PFKFB2

Summary

PFKFB2 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2, HGNC:8873) is a protein-coding gene on chromosome 1q32.1, encoding 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (O60825). Synthesis and degradation of fructose 2,6-bisphosphate.

The protein encoded by this gene is involved in both the synthesis and degradation of fructose-2,6-bisphosphate, a regulatory molecule that controls glycolysis in eukaryotes. The encoded protein has a 6-phosphofructo-2-kinase activity that catalyzes the synthesis of fructose-2,6-bisphosphate, and a fructose-2,6-biphosphatase activity that catalyzes the degradation of fructose-2,6-bisphosphate. This protein regulates fructose-2,6-bisphosphate levels in the heart, while a related enzyme encoded by a different gene regulates fructose-2,6-bisphosphate levels in the liver and muscle. This enzyme functions as a homodimer. Two transcript variants encoding two different isoforms have been found for this gene.

Source: NCBI Gene 5208 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 137 total
• Druggable target: yes
• MANE Select transcript: NM_006212

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8873
Approved symbol	PFKFB2
Name	6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000123836
Ensembl biotype	protein_coding
OMIM	171835
Entrez	5208

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 17 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000367079, ENST00000367080, ENST00000411990, ENST00000464777, ENST00000468857, ENST00000473310, ENST00000483688, ENST00000545806, ENST00000615360, ENST00000618513, ENST00000906543, ENST00000906544, ENST00000906545, ENST00000906546, ENST00000906547, ENST00000906548, ENST00000906549, ENST00000924204, ENST00000948257, ENST00000948258, ENST00000948259, ENST00000948260, ENST00000948261

RefSeq mRNA: 2 — MANE Select: NM_006212 NM_001018053, NM_006212

CCDS: CCDS31003, CCDS31004

Canonical transcript exons

ENST00000367080 — 15 exons

Exon	Start	End
ENSE00001185299	207072204	207077817
ENSE00001399727	207053275	207053366
ENSE00002294124	207065036	207065160
ENSE00003494606	207069424	207069528
ENSE00003530485	207071188	207071250
ENSE00003568260	207061953	207062078
ENSE00003635459	207071509	207071573
ENSE00003640846	207062620	207062716
ENSE00003714830	207054701	207054802
ENSE00003719916	207063347	207063421
ENSE00003721982	207070280	207070409
ENSE00003728503	207068163	207068309
ENSE00003737521	207067499	207067706
ENSE00003742061	207063773	207063829
ENSE00003789386	207063143	207063209

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 96.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.0140 / max 274.3380, expressed in 1656 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8175	10.0704	1438
8174	2.5572	1217
8179	0.1965	81
8178	0.1103	63
8177	0.0344	15
8176	0.0236	10
8173	0.0215	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	96.02	gold quality
oocyte	CL:0000023	93.89	gold quality
right lobe of thyroid gland	UBERON:0001119	93.72	gold quality
left lobe of thyroid gland	UBERON:0001120	93.16	gold quality
thyroid gland	UBERON:0002046	93.06	gold quality
gastrocnemius	UBERON:0001388	92.38	gold quality
rectum	UBERON:0001052	92.05	gold quality
apex of heart	UBERON:0002098	91.85	gold quality
muscle of leg	UBERON:0001383	91.11	gold quality
duodenum	UBERON:0002114	91.09	gold quality
adenohypophysis	UBERON:0002196	91.03	gold quality
heart left ventricle	UBERON:0002084	90.81	gold quality
cardiac ventricle	UBERON:0002082	90.41	gold quality
mucosa of transverse colon	UBERON:0004991	89.68	gold quality
secondary oocyte	CL:0000655	89.63	gold quality
type B pancreatic cell	CL:0000169	89.53	gold quality
pituitary gland	UBERON:0000007	89.49	gold quality
olfactory bulb	UBERON:0002264	89.26	gold quality
esophagus squamous epithelium	UBERON:0006920	88.99	gold quality
corpus callosum	UBERON:0002336	88.47	gold quality
transverse colon	UBERON:0001157	88.33	gold quality
jejunal mucosa	UBERON:0000399	88.20	gold quality
diaphragm	UBERON:0001103	88.01	gold quality
hindlimb stylopod muscle	UBERON:0004252	87.95	gold quality
muscle organ	UBERON:0001630	87.57	gold quality
pigmented layer of retina	UBERON:0001782	87.55	gold quality
caudate nucleus	UBERON:0001873	87.55	gold quality
adult mammalian kidney	UBERON:0000082	87.46	gold quality
colonic epithelium	UBERON:0000397	87.36	gold quality
caput epididymis	UBERON:0004358	87.30	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-GEOD-81608	yes	5753.34
E-ENAD-27	yes	3182.21
E-MTAB-5061	yes	958.73
E-GEOD-81547	yes	15.90
E-MTAB-8498	yes	13.35
E-GEOD-83139	yes	12.33
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, HIF1A

miRNA regulators (miRDB)

126 targeting PFKFB2, 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-513A-5P	100.00	69.77	2465
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482

Literature-anchored findings (GeneRIF, showing 18)

• Human islets expressed the PFKFB2 and PFKFB3 isoforms. PFK-2/FBPase-2 protein rather than its product fructose 2,6-P(2) is the over-riding determinant of glucose-induced insulin secretion through regulation of glucokinase activity (PMID:18039179)
• induction of de novo lipid synthesis by androgen requires transcriptional up-regulation of HK2 and PFKFB2, and phosphorylation of PFKFB2 generated by the PI3K/Akt signal pathway to supply the source for lipogenesis from glucose in prostate cancer cells. (PMID:20958264)
• Suggest that PFKFB2 is not an essential upstream regulator of the anti-leukemic effects of glucocorticoids. (PMID:21092265)
• A persistent increase in 6-phosphofructo-2-kinase produced by a change in PFK-2/FBPase-2 isoform expression that may play an important role in the regulation of muscle glycolysis. (PMID:22241065)
• amino acids stimulate Fru-2,6-P2 synthesis by Akt-dependent PFKFB2 phosphorylation and activation and show how signaling and metabolism are inextricably linked. (PMID:23457334)
• Highly expressed PFKFB2 protein is associated with hepatocellular carcinoma. (PMID:24568531)
• bifunctionality of PFK-2/FBPase-2 complements the metabolic zonation of the liver by ensuring coherent switching in response to insulin and glucagon. (PMID:24634222)
• Variation in PFKFB2 appears to reduce PFKFB2 expression in adipose and kidney tissues, and thereby increase risk for adiposity and diabetic nephropathy. (PMID:25662186)
• Crystal structure of human and cattle heart PFKFB2 and the inhibitory influence of citrate on substrate binding has been described. (PMID:27802586)
• these results indicate that RSK-mediated phosphorylation of PFKFB2 plays a key role in the metabolism and growth of BRAF-mutated melanomas.Significance: RSK promotes glycolytic metabolism and the growth of BRAF-mutated melanoma by driving phosphorylation of an important glycolytic enzyme (PMID:29440170)
• UCA1/miR-182/PFKFB2 axis modulates chemokine CXCL14 secretion, glycolysis and invasion of glioma cells in glioblastoma-associated stromal cells . (PMID:29655792)
• This study aims to characterise the expression and phosphorylation of isozymes of the key glycolytic regulatory protein, 6-phosphofructokinase-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2), in urinary exosomes of subjects with pre-eclampsia . (PMID:30819197)
• Lower PFKFB2 methylation levels was an independent factor of high relapse risk (Hazard Ratio = 3.2; CI95% = 1.19.5). PFKFB2 promoter methylation analysis has potential applicability to better stratify well-differentiated thyroid carcinomas (WDTC) patients according to the recurrence risk, independently of BRAF and TERT mutations. (PMID:30884810)
• miR-613 served as a tumor suppressor by targeting PFKFB2, indicating that detecting miR-613 and modulation of miR-613 expression could be potential marker and clinical approach in gastric cancer patients (PMID:31122697)
• PFKFB2 regulates glycolysis and proliferation in pancreatic cancer cells. (PMID:32415418)
• Knockdown circZNF131 Inhibits Cell Progression and Glycolysis in Gastric Cancer Through miR-186-5p/PFKFB2 Axis. (PMID:35059934)
• PFKFB2 is a favorable prognostic biomarker for colorectal cancer by suppressing metastasis and tumor glycolysis. (PMID:37311985)
• miR-21-5p inhibits the growth of brain glioma cells through regulating the glycolysis mediated by PFKFB2. (PMID:37864733)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	pfkfb2b	ENSDARG00000002037
danio_rerio	pfkfb2a	ENSDARG00000023840
mus_musculus	Pfkfb2	ENSMUSG00000026409
rattus_norvegicus	Pfkfb2	ENSRNOG00000004162
drosophila_melanogaster	Pfrx	FBGN0027621
caenorhabditis_elegans		WBGENE00019295
caenorhabditis_elegans	pfkb-1.1	WBGENE00022456

Paralogs (3): PFKFB4 (ENSG00000114268), PFKFB1 (ENSG00000158571), PFKFB3 (ENSG00000170525)

Protein

Protein identifiers

6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 — O60825 (reviewed: O60825)

Alternative names: 6PF-2-K/Fru-2,6-P2ase heart-type isozyme

All UniProt accessions (5): A0A087X278, A0A087X2H4, O60825, F6RAZ1, F6XNB3

UniProt curated annotations — full annotation on UniProt →

Function. Synthesis and degradation of fructose 2,6-bisphosphate.

Subunit / interactions. Homodimer. Forms a heterodimer with PFKFB3.

Tissue specificity. Heart.

Post-translational modifications. Phosphorylation by AMPK stimulates activity.

Activity regulation. Phosphorylation results in the activation of the kinase activity.

Similarity. In the C-terminal section; belongs to the phosphoglycerate mutase family.

Isoforms (2)

UniProt ID	Names	Canonical?
O60825-1	1	yes
O60825-2	2

RefSeq proteins (2): NP_001018063, NP_006203* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001345	PG/BPGM_mutase_AS	Active_site
IPR003094	6Pfruct_kin	Family
IPR013078	His_Pase_superF_clade-1	Family
IPR013079	6Phosfructo_kin	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR029033	His_PPase_superfam	Homologous_superfamily

Pfam: PF00300, PF01591

Enzyme classification (BRENDA):

• EC 2.7.1.105 — 6-phosphofructo-2-kinase (BRENDA: 25 organisms, 68 substrates, 145 inhibitors, 158 Km, 41 kcat entries)
• EC 3.1.3.46 — fructose-2,6-bisphosphate 2-phosphatase (BRENDA: 28 organisms, 27 substrates, 93 inhibitors, 21 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
BETA-D-FRUCTOSE 6-PHOSPHATE	0.0038–39	63
ATP	0.0009–1.62	35
MGATP2-	0.0072–2	21
FRUCTOSE 2,6-BISPHOSPHATE	0.0001–1.4	15
D-FRUCTOSE 6-PHOSPHATE	0.0094–0.1	4
BETA-D-FRUCTOSE 2,6-BISPHOSPHATE	0.0102–0.204	3
BETA-D-FRUCTOSE 2,6-BISPHOSPHATE	0.02–0.21	2
CTP	0.9–2	2
GTP	0.35–1.5	2
UTP	0.78–2.3	2
D-PSICOSE 6-PHOSPHATE	7.4	1
D-TAGATOSE 6-PHOSPHATE	15	1
ITP	0.3	1
L-SORBOSE 6-PHOSPHATE	0.175	1
D-FRUCTOSE 2,6-BISPHOSPHATE	0.0001	1

Catalyzed reactions (Rhea), 2 shown:

• beta-D-fructose 6-phosphate + ATP = beta-D-fructose 2,6-bisphosphate + ADP + H(+) (RHEA:15653)
• beta-D-fructose 2,6-bisphosphate + H2O = beta-D-fructose 6-phosphate + phosphate (RHEA:17289)

UniProt features (85 total): binding site 21, helix 18, strand 12, modified residue 8, sequence conflict 6, active site 4, region of interest 4, turn 4, site 3, initiator methionine 1, chain 1, splice variant 1, mutagenesis site 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5HTK	X-RAY DIFFRACTION	2.01

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60825-F1	85.26	0.72

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 (7): 326 (proton donor/acceptor); 256 (transition state stabilizer); 263 (transition state stabilizer); 391 (transition state stabilizer); 128; 158; 257 (tele-phosphohistidine intermediate)

Ligand- & substrate-binding residues (21): 45–53; 78; 102; 130; 136; 167–172; 172; 193; 197; 256; 263; 269 …

Post-translational modifications (8): 2, 29, 466, 468, 475, 483, 486, 493

Mutagenesis-validated functional residues (1):

Position	Phenotype
466	constitutively active mutant that cannot be phosphorylated and further activated by ampk.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9634600	Regulation of glycolysis by fructose 2,6-bisphosphate metabolism

MSigDB gene sets: 259 (showing top): MODULE_52, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, MODULE_45, GOBP_INSULIN_SECRETION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_MONOSACCHARIDE_CATABOLIC_PROCESS, GOBP_HORMONE_TRANSPORT, GOBP_CARBOHYDRATE_PHOSPHORYLATION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, MODULE_16, CAGGTCC_MIR492

GO Biological Process (10): fructose metabolic process (GO:0006000), fructose 2,6-bisphosphate metabolic process (GO:0006003), glucose catabolic process (GO:0006007), gluconeogenesis (GO:0006094), glycolytic process (GO:0006096), response to glucose (GO:0009749), lactate biosynthetic process (GO:0019249), positive regulation of insulin secretion (GO:0032024), pyruvate biosynthetic process (GO:0042866), carbohydrate phosphorylation (GO:0046835)

GO Molecular Function (11): 6-phosphofructo-2-kinase activity (GO:0003873), fructose-2,6-bisphosphate 2-phosphatase activity (GO:0004331), ATP binding (GO:0005524), protein kinase binding (GO:0019901), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), hydrolase activity (GO:0016787), kinase binding (GO:0019900)

GO Cellular Component (3): nucleoplasm (GO:0005654), cytosol (GO:0005829), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase complex (GO:0043540)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Glycolysis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
glucose metabolic process	2
pyruvate metabolic process	2
monocarboxylic acid biosynthetic process	2
catalytic activity	2
cellular anatomical structure	2
hexose metabolic process	1
organophosphate metabolic process	1
carbohydrate derivative metabolic process	1
hexose catabolic process	1
hexose biosynthetic process	1
phosphoglycerate kinase activity	1
phosphoglycerate mutase activity	1
phosphopyruvate hydratase activity	1
pyruvate kinase activity	1
generation of precursor metabolites and energy	1
aerobic respiration	1
carbohydrate catabolic process	1
pyridine nucleotide catabolic process	1
glyceraldehyde-3-phosphate dehydrogenase [NAD(P)+] (phosphorylating) activity	1
ADP catabolic process	1
ATP metabolic process	1
nicotinamide nucleotide metabolic process	1
response to hexose	1
lactate metabolic process	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
carbohydrate metabolic process	1
phosphorylation	1
phosphofructokinase activity	1
sugar-phosphatase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
kinase binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
transferase activity, transferring phosphorus-containing groups	1

Protein interactions and networks

STRING

1286 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PFKFB2	GCK	P35557	822
PFKFB2	PFKM	P08237	749
PFKFB2	FBP2	O00757	708
PFKFB2	TIGAR	Q9NQ88	588
PFKFB2	HK2	P52789	580
PFKFB2	PKM	P14618	566
PFKFB2	H6PD	O95479	544
PFKFB2	SLC2A1	P11166	515
PFKFB2	LDHA	P00338	512
PFKFB2	PFKL	P17858	507
PFKFB2	GPI	P06744	503
PFKFB2	PFKP	Q01813	488
PFKFB2	TPI1	P00938	483
PFKFB2	FBP1	P09467	477
PFKFB2	SLC16A3	O15427	461

IntAct

58 interactions, top by confidence:

A	B	Type	Score
YWHAQ	WDR62	psi-mi:“MI:0914”(association)	0.830
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
YWHAZ	PFKFB2	psi-mi:“MI:0915”(physical association)	0.800
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAZ	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
YWHAB	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAE	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
PFKFB2		psi-mi:“MI:0914”(association)	0.350
NS1		psi-mi:“MI:0914”(association)	0.350
PB2		psi-mi:“MI:0914”(association)	0.350
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
PFKFB3	PFKFB2	psi-mi:“MI:0914”(association)	0.350
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
YWHAZ	SPEG	psi-mi:“MI:0914”(association)	0.350
NSD2	PFKFB2	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
Dnajc11	DDX3X	psi-mi:“MI:0914”(association)	0.350

BioGRID (81): PFKFB2 (Co-fractionation), PFKFB2 (Affinity Capture-MS), PDE4D (Affinity Capture-MS), TRIM21 (Affinity Capture-MS), ZC3H11A (Affinity Capture-MS), SRRM2 (Affinity Capture-MS), PGAP2 (Affinity Capture-MS), ZCCHC17 (Affinity Capture-MS), RMDN3 (Affinity Capture-MS), RBM15 (Affinity Capture-MS), CPSF7 (Affinity Capture-MS), DOCK8 (Affinity Capture-MS), POLDIP3 (Affinity Capture-MS), SARNP (Affinity Capture-MS), FAM83B (Affinity Capture-MS)

ESM2 similar proteins: A0A0K0JFP3, A1ZAI3, A1ZAI5, B3MZN7, B3NY19, B4M891, B4NDG5, F1QLP1, O02298, O16881, O44952, O60825, P26285, P37059, P56523, P70265, Q02337, Q02338, Q0KHU5, Q0P5J1, Q0WRB0, Q1PEI6, Q39152, Q43793, Q5R834, Q5XGF7, Q5ZM72, Q66H50, Q6DCT3, Q6NRV4, Q7T2D1, Q7TNT2, Q7ZXF5, Q80XN0, Q80ZF7, Q8HZT6, Q8IZV5, Q8LG50, Q8MS59, Q8WVX9

Diamond homologs: A1AJW4, A1JJB8, A1K9B9, A1TC01, A1WDX2, A2SDN6, A4TQH5, A4W6B3, A6LUA1, A6TI09, A7FMF8, A7GPN5, A7MIJ0, A7ZVT7, A8A8C4, A8ALW1, A8G9J4, A9MR94, A9N7F5, A9R032, B1GZZ1, B1IS24, B1JL20, B1LEK2, B1WAX6, B1XFK5, B2K3K5, B2RHB7, B2TZS8, B2VH13, B4EY52, B4T4I9, B4TH18, B4TU55, B5BAL1, B5F543, B5FTD9, B5R3B7, B5R9W3, B5Y264

SIGNOR signaling

25 interactions.

A	Effect	B	Mechanism
AKT	“up-regulates activity”	PFKFB2	phosphorylation
AMPK	“up-regulates activity”	PFKFB2	phosphorylation
PFKFB2	up-regulates	Glycolysis
RPS6KA3	“up-regulates activity”	PFKFB2	phosphorylation
RPS6KB1	“up-regulates activity”	PFKFB2	phosphorylation
PRKAA2	“up-regulates activity”	PFKFB2	phosphorylation
AKT	unknown	PFKFB2	phosphorylation
AKT1	“up-regulates activity”	PFKFB2	phosphorylation
AKT1	unknown	PFKFB2	phosphorylation
PRKAA1	“up-regulates activity”	PFKFB2	phosphorylation
PRKCA	“up-regulates activity”	PFKFB2	phosphorylation
PRKACA	“up-regulates activity”	PFKFB2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 44 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
Activation of BAD and translocation to mitochondria	6	163.1×	6e-11
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	143.9×	8e-11
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	143.9×	8e-11
Activation of BH3-only proteins	6	106.4×	5e-10
RHO GTPases activate PKNs	6	68.0×	6e-09
Intrinsic Pathway for Apoptosis	6	62.8×	8e-09
Apoptosis	7	42.0×	6e-09
Translocation of SLC2A4 (GLUT4) to the plasma membrane	7	38.6×	8e-09

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	50.9×	7e-06
intracellular protein localization	7	20.4×	7e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	111
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2459 predictions. Top by Δscore:

Variant	Effect	Δscore
1:207050682:CCTTA:C	donor_loss	1.0000
1:207050683:CTTAC:C	donor_loss	1.0000
1:207050684:TTAC:T	donor_loss	1.0000
1:207050685:TACCA:T	donor_loss	1.0000
1:207050686:A:AC	donor_gain	1.0000
1:207050686:A:C	donor_loss	1.0000
1:207050687:C:CA	donor_loss	1.0000
1:207050687:C:CC	donor_gain	1.0000
1:207050687:CCAG:C	donor_gain	1.0000
1:207050687:CCAGA:C	donor_gain	1.0000
1:207050708:T:TA	donor_gain	1.0000
1:207054756:C:G	donor_gain	1.0000
1:207054800:GTT:G	donor_gain	1.0000
1:207054803:G:GG	donor_gain	1.0000
1:207054821:G:GT	donor_gain	1.0000
1:207061941:A:AG	acceptor_gain	1.0000
1:207061942:T:G	acceptor_gain	1.0000
1:207061947:TTCTA:T	acceptor_loss	1.0000
1:207061948:TCTA:T	acceptor_loss	1.0000
1:207061949:CTAG:C	acceptor_loss	1.0000
1:207061950:TAG:T	acceptor_loss	1.0000
1:207061951:A:AG	acceptor_gain	1.0000
1:207061951:AGCA:A	acceptor_loss	1.0000
1:207061951:AGCAT:A	acceptor_gain	1.0000
1:207061952:G:GG	acceptor_gain	1.0000
1:207061952:GC:G	acceptor_gain	1.0000
1:207061952:GCA:G	acceptor_gain	1.0000
1:207061952:GCAT:G	acceptor_gain	1.0000
1:207061952:GCATG:G	acceptor_gain	1.0000
1:207062074:CAAAG:C	donor_gain	1.0000

AlphaMissense

3332 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:207070326:T:C	L380P	1.000
1:207062015:G:C	G50R	0.999
1:207062016:G:A	G50D	0.999
1:207062019:A:T	K51I	0.999
1:207062022:C:T	T52I	0.999
1:207062040:T:C	L58P	0.999
1:207062046:G:C	R60P	0.999
1:207062052:T:C	L62P	0.999
1:207062057:T:A	W64R	0.999
1:207062057:T:C	W64R	0.999
1:207062679:T:C	F91L	0.999
1:207062681:T:A	F91L	0.999
1:207062681:T:G	F91L	0.999
1:207062712:C:A	R102S	0.999
1:207063356:G:C	A129P	0.999
1:207063364:T:A	N131K	0.999
1:207063364:T:G	N131K	0.999
1:207063382:G:C	R137S	0.999
1:207063382:G:T	R137S	0.999
1:207065096:T:C	F190L	0.999
1:207065098:C:A	F190L	0.999
1:207065098:C:G	F190L	0.999
1:207067591:T:C	L242P	0.999
1:207068220:T:A	W300R	0.999
1:207068220:T:C	W300R	0.999
1:207068226:A:C	S302R	0.999
1:207068227:G:T	S302I	0.999
1:207068228:C:A	S302R	0.999
1:207068228:C:G	S302R	0.999
1:207068293:T:C	L324P	0.999

dbSNP variants (sampled 300 via entrez): RS1000066312 (1:207068489 G>T), RS1000122185 (1:207075956 T>C,G), RS1000226657 (1:207075298 C>T), RS1000360107 (1:207078700 G>A), RS1000492603 (1:207075572 C>G,T), RS1000697586 (1:207041452 T>A), RS1000749551 (1:207040688 G>A), RS1000795304 (1:207065353 G>C), RS1000858662 (1:207049291 A>C,G), RS1000951838 (1:207058132 C>T), RS1000962571 (1:207055099 T>G), RS1000972941 (1:207071739 T>G), RS1001052639 (1:207051120 G>A,C), RS1001208849 (1:207038281 T>A), RS1001284108 (1:207062315 T>C)

Disease associations

OMIM: gene MIM:171835 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006627_43	Diastolic blood pressure	2.000000e-11
GCST008058_283	Estimated glomerular filtration rate	1.000000e-11
GCST90002407_23	White blood cell count	1.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3421525 (SINGLE PROTEIN)

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

ChEMBL bioactivities

20 potent at pChembl≥5 of 30 total, top 20 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.82	IC50	15	nM	CHEMBL3422677
7.60	IC50	25	nM	CHEMBL3422678
6.97	IC50	108	nM	CHEMBL3422674
6.85	IC50	141	nM	CHEMBL3421733
6.80	IC50	159	nM	CHEMBL3422676
6.73	IC50	188	nM	CHEMBL3422675
6.72	IC50	190	nM	CHEMBL3421734
6.43	IC50	374	nM	CHEMBL3422673
6.42	IC50	384	nM	CHEMBL3422651
6.37	IC50	429	nM	CHEMBL3422672
6.09	IC50	818	nM	CHEMBL3421731
5.84	IC50	1450	nM	CHEMBL3421736
5.83	IC50	1480	nM	CHEMBL3422658
5.74	IC50	1820	nM	CHEMBL3422664
5.63	IC50	2350	nM	CHEMBL3422670
5.60	IC50	2520	nM	CHEMBL3422657
5.45	IC50	3570	nM	CHEMBL3422680
5.21	IC50	6150	nM	CHEMBL3421732
5.17	IC50	6840	nM	CHEMBL3422659
5.04	IC50	9180	nM	CHEMBL3422652

PubChem BioAssay actives

20 with measured affinity, of 38 total; 20 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
(2S)-N-[4-[3-cyano-1-(2-methylpropyl)indazol-5-yl]oxyphenyl]pyrrolidine-2-carboxamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	0.0150	uM
(2S)-N-[4-[3-cyano-1-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]indazol-5-yl]oxyphenyl]pyrrolidine-2-carboxamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	0.0250	uM
(2S)-N-[4-[3-cyano-1-(2-methyl-1-oxo-3H-isoindol-5-yl)indol-5-yl]oxyphenyl]pyrrolidine-2-carboxamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	0.1080	uM
(2S)-N-[4-[[3-cyano-1-(2-methylpropyl)indol-5-yl]-methylamino]phenyl]pyrrolidine-2-carboxamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	0.1410	uM
(2S)-N-[4-[3-cyano-1-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]indol-5-yl]oxyphenyl]pyrrolidine-2-carboxamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	0.1590	uM
(2S)-N-[4-(1-benzyl-3-cyanoindol-5-yl)oxyphenyl]pyrrolidine-2-carboxamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	0.1880	uM
(2S)-N-[4-[3-cyano-1-(2-methylpropyl)indol-5-yl]sulfanylphenyl]pyrrolidine-2-carboxamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	0.1900	uM
(2S)-N-[4-(3-cyano-1-phenylindol-5-yl)oxyphenyl]pyrrolidine-2-carboxamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	0.3740	uM
(2S)-N-[4-[3-cyano-1-(2-methylpropyl)indol-5-yl]oxyphenyl]pyrrolidine-2-carboxamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	0.3840	uM
(2S)-N-[4-[3-cyano-1-(oxan-4-ylmethyl)indol-5-yl]oxyphenyl]pyrrolidine-2-carboxamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	0.4290	uM
(2S)-N-[4-[1-methyl-3-(1-methylpyrazol-4-yl)indol-5-yl]oxyphenyl]pyrrolidine-2-carboxamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	0.8180	uM
(2S)-N-[4-[[3-cyano-1-(2-methylpropyl)indol-5-yl]methyl]phenyl]pyrrolidine-2-carboxamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	1.4500	uM
2-amino-N-[4-(2-amino-1-benzyl-3-cyanoindol-5-yl)oxyphenyl]acetamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	1.4800	uM
(2S)-N-[4-(3-cyano-1-ethylindol-5-yl)oxyphenyl]pyrrolidine-2-carboxamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	1.8200	uM
(2S)-N-[4-[3-cyano-1-[2-(methylamino)-2-oxoethyl]indol-5-yl]oxyphenyl]pyrrolidine-2-carboxamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	2.3500	uM
2-amino-N-[4-[2-amino-3-cyano-1-(2-methylpropyl)indol-5-yl]oxyphenyl]acetamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	2.5200	uM
(2S)-N-[4-[[3-(1-methylpyrazol-4-yl)-1H-indol-5-yl]oxy]phenyl]pyrrolidine-2-carboxamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	3.5700	uM
(2S)-N-[4-[[3-cyano-1-(2-methylpropyl)indol-5-yl]amino]phenyl]pyrrolidine-2-carboxamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	6.1500	uM
2-amino-N-[4-[2-amino-3-cyano-1-[2-(dimethylamino)-2-oxoethyl]indol-5-yl]oxyphenyl]acetamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	6.8400	uM
2-amino-N-[4-(2-amino-3-cyano-1-ethylindol-5-yl)oxyphenyl]acetamide	1203857: Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	9.1800	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, increases expression	2
FR900359	affects phosphorylation, decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Caffeine	decreases phosphorylation	1
Calcitriol	increases expression, affects cotreatment	1
Carmustine	decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Estradiol	affects expression	1
Formaldehyde	increases expression	1
Lead	affects expression	1
Plant Extracts	affects cotreatment, increases expression	1
Silicon Dioxide	increases expression	1
Dihydrotestosterone	increases expression	1
Testosterone	affects cotreatment, increases expression	1
Thimerosal	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	affects expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3425139	Binding	Inhibition of recombinant human PFKFB2 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase PFKFB3. — J Med Chem

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7WS	Ubigene A-549 PFKFB2 KO	Cancer cell line	Male
CVCL_D8S5	Ubigene HCT 116 PFKFB2 KO	Cancer cell line	Male
CVCL_D9ML	Ubigene HEK293 PFKFB2 KO	Transformed cell line	Female
CVCL_E0JY	Ubigene HeLa PFKFB2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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