PFKFB1

Summary

PFKFB1 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1, HGNC:8872) is a protein-coding gene on chromosome Xp11.21, encoding 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1 (P16118). Synthesis and degradation of fructose 2,6-bisphosphate.

This gene encodes a member of the family of bifunctional 6-phosphofructo-2-kinase:fructose-2,6-biphosphatase enzymes. The enzyme forms a homodimer that catalyzes both the synthesis and degradation of fructose-2,6-biphosphate using independent catalytic domains. Fructose-2,6-biphosphate is an activator of the glycolysis pathway and an inhibitor of the gluconeogenesis pathway. Consequently, regulating fructose-2,6-biphosphate levels through the activity of this enzyme is thought to regulate glucose homeostasis. Multiple alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 5207 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 95 total
• Druggable target: yes
• MANE Select transcript: NM_002625

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8872
Approved symbol	PFKFB1
Name	6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1
Location	Xp11.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000158571
Ensembl biotype	protein_coding
OMIM	311790
Entrez	5207

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 19 protein_coding

ENST00000374992, ENST00000375006, ENST00000545676, ENST00000899202, ENST00000899203, ENST00000899204, ENST00000899205, ENST00000899206, ENST00000899207, ENST00000899208, ENST00000899209, ENST00000899210, ENST00000899211, ENST00000899212, ENST00000899213, ENST00000899214, ENST00000899215, ENST00000899216, ENST00000899217

RefSeq mRNA: 3 — MANE Select: NM_002625 NM_001271804, NM_001271805, NM_002625

CCDS: CCDS14364, CCDS65273

Canonical transcript exons

ENST00000375006 — 14 exons

Exon	Start	End
ENSE00000671730	54934947	54935009
ENSE00001039648	54956153	54956274
ENSE00001039652	54951905	54952112
ENSE00001138149	54949075	54949221
ENSE00001138167	54958306	54958362
ENSE00001138173	54958851	54958925
ENSE00001138182	54959827	54959893
ENSE00001138192	54960824	54960917
ENSE00001278630	54963257	54963382
ENSE00001613745	54937595	54937724
ENSE00001666471	54933821	54933885
ENSE00001672492	54945439	54945543
ENSE00001908241	54932961	54933462
ENSE00003891008	54993911	54994188

Expression profiles

Bgee: expression breadth ubiquitous, 161 present calls, max score 93.18.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5611 / max 90.8100, expressed in 69 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199402	0.3590	45
199401	0.0686	33
199400	0.0619	12
199398	0.0540	18
199399	0.0176	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	93.18	gold quality
right lobe of liver	UBERON:0001114	92.92	gold quality
gastrocnemius	UBERON:0001388	91.11	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	90.36	gold quality
muscle of leg	UBERON:0001383	90.02	gold quality
muscle organ	UBERON:0001630	89.07	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.52	gold quality
vastus lateralis	UBERON:0001379	87.47	silver quality
quadriceps femoris	UBERON:0001377	86.82	silver quality
skeletal muscle tissue	UBERON:0001134	86.22	gold quality
liver	UBERON:0002107	85.89	gold quality
biceps brachii	UBERON:0001507	85.63	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.55	gold quality
triceps brachii	UBERON:0001509	85.52	gold quality
diaphragm	UBERON:0001103	85.11	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	83.80	gold quality
deltoid	UBERON:0001476	82.34	gold quality
muscle tissue	UBERON:0002385	81.78	gold quality
adipose tissue	UBERON:0001013	81.58	gold quality
subcutaneous adipose tissue	UBERON:0002190	81.56	gold quality
adipose tissue of abdominal region	UBERON:0007808	80.53	gold quality
omental fat pad	UBERON:0010414	80.48	gold quality
peritoneum	UBERON:0002358	80.38	gold quality
connective tissue	UBERON:0002384	79.65	gold quality
gluteal muscle	UBERON:0002000	74.91	silver quality
tibialis anterior	UBERON:0001385	70.63	silver quality
pancreatic ductal cell	CL:0002079	64.94	silver quality
olfactory bulb	UBERON:0002264	64.24	gold quality
cardiac muscle of right atrium	UBERON:0003379	64.12	gold quality
type B pancreatic cell	CL:0000169	63.95	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-GEOD-99795	no	14.81
E-ANND-3	no	3.23

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, E2F1, FOXA1, HIF1A, IFNG, NCOR1, NR1H2, NR1H3, SREBF1

miRNA regulators (miRDB)

22 targeting PFKFB1, 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-6740-5P	100.00	65.64	932
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-2682-5P	99.73	67.38	1055
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-1264	99.25	66.81	1317
HSA-MIR-887-5P	98.82	65.90	1347
HSA-MIR-1910-3P	98.44	67.51	1695
HSA-MIR-6837-3P	98.42	66.71	1149
HSA-MIR-4691-5P	98.41	66.77	1343
HSA-MIR-6792-3P	98.41	66.86	1359
HSA-MIR-653-3P	98.31	67.71	1542
HSA-MIR-6511A-5P	98.13	67.47	1770
HSA-MIR-6806-5P	96.37	68.74	587

Literature-anchored findings (GeneRIF, showing 2)

• Results describe structural differences between two isozymes of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase from liver and testis. (PMID:12379646)
• Insulin resistance in obese boys leads to up-regulation of INSIG2 gene expression as well as to down-regulation of PFKFB1, PFKFB3, and HK2 genes in the blood cells as compared to obese patients with normal insulin sensitivity. (PMID:26827442)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	pfkfb1	ENSDARG00000037140
danio_rerio	si:dkey-96f10.1	ENSDARG00000074457
mus_musculus	Pfkfb1	ENSMUSG00000025271
rattus_norvegicus	Pfkfb1	ENSRNOG00000000165
drosophila_melanogaster	Pfrx	FBGN0027621
caenorhabditis_elegans		WBGENE00019295
caenorhabditis_elegans	pfkb-1.1	WBGENE00022456

Paralogs (3): PFKFB4 (ENSG00000114268), PFKFB2 (ENSG00000123836), PFKFB3 (ENSG00000170525)

Protein

Protein identifiers

6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 1 — P16118 (reviewed: P16118)

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

All UniProt accessions (3): P16118, I1Z9G4, Q4VBA9

UniProt curated annotations — full annotation on UniProt →

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

Subunit / interactions. Homodimer.

Tissue specificity. Liver.

Activity regulation. Phosphorylation at Ser-33 inhibits the kinase and activates the bisphosphatase.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P16118-1	1	yes
P16118-2	2

RefSeq proteins (3): NP_001258733, NP_001258734, NP_002616* (*=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 (72 total): binding site 22, helix 19, strand 11, active site 4, turn 4, modified residue 3, sequence conflict 3, region of interest 2, initiator methionine 1, chain 1, site 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1K6M	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16118-F1	92.11	0.82

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 (5): 393 (transition state stabilizer); 131; 161; 259 (tele-phosphohistidine intermediate); 328 (proton donor/acceptor)

Ligand- & substrate-binding residues (22): 105; 133; 139; 170–175; 175; 196; 200; 258; 265; 271; 308; 339 …

Post-translational modifications (3): 2, 33, 141

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-163358	PKA-mediated phosphorylation of key metabolic factors
R-HSA-163767	PP2A-mediated dephosphorylation of key metabolic factors
R-HSA-9634600	Regulation of glycolysis by fructose 2,6-bisphosphate metabolism

MSigDB gene sets: 200 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, MODULE_64, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_PHOSPHORYLATION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GGGTGGRR_PAX4_03, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, CEBALLOS_TARGETS_OF_TP53_AND_MYC_UP, GATA3_01, GOBP_REGULATION_OF_CATABOLIC_PROCESS

GO Biological Process (6): fructose metabolic process (GO:0006000), fructose 2,6-bisphosphate metabolic process (GO:0006003), gluconeogenesis (GO:0006094), glycolytic process (GO:0006096), negative regulation of glycolytic process through fructose-6-phosphate (GO:1904539), carbohydrate phosphorylation (GO:0046835)

GO Molecular Function (10): 6-phosphofructo-2-kinase activity (GO:0003873), fructose-2,6-bisphosphate 2-phosphatase activity (GO:0004331), ATP binding (GO:0005524), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), hydrolase activity (GO:0016787)

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

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Integration of energy metabolism	2
Glycolysis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catalytic activity	2
hexose metabolic process	1
organophosphate metabolic process	1
carbohydrate derivative metabolic process	1
glucose metabolic process	1
hexose biosynthetic process	1
phosphoglycerate kinase activity	1
phosphoglycerate mutase activity	1
phosphopyruvate hydratase activity	1
pyruvate kinase activity	1
pyruvate metabolic process	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
negative regulation of glycolytic process	1
glycolytic process through fructose-6-phosphate	1
carbohydrate metabolic process	1
phosphorylation	1
phosphofructokinase activity	1
sugar-phosphatase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
cytoplasm	1
cellular anatomical structure	1
cytosol	1
transferase complex, transferring phosphorus-containing groups	1

Protein interactions and networks

STRING

1482 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PFKFB1	GCK	P35557	775
PFKFB1	HNF4G	Q14541	766
PFKFB1	PFKM	P08237	756
PFKFB1	PCK1	P35558	690
PFKFB1	ALAS2	P22557	689
PFKFB1	FBP2	O00757	634
PFKFB1	PKM	P14618	564
PFKFB1	ONECUT1	Q9UBC0	543
PFKFB1	PFKL	P17858	542
PFKFB1	H6PD	O95479	540
PFKFB1	FOXM1	Q08050	533
PFKFB1	TIGAR	Q9NQ88	528
PFKFB1	HK2	P52789	518
PFKFB1	FBP1	P09467	497
PFKFB1	PFKP	Q01813	492

IntAct

53 interactions, top by confidence:

A	B	Type	Score
PFKFB1	PFKFB1	psi-mi:“MI:0915”(physical association)	0.750
PFKFB1	PFKFB1	psi-mi:“MI:0407”(direct interaction)	0.750
PFKFB1	PFKFB4	psi-mi:“MI:0915”(physical association)	0.670
PFKFB1	ZNF276	psi-mi:“MI:0915”(physical association)	0.560
PFKFB1	PLEKHG4	psi-mi:“MI:0915”(physical association)	0.560
PFKFB1	PFKFB3	psi-mi:“MI:0915”(physical association)	0.560
PFKFB1	DDIT4L	psi-mi:“MI:0915”(physical association)	0.560
PFKFB1	VWC2	psi-mi:“MI:0915”(physical association)	0.560
PFKFB1	PDE4A	psi-mi:“MI:0915”(physical association)	0.560
PFKFB1	KATNBL1	psi-mi:“MI:0915”(physical association)	0.560
PFKFB1	ZNF474	psi-mi:“MI:0915”(physical association)	0.560
PFKFB1	ZNF655	psi-mi:“MI:0915”(physical association)	0.560
ZNF688	PFKFB1	psi-mi:“MI:0915”(physical association)	0.560
GCK	PFKFB1	psi-mi:“MI:0407”(direct interaction)	0.560
PFKFB1	GCK	psi-mi:“MI:0407”(direct interaction)	0.560
PASK	PFKFB1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
M	IPO5	psi-mi:“MI:0914”(association)	0.350
NS1		psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
PFKFB4	PFKFB2	psi-mi:“MI:0914”(association)	0.350
PFKFB1	MAPK3	psi-mi:“MI:0915”(physical association)	0.000
PFKFB1	PFKFB4	psi-mi:“MI:0915”(physical association)	0.000
PFKFB1	PLEKHG4	psi-mi:“MI:0915”(physical association)	0.000
PFKFB1	PFKFB1	psi-mi:“MI:0915”(physical association)	0.000
PFKFB1	PFKFB3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (31): PFKFB1 (Two-hybrid), PFKFB1 (Affinity Capture-RNA), PRKAA1 (Negative Genetic), PFKFB1 (Negative Genetic), PFKFB1 (Negative Genetic), PFKFB1 (Positive Genetic), PFKFB1 (Positive Genetic), PFKFB1 (Positive Genetic), PFKFB1 (Affinity Capture-MS), PFKFB1 (Two-hybrid), PFKFB1 (Two-hybrid), PFKFB1 (Two-hybrid), PFKFB1 (Two-hybrid), PFKFB1 (Two-hybrid), ZNF276 (Two-hybrid)

ESM2 similar proteins: A0A4X1T4U3, A4IFD0, O00329, O14936, O35904, O61069, O65583, O70589, P07953, P16118, P25114, P49872, P70266, Q13057, Q16875, Q16877, Q24210, Q28901, Q298L5, Q2UM43, Q32M07, Q4R3W4, Q4R8B6, Q4V8A1, Q502L7, Q5B5L3, Q5M7G4, Q5R9C1, Q623S8, Q62915, Q68FP8, Q6DGQ8, Q6DTY7, Q6P618, Q80UN9, Q8IMX7, Q8MIR4, Q91309, Q91348, Q91YL3

Diamond homologs: A1AJW4, A1BE55, A1JJB8, A1TC01, A4T096, A4TQH5, A4W6B3, A6TI09, A6UEW3, A6WYJ2, A7FMF8, A7HZ35, A7MIJ0, A7ZVT7, A8A8C4, A8ALW1, A8G9J4, A9MR94, A9N7F5, A9R032, B0SY17, B0UBD4, B1IS24, B1JL20, B1LEK2, B1WAX6, B1XFK5, B1YNA6, B2IEV6, B2K3K5, B2TZS8, B2VH13, B3EFK8, B4EA64, B4EY52, B4T4I9, B4TH18, B4TU55, B5BAL1, B5F543

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	51
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2274 predictions. Top by Δscore:

Variant	Effect	Δscore
X:54933551:C:A	donor_gain	1.0000
X:54933887:T:C	acceptor_gain	1.0000
X:54937592:TAC:T	donor_loss	1.0000
X:54937593:A:C	donor_loss	1.0000
X:54937594:C:CA	donor_loss	1.0000
X:54937596:TGA:T	donor_gain	1.0000
X:54937720:TAGGA:T	acceptor_gain	1.0000
X:54937721:AGGA:A	acceptor_gain	1.0000
X:54937725:C:CC	acceptor_gain	1.0000
X:54952125:C:T	acceptor_gain	1.0000
X:54956147:TCTTA:T	donor_loss	1.0000
X:54956148:CTTAC:C	donor_loss	1.0000
X:54956149:TTA:T	donor_loss	1.0000
X:54956151:A:AG	donor_loss	1.0000
X:54956152:C:CA	donor_loss	1.0000
X:54956275:C:CC	acceptor_gain	1.0000
X:54958846:CATA:C	donor_loss	1.0000
X:54958847:ATAC:A	donor_loss	1.0000
X:54958848:TA:T	donor_loss	1.0000
X:54958850:CCTT:C	donor_loss	1.0000
X:54958925:CCTA:C	acceptor_loss	1.0000
X:54959825:A:AC	donor_gain	1.0000
X:54959826:C:CC	donor_gain	1.0000
X:54959826:C:CG	donor_loss	1.0000
X:54959840:T:A	donor_gain	1.0000
X:54959905:C:CT	acceptor_gain	1.0000
X:54959906:A:T	acceptor_gain	1.0000
X:54960822:A:AC	donor_gain	1.0000
X:54960823:C:CC	donor_gain	1.0000
X:54960825:T:TA	donor_gain	1.0000

AlphaMissense

3090 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:54933834:C:G	R448P	0.999
X:54934964:A:G	L425P	0.999
X:54937626:G:C	C399W	0.999
X:54937657:A:G	L389P	0.999
X:54937672:C:G	R384P	0.999
X:54937678:A:G	L382P	0.999
X:54937699:A:G	L375P	0.999
X:54937703:G:T	R374S	0.999
X:54937711:A:G	L371P	0.999
X:54937721:A:G	Y368H	0.999
X:54937724:A:G	S367P	0.999
X:54945443:C:A	G365V	0.999
X:54945443:C:T	G365E	0.999
X:54945444:C:G	G365R	0.999
X:54945444:C:T	G365R	0.999
X:54945453:A:G	Y362H	0.999
X:54945455:C:G	R361P	0.999
X:54945456:G:T	R361S	0.999
X:54945466:T:A	K357N	0.999
X:54945466:T:G	K357N	0.999
X:54945467:T:A	K357I	0.999
X:54945468:T:C	K357E	0.999
X:54945479:C:G	R353P	0.999
X:54945542:C:T	G332D	0.999
X:54945543:C:G	G332R	0.999
X:54949085:T:A	E328V	0.999
X:54949091:A:G	L326P	0.999
X:54949156:A:C	S304R	0.999
X:54949156:A:T	S304R	0.999
X:54949158:T:G	S304R	0.999

dbSNP variants (sampled 300 via entrez): RS1000074442 (X:54990917 G>C), RS1000159104 (X:54962964 A>G), RS1000161734 (X:54937128 C>G,T), RS1000307846 (X:54943828 T>G), RS1000308367 (X:54952928 C>T), RS1000320628 (X:54941107 T>C), RS1000330368 (X:54979806 G>A), RS1000361704 (X:54967084 A>G), RS1000383009 (X:54941463 G>A), RS1000391266 (X:54968448 G>T), RS1000495208 (X:54957921 G>T), RS1000570521 (X:54955765 G>T), RS1000663468 (X:54938411 A>C), RS1000695260 (X:54949423 A>G), RS1000717169 (X:54971778 T>C)

Disease associations

OMIM: gene MIM:311790 | disease phenotypes: MIM:192500

GenCC curated gene-disease

Mondo (1): familial long QT syndrome (MONDO:0019171)

Orphanet (2): Romano-Ward syndrome (Orphanet:101016), Congenital long QT syndrome (Orphanet:768)

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST90002390_289	Mean corpuscular hemoglobin	2.000000e-50
GCST90002392_236	Mean corpuscular volume	1.000000e-49
GCST90002396_101	Mean reticulocyte volume	1.000000e-17
GCST90002397_155	Mean spheric corpuscular volume	4.000000e-18

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3421524 (SINGLE PROTEIN)

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

ChEMBL bioactivities

17 potent at pChembl≥5 of 34 total, top 17 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.72	IC50	191	nM	CHEMBL3422678
6.53	IC50	294	nM	CHEMBL3422677
6.49	IC50	321	nM	CHEMBL3421735
6.15	IC50	701	nM	CHEMBL3422674
5.95	IC50	1130	nM	CHEMBL3422676
5.78	IC50	1660	nM	CHEMBL3421734
5.74	IC50	1830	nM	CHEMBL3422675
5.71	IC50	1930	nM	CHEMBL3422673
5.69	IC50	2060	nM	CHEMBL3422651
5.63	IC50	2350	nM	CHEMBL3421731
5.60	IC50	2530	nM	CHEMBL3422659
5.58	IC50	2660	nM	CHEMBL3422658
5.50	IC50	3180	nM	CHEMBL3422657
5.46	IC50	3470	nM	CHEMBL3422672
5.43	IC50	3740	nM	CHEMBL3422667
5.30	IC50	5000	nM	CHEMBL3421733
5.23	IC50	5920	nM	CHEMBL3421736

PubChem BioAssay actives

17 with measured affinity, of 38 total; 17 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-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]indazol-5-yl]oxyphenyl]pyrrolidine-2-carboxamide	1203856: Inhibition of recombinant human PFKFB1 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	0.1910	uM
(2S)-N-[4-[3-cyano-1-(2-methylpropyl)indazol-5-yl]oxyphenyl]pyrrolidine-2-carboxamide	1203856: Inhibition of recombinant human PFKFB1 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	0.2940	uM
(2S)-N-[4-[3-cyano-1-(2-methylpropyl)indol-5-yl]sulfonylphenyl]pyrrolidine-2-carboxamide	1203856: Inhibition of recombinant human PFKFB1 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	0.3210	uM
(2S)-N-[4-[3-cyano-1-(2-methyl-1-oxo-3H-isoindol-5-yl)indol-5-yl]oxyphenyl]pyrrolidine-2-carboxamide	1203856: Inhibition of recombinant human PFKFB1 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	0.7010	uM
(2S)-N-[4-[3-cyano-1-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]indol-5-yl]oxyphenyl]pyrrolidine-2-carboxamide	1203856: Inhibition of recombinant human PFKFB1 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	1.1300	uM
(2S)-N-[4-[3-cyano-1-(2-methylpropyl)indol-5-yl]sulfanylphenyl]pyrrolidine-2-carboxamide	1203856: Inhibition of recombinant human PFKFB1 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	1.6600	uM
(2S)-N-[4-(1-benzyl-3-cyanoindol-5-yl)oxyphenyl]pyrrolidine-2-carboxamide	1203856: Inhibition of recombinant human PFKFB1 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	1.8300	uM
(2S)-N-[4-(3-cyano-1-phenylindol-5-yl)oxyphenyl]pyrrolidine-2-carboxamide	1203856: Inhibition of recombinant human PFKFB1 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	1.9300	uM
(2S)-N-[4-[3-cyano-1-(2-methylpropyl)indol-5-yl]oxyphenyl]pyrrolidine-2-carboxamide	1203856: Inhibition of recombinant human PFKFB1 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	2.0600	uM
(2S)-N-[4-[1-methyl-3-(1-methylpyrazol-4-yl)indol-5-yl]oxyphenyl]pyrrolidine-2-carboxamide	1203856: Inhibition of recombinant human PFKFB1 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-(dimethylamino)-2-oxoethyl]indol-5-yl]oxyphenyl]acetamide	1203856: Inhibition of recombinant human PFKFB1 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	2.5300	uM
2-amino-N-[4-(2-amino-1-benzyl-3-cyanoindol-5-yl)oxyphenyl]acetamide	1203856: Inhibition of recombinant human PFKFB1 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	2.6600	uM
2-amino-N-[4-[2-amino-3-cyano-1-(2-methylpropyl)indol-5-yl]oxyphenyl]acetamide	1203856: Inhibition of recombinant human PFKFB1 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	3.1800	uM
(2S)-N-[4-[3-cyano-1-(oxan-4-ylmethyl)indol-5-yl]oxyphenyl]pyrrolidine-2-carboxamide	1203856: Inhibition of recombinant human PFKFB1 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	3.4700	uM
(2S)-N-[4-(3-cyano-1-ethylindol-5-yl)oxyphenyl]azetidine-2-carboxamide	1203856: Inhibition of recombinant human PFKFB1 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	3.7400	uM
(2S)-N-[4-[[3-cyano-1-(2-methylpropyl)indol-5-yl]-methylamino]phenyl]pyrrolidine-2-carboxamide	1203856: Inhibition of recombinant human PFKFB1 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	5.0000	uM
(2S)-N-[4-[[3-cyano-1-(2-methylpropyl)indol-5-yl]methyl]phenyl]pyrrolidine-2-carboxamide	1203856: Inhibition of recombinant human PFKFB1 using fructose 6 phosphate as substrate assessed as ADP generation after 1 hr by ADP Glo assay	ic50	5.9200	uM

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	affects expression, decreases expression, decreases methylation	5
Benzo(a)pyrene	affects methylation, decreases expression	4
Tetrachlorodibenzodioxin	decreases expression, affects expression	4
Valproic Acid	affects cotreatment, decreases expression	3
Cyclosporine	decreases expression, increases expression	3
lasiocarpine	decreases expression	2
methyleugenol	decreases expression	2
Acetaminophen	decreases expression	2
N-Nitrosopyrrolidine	decreases expression	2
tris(2-butoxyethyl) phosphate	affects expression	1
sodium arsenite	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
obeticholic acid	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Rosiglitazone	decreases expression	1
Sunitinib	decreases expression	1
Estradiol	decreases expression	1
Urethane	decreases expression	1
Okadaic Acid	decreases expression	1
Permethrin	increases 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
CHEMBL3425138	Binding	Inhibition of recombinant human PFKFB1 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

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9MK	Ubigene HEK293 PFKFB1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
NCT02680080	Not specified	COMPLETED	Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome
NCT02775513	Not specified	UNKNOWN	Metabolism of Patients With Genetically Caused Cardiac Arrhythmia
NCT02814981	Not specified	UNKNOWN	Hydroxyzine and Risk of Prolongation of QT Interval
NCT02876380	Not specified	COMPLETED	Prospective Identification of Long QT Syndrome in Fetal Life
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03544918	Not specified	COMPLETED	Prevalence of Congenital Long QT Syndrome and Acquired QT Prolongation in a Hospital Cohort
NCT03642405	Not specified	UNKNOWN	Drug-induced Repolarization ECG Changes
NCT03678311	Not specified	COMPLETED	Long QT Syndrome and Sleep Apnea