ser79) antibody-based ELISA	ec50	0.0120	uM
N-[1-[(4-fluorophenyl)methyl]piperidin-4-yl]-6-[4-(4-pyrrolidin-1-ylbenzoyl)piperidine-1-carbonyl]pyridine-3-carboxamide	1855898: Activation of AMPK in human HepG2 cells assessed as increase in ACC phosphorylation at Ser79 incubated for 1 hr	ec50	0.0120	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526218: Binding affinity to recombinant human full-length GST N-Terminal tagged-AMPK alpha1/N-Terminal GST tagged-AMPK beta1/N-Terminal his-tagged AMPK gamma1 expressed in baculovirus expression system incubated for 1 hr by TR-FRET assay	kd	0.0130	uM
2-[[6-chloro-5-[4-(2-hydroxyphenyl)phenyl]-1H-benzimidazol-2-yl]sulfanyl]acetic acid	1189222: Activation of human AMPK alpha1beta1gamma1	ec50	0.0130	uM

CTD chemical–gene interactions

130 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
dorsomorphin	decreases activity, decreases reaction, affects cotreatment, increases phosphorylation, decreases phosphorylation (+4 more)	9
Acetylcysteine	decreases phosphorylation, decreases reaction, increases phosphorylation, decreases expression, increases activity (+1 more)	7
Metformin	decreases phosphorylation, increases chemical synthesis, decreases expression, decreases reaction, decreases activity (+5 more)	7
Resveratrol	decreases activity, decreases phosphorylation, decreases reaction, increases expression, increases reaction (+3 more)	6
sodium arsenite	affects reaction, increases expression, increases secretion, decreases expression, increases activity (+3 more)	5
AICA ribonucleotide	affects reaction, increases activity, increases phosphorylation, increases reaction, increases expression	5
Glucose	affects reaction, increases chemical synthesis, increases abundance, increases activity, decreases activity (+4 more)	5
bisphenol A	decreases expression, increases expression, increases phosphorylation	4
Reactive Oxygen Species	decreases reaction, increases chemical synthesis, increases abundance, increases activity, affects abundance (+1 more)	4
acadesine	increases expression, increases reaction, increases phosphorylation	3
Quercetin	decreases reaction, increases activity, increases phosphorylation, increases reaction, affects cotreatment	3
Rotenone	decreases reaction, increases expression, decreases expression	3
Palmitic Acid	affects cotreatment, affects expression, increases oxidation, decreases phosphorylation, decreases reaction	3
nuciferine	decreases phosphorylation, decreases reaction, affects reaction, decreases expression, increases phosphorylation	2
cobaltous chloride	increases secretion, decreases reaction, increases phosphorylation, increases activity, affects reaction (+1 more)	2
6,8-diallyl 5,7-dihydroxy 2-(2-allyl 3-hydroxy 4-methoxyphenyl)1-H benzo(b)pyran-4-one	decreases phosphorylation, decreases reaction, increases activity, increases phosphorylation, increases reaction (+1 more)	2
Ethanol	decreases reaction, increases expression, increases reaction, decreases expression	2
Capsaicin	increases expression, increases reaction, increases phosphorylation, decreases reaction, affects cotreatment (+1 more)	2
Cisplatin	increases expression	2
Formaldehyde	decreases expression	2
Hydrogen Peroxide	decreases expression, increases activity, increases expression, increases phosphorylation	2
Lipopolysaccharides	increases reaction, decreases phosphorylation, decreases reaction, increases secretion, increases expression	2
Fenofibrate	affects reaction, increases abundance, increases activity, decreases response to substance	2
Vanadates	increases expression, increases secretion, increases activity, increases phosphorylation, affects reaction	2
aristolochic acid I	affects cotreatment, decreases expression	1
FR900359	affects phosphorylation	1
moringin	affects cotreatment, increases expression	1
TAK-243	increases sumoylation	1
geldanamycin	decreases phosphorylation, decreases reaction, decreases expression	1
taxifolin	decreases phosphorylation	1

ChEMBL screening assays

738 unique, capped per target: 734 binding, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1053698	Binding	Induction of AMPK phosphorylation in human HepG2 cells by Western blot analysis in presence of 33 mM glucose	Palbinone and triterpenes from Moutan Cortex (Paeonia suffruticosa, Paeoniaceae) stimulate glucose uptake and glycogen synthesis via activation of AMPK in insulin-resistant human HepG2 Cells. — Bioorg Med Chem Lett
CHEMBL4649950	Functional	AMP-dependent Kinase enzyme assay. An in vitro enzyme assay that detects ADP turnover that is directly proportional to AMPK activity. This uses naive AMPK that is activated during the assay with MK-8722	University of Dundee, Small-Polar-MMV Screening Library

Cellosaurus cell lines

10 cell lines: 9 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8N1	Abcam HCT 116 PRKAA1 KO	Cancer cell line	Male
CVCL_B9AM	Abcam MCF-7 PRKAA1 KO	Cancer cell line	Female
CVCL_B9QA	Abcam A-549 PRKAA1 KO	Cancer cell line	Male
CVCL_D7Y9	Ubigene A-549 PRKAA1 KO	Cancer cell line	Male
CVCL_D8TQ	Ubigene HCT 116 PRKAA1 KO	Cancer cell line	Male
CVCL_D9PC	Ubigene HEK293 PRKAA1 KO	Transformed cell line	Female
CVCL_E0LN	Ubigene HeLa PRKAA1 KO	Cancer cell line	Female
CVCL_E1G1	Abcam HeLa PRKAA1 KO	Cancer cell line	Female
CVCL_TG60	HAP1 PRKAA1 (-) 1	Cancer cell line	Male
CVCL_TG61	HAP1 PRKAA1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.