PFKM

Summary

PFKM (phosphofructokinase, muscle, HGNC:8877) is a protein-coding gene on chromosome 12q13.11, encoding ATP-dependent 6-phosphofructokinase, muscle type (P08237). Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis.

Three phosphofructokinase isozymes exist in humans: muscle, liver and platelet. These isozymes function as subunits of the mammalian tetramer phosphofructokinase, which catalyzes the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate. Tetramer composition varies depending on tissue type. This gene encodes the muscle-type isozyme. Mutations in this gene have been associated with glycogen storage disease type VII, also known as Tarui disease. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 5213 — RefSeq curated summary.

At a glance

• Gene–disease (curated): glycogen storage disease VII (Definitive, GenCC)
• GWAS associations: 14
• Clinical variants (ClinVar): 1,117 total — 31 pathogenic, 84 likely-pathogenic
• Phenotypes (HPO): 30
• Druggable target: yes
• MANE Select transcript: NM_000289

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8877
Approved symbol	PFKM
Name	phosphofructokinase, muscle
Location	12q13.11
Locus type	gene with protein product
Status	Approved
Aliases	PFK-1, PPP1R122
Ensembl gene	ENSG00000152556
Ensembl biotype	protein_coding
OMIM	610681
Entrez	5213

Gene structure

Transcript identifiers

Ensembl transcripts: 96 — 84 protein_coding, 6 retained_intron, 5 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000312352, ENST00000340802, ENST00000359794, ENST00000546465, ENST00000546755, ENST00000546964, ENST00000547066, ENST00000547148, ENST00000547581, ENST00000547587, ENST00000548288, ENST00000548345, ENST00000548720, ENST00000549003, ENST00000549022, ENST00000549366, ENST00000549941, ENST00000550257, ENST00000550345, ENST00000550802, ENST00000550924, ENST00000551339, ENST00000551485, ENST00000551548, ENST00000551804, ENST00000552214, ENST00000552752, ENST00000552792, ENST00000552818, ENST00000552989, ENST00000629846, ENST00000642730, ENST00000873517, ENST00000873518, ENST00000873519, ENST00000873520, ENST00000873521, ENST00000873522, ENST00000873523, ENST00000873524, ENST00000873525, ENST00000873526, ENST00000873527, ENST00000873528, ENST00000873529, ENST00000873530, ENST00000873531, ENST00000873532, ENST00000873533, ENST00000873534, ENST00000873535, ENST00000873536, ENST00000873537, ENST00000873538, ENST00000934924, ENST00000934925, ENST00000934926, ENST00000934927, ENST00000934928, ENST00000934929, ENST00000934930, ENST00000934931, ENST00000942221, ENST00000942222, ENST00000942223, ENST00000942224, ENST00000942225, ENST00000942226, ENST00000942227, ENST00000942228, ENST00000942229, ENST00000942230, ENST00000942231, ENST00000942232, ENST00000942233, ENST00000942234, ENST00000942235, ENST00000942236, ENST00000942237, ENST00000942238, ENST00000942239, ENST00000942240, ENST00000942241, ENST00000942242, ENST00000942243, ENST00000942244, ENST00000942245, ENST00000942246, ENST00000942247, ENST00000942248, ENST00000942249, ENST00000942250, ENST00000942251, ENST00000942252, ENST00000942253, ENST00000942254

RefSeq mRNA: 19 — MANE Select: NM_000289 NM_000289, NM_001166686, NM_001166687, NM_001166688, NM_001354735, NM_001354736, NM_001354737, NM_001354738, NM_001354739, NM_001354740, NM_001354741, NM_001354742, NM_001354743, NM_001354744, NM_001354745, NM_001354746, NM_001354747, NM_001354748, NM_001363619

CCDS: CCDS53786, CCDS86294, CCDS86295, CCDS8760

Canonical transcript exons

ENST00000359794 — 23 exons

Exon	Start	End
ENSE00001604638	48145564	48146404
ENSE00001650033	48119364	48119406
ENSE00003468832	48139285	48139349
ENSE00003478653	48145031	48145130
ENSE00003489945	48139849	48139912
ENSE00003499431	48144046	48144157
ENSE00003518565	48140722	48140871
ENSE00003533607	48134943	48135038
ENSE00003540367	48141740	48141827
ENSE00003548087	48122767	48122859
ENSE00003597724	48141311	48141381
ENSE00003601910	48131316	48131393
ENSE00003602515	48135291	48135383
ENSE00003624825	48143753	48143814
ENSE00003627820	48137721	48137846
ENSE00003629396	48132868	48133057
ENSE00003635953	48134721	48134829
ENSE00003653751	48134232	48134276
ENSE00003658387	48141914	48142066
ENSE00003666513	48133315	48133480
ENSE00003670446	48145210	48145315
ENSE00003685157	48142782	48142946
ENSE00003692498	48130363	48130436

Expression profiles

Bgee: expression breadth ubiquitous, 302 present calls, max score 99.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.0605 / max 656.2468, expressed in 1752 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125249	23.9515	1706
125251	0.7342	39
125253	0.5506	40
125245	0.5141	244
125252	0.2401	31
125244	0.2300	80
125243	0.1954	41
125248	0.1706	66
125247	0.1638	64
206685	0.1214	47

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gluteal muscle	UBERON:0002000	99.65	gold quality
triceps brachii	UBERON:0001509	99.61	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.61	gold quality
skeletal muscle tissue	UBERON:0001134	99.60	gold quality
deltoid	UBERON:0001476	99.59	gold quality
heart right ventricle	UBERON:0002080	99.59	gold quality
gastrocnemius	UBERON:0001388	99.58	gold quality
biceps brachii	UBERON:0001507	99.57	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.57	gold quality
quadriceps femoris	UBERON:0001377	99.56	gold quality
vastus lateralis	UBERON:0001379	99.56	gold quality
body of tongue	UBERON:0011876	99.52	gold quality
tibialis anterior	UBERON:0001385	99.50	gold quality
left ventricle myocardium	UBERON:0006566	99.50	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.44	gold quality
muscle organ	UBERON:0001630	99.34	gold quality
skeletal muscle organ	UBERON:0014892	99.34	gold quality
muscle of leg	UBERON:0001383	99.24	gold quality
apex of heart	UBERON:0002098	99.11	gold quality
diaphragm	UBERON:0001103	99.07	gold quality
myocardium	UBERON:0002349	98.87	gold quality
cardiac ventricle	UBERON:0002082	98.84	gold quality
heart left ventricle	UBERON:0002084	98.82	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.79	gold quality
muscle tissue	UBERON:0002385	98.63	gold quality
cardiac muscle of right atrium	UBERON:0003379	98.46	gold quality
cardiac atrium	UBERON:0002081	98.32	gold quality
right atrium auricular region	UBERON:0006631	98.29	gold quality
heart	UBERON:0000948	98.10	gold quality
cortical plate	UBERON:0005343	98.06	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.21
E-MTAB-4850	no	383.84

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC, NR4A1

miRNA regulators (miRDB)

51 targeting PFKM, 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-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
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
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-142-3P	99.62	71.30	974
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-2053	99.57	69.15	1635
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-122B-5P	99.46	70.81	1457
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-542-3P	99.34	67.58	1270

Literature-anchored findings (GeneRIF, showing 26)

• Identification of novel PFK-M transcripts in the testis and embryo. (PMID:15020257)
• Two phosphofructokinase (PFK) chimeras were constructed by exchanging the N- and C-terminal halves of the mammalian M- and C-type isozymes. (PMID:17544406)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• Glycolytic efficiency, which is important for the survival of cancer cells, depends primarily on the preferential expression of PFK-L over the M and P isoforms. (PMID:20483646)
• Data indicate that substitution of residue at the citrate-binding site (D591V) of PFK-M resulted in the complete loss of activity. (PMID:21124851)
• Posttranslational modification of PFK1 enzyme might be the pivotal factor of deregulated glycolytic flux in tumors (PMID:21573193)
• Molecular genetic findings demonstrated the absence of specific genotype-phenotype correlations in PFKM gene mutations. (PMID:22133655)
• eukaryotic Pfk did not evolve from prokaryotic ancestors, reciprocal linkage of functionally opposed allosteric binding sites must have developed independently in prokaryotic and eukaryotic Pfk (convergent evolution). (PMID:22474333)
• Asp(543)Ala, a naturally occurring Tarui disease-causing mutation in the activating binding site, causes an increased efficacy of ATP at the inhibitory allosteric binding site. (PMID:22995305)
• insulin/phosphofructokinase (PFKM), overlaps with an expression quantitative trait loci (PMID:24306210)
• Gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 x 10(-6). (PMID:24493630)
• characterize three PFK1 mutations and show they have distinct effects on allosteric regulation of PFKP activity and lactate production. (PMID:25985179)
• Data indicate that 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase3 (PFKFB3) and phosphofructokinase (PFK1) expression allows discrimination between induced pluripotent stem cells (iPS) and cancer stem cells (CSCs). (PMID:26337471)
• KLK6 may be the key protease involved in the proteolytic modification of PFK-M. (PMID:29563071)
• MiR-135 targets phosphofructokinase-1 in the ancreatic ductal adenocarcinoma cells. (PMID:30778058)
• The authors experimentally provide evidence for pulsatile PFK-1 activity-induced synchronized dissociation of PKM2 tetramers and the subsequent accumulation of PKM2 dimers under high levels of fructose-1,6-bisphosphate in HeLa cells. (PMID:31469100)
• TRAP1 enhances Warburg metabolism through modulation of PFK1 expression/activity and favors resistance to EGFR inhibitors in human colorectal carcinomas. (PMID:33025742)
• Biochemical and transcript level differences between the three human phosphofructokinases show optimisation of each isoform for specific metabolic niches. (PMID:33141153)
• RNAi-mediated knockdown of PFK1 decreases the invasive capability and metastasis of nasopharyngeal carcinoma cell line, CNE-2. (PMID:33404290)
• PFK activation is essential for the odontogenic differentiation of human dental pulp stem cells. (PMID:33516882)
• ZEB1 enhances Warburg effect to facilitate tumorigenesis and metastasis of HCC by transcriptionally activating PFKM. (PMID:33897890)
• Expression of HK2, PKM2, and PFKM Is Associated with Metastasis and Late Disease Onset in Breast Cancer Patients. (PMID:35328104)
• Association of PFKM gene polymorphisms and susceptibility to cryptorchidism in a Chinese Han population. (PMID:35838787)
• Bone marrow mesenchymal stem cell-derived exosomal miR-21a-5p alleviates renal fibrosis by attenuating glycolysis by targeting PFKM. (PMID:36253358)
• RNAi screening reveals a synthetic chemical-genetic interaction between ATP synthase and PFK1 in cancer cells. (PMID:36601784)
• Cancer-associated somatic mutations in human phosphofructokinase-1 reveal a critical electrostatic interaction for allosteric regulation of enzyme activity. (PMID:37622331)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pfkma	ENSDARG00000014179
danio_rerio	pfkmb	ENSDARG00000060797
mus_musculus	Pfkm	ENSMUSG00000033065
rattus_norvegicus	Pfkm	ENSRNOG00000057988
drosophila_melanogaster	Pfk	FBGN0003071
caenorhabditis_elegans		WBGENE00022199

Paralogs (2): PFKP (ENSG00000067057), PFKL (ENSG00000141959)

Protein

Protein identifiers

ATP-dependent 6-phosphofructokinase, muscle type — P08237 (reviewed: P08237)

Alternative names: 6-phosphofructokinase type A, Phosphofructo-1-kinase isozyme A, Phosphohexokinase

All UniProt accessions (20): P08237, A0A024R0Y5, A0A0S2Z4A1, A0A0S2Z4I1, A0A2R8Y891, F8VNZ1, F8VP00, F8VSF5, F8VSF7, F8VTQ3, F8VTT5, F8VUB8, F8VVE3, F8VW30, F8VX13, F8VYK8, F8VZ53, F8VZI0, F8VZQ1, H0YHB8

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis.

Subunit / interactions. Homo- and heterotetramers. Phosphofructokinase (PFK) enzyme functions as a tetramer composed of different combinations of 3 types of subunits, called PFKM (where M stands for Muscle), PFKL (Liver) and PFKP (Platelet). The composition of the PFK tetramer differs according to the tissue type it is present in. In muscles, it is composed of 4 PFKM subunits (also called M4). In the liver, the predominant form is a tetramer of PFKL subunits (L4). In erythrocytes, both PFKM and PFKL subunits randomly tetramerize to form M4, L4 and other combinations (ML3, M2L2, M3L). The kinetic and regulatory properties of the tetrameric enzyme are dependent on the subunit composition, hence can vary across tissues. Interacts (via C-terminus) with HK1 (via N-terminal spermatogenic cell-specific region).

Subcellular location. Cytoplasm.

Post-translational modifications. GlcNAcylation decreases enzyme activity.

Disease relevance. Glycogen storage disease 7 (GSD7) [MIM:232800] A metabolic disorder characterized by exercise intolerance with associated nausea and vomiting, muscle cramping, exertional myopathy and compensated hemolysis. Short bursts of intense activity are particularly difficult. Severe muscle cramps and myoglobinuria develop after vigorous exercise. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Allosterically activated by ADP, AMP, or fructose 2,6-bisphosphate, and allosterically inhibited by ATP or citrate.

Pathway. Carbohydrate degradation; glycolysis; D-glyceraldehyde 3-phosphate and glycerone phosphate from D-glucose: step 3/4.

Miscellaneous. In human PFK exists as a system of 3 types of subunits, PFKM (muscle), PFKL (liver) and PFKP (platelet) isoenzymes.

Similarity. Belongs to the phosphofructokinase type A (PFKA) family. ATP-dependent PFK group I subfamily. Eukaryotic two domain clade ‘E’ sub-subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P08237-1	1	yes
P08237-2	2
P08237-3	3

RefSeq proteins (19): NP_000280, NP_001160158, NP_001160159, NP_001160160, NP_001341664, NP_001341665, NP_001341666, NP_001341667, NP_001341668, NP_001341669, NP_001341670, NP_001341671, NP_001341672, NP_001341673, NP_001341674, NP_001341675, NP_001341676, NP_001341677, NP_001350548 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000023	Phosphofructokinase_dom	Domain
IPR009161	6-Pfructokinase_euk	Family
IPR015912	Phosphofructokinase_CS	Conserved_site
IPR022953	ATP_PFK	Family
IPR035966	PKF_sf	Homologous_superfamily
IPR041914	PFK_vert-type	Family

Pfam: PF00365

Enzyme classification (BRENDA):

• EC 2.7.1.11 — 6-phosphofructokinase (BRENDA: 98 organisms, 152 substrates, 280 inhibitors, 278 Km, 43 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ATP	0.005–0.82	125
D-FRUCTOSE 6-PHOSPHATE	0.007–254	69
GTP	0.0006–4.3	9
CTP	0.018–11	8
UTP	0.009–5.1	8
ITP	0.003–2.2	6
ADP	0.32–1.4	5
FRUCTOSE 6-PHOSPHATE	0.01–0.2	4
D-FRUCTOSE 1,6-BISPHOSPHATE	0.7–16.7	3
MG2+	0.01–0.025	2
2-DEHYDRO-3-DEOXY-D-GLUCONATE	8.8	1
ADENOSINE	1	1
AMP	1.57	1
D-GLUCOSE	90	1
D-GLUCOSE 6-PHOSPHATE	0.6	1

Catalyzed reactions (Rhea), 1 shown:

• beta-D-fructose 6-phosphate + ATP = beta-D-fructose 1,6-bisphosphate + ADP + H(+) (RHEA:16109)

UniProt features (46 total): binding site 18, sequence variant 11, modified residue 6, region of interest 3, splice variant 2, sequence conflict 2, initiator methionine 1, chain 1, glycosylation site 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4OMT	X-RAY DIFFRACTION	6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08237-F1	91.66	0.83

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): 166 (proton acceptor)

Ligand- & substrate-binding residues (18): 164–166 (in other chain); 201; 208–210 (in other chain); 264 (in other chain); 292; 298–301 (in other chain); 471 (in other chain); 528–532 (in other chain); 566; 573–575 (in other chain); 629 (in other chain); 655 …

Post-translational modifications (6): 2, 133, 377, 557, 667, 775

Glycosylation sites (1): 530

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-70171	Glycolysis

MSigDB gene sets: 380 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_INSULIN_SECRETION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, 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_453, KEGG_GLYCOLYSIS_GLUCONEOGENESIS

GO Biological Process (12): glycogen catabolic process (GO:0005980), fructose 6-phosphate metabolic process (GO:0006002), glycolytic process (GO:0006096), fructose 1,6-bisphosphate metabolic process (GO:0030388), positive regulation of insulin secretion (GO:0032024), glucose homeostasis (GO:0042593), positive regulation of transcription by RNA polymerase II (GO:0045944), muscle cell cellular homeostasis (GO:0046716), glycolytic process through fructose-6-phosphate (GO:0061615), canonical glycolysis (GO:0061621), glycolysis from storage polysaccharide through glucose-1-phosphate (GO:0093001), carbohydrate phosphorylation (GO:0046835)

GO Molecular Function (13): 6-phosphofructokinase activity (GO:0003872), ATP binding (GO:0005524), kinase binding (GO:0019900), identical protein binding (GO:0042802), metal ion binding (GO:0046872), fructose binding (GO:0070061), fructose-6-phosphate binding (GO:0070095), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), phosphofructokinase activity (GO:0008443), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (7): nucleus (GO:0005634), cytosol (GO:0005829), 6-phosphofructokinase complex (GO:0005945), membrane (GO:0016020), apical plasma membrane (GO:0016324), sperm principal piece (GO:0097228), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Glucose metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
organophosphate metabolic process	2
carbohydrate derivative metabolic process	2
glycogen metabolic process	1
glucan catabolic 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
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
carbohydrate homeostasis	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
cellular homeostasis	1
6-phosphofructokinase activity	1
fructose-bisphosphate aldolase activity	1
triose-phosphate isomerase activity	1
glycolytic process	1
glucokinase activity	1
glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity	1
glucose catabolic process	1
glycolytic process through glucose-6-phosphate	1
polysaccharide catabolic process	1
glycolytic process through glucose-1-phosphate	1
carbohydrate metabolic process	1
phosphorylation	1
phosphofructokinase activity	1

Protein interactions and networks

STRING

3292 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PFKM	PFKFB3	Q16875	956
PFKM	HK1	P19367	887
PFKM	PKM	P14618	804
PFKM	LDHA	P00338	793
PFKM	ALDOA	P04075	788
PFKM	J3KPS3	J3KPS3	786
PFKM	TPI1	P00938	783
PFKM	G6PC1	P35575	782
PFKM	GPI	P06744	781
PFKM	HK2	P52789	763
PFKM	PFKFB1	P16118	756
PFKM	PFKFB2	O60825	749
PFKM	PGK1	P00558	733
PFKM	DGKA	P23743	732
PFKM	H6PD	O95479	731

IntAct

196 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PFKP	PFKM	psi-mi:“MI:0915”(physical association)	0.590
PFKM	PFKM	psi-mi:“MI:0915”(physical association)	0.570
PFKM	PFKL	psi-mi:“MI:0915”(physical association)	0.570
PFKL	PFKM	psi-mi:“MI:0915”(physical association)	0.570
PFKM	SIAH1	psi-mi:“MI:0915”(physical association)	0.560
SIAH1	PFKM	psi-mi:“MI:0915”(physical association)	0.560
	MYL12B	psi-mi:“MI:0914”(association)	0.460
PFKM	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
PFKM	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
PFKM	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
NOS1	PFKM	psi-mi:“MI:0407”(direct interaction)	0.440
PFKM	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
PFKM	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
MAST1	PFKM	psi-mi:“MI:0407”(direct interaction)	0.440
PFKM	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.440
PFKM	SYNJ2BP	psi-mi:“MI:0407”(direct interaction)	0.440
PFKM	FRMPD2	psi-mi:“MI:0407”(direct interaction)	0.440
DLG1	PFKM	psi-mi:“MI:0407”(direct interaction)	0.440
PFKM	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (222): PFKM (Two-hybrid), SIAH1 (Two-hybrid), PFKM (Affinity Capture-RNA), PFKM (Affinity Capture-RNA), PFKM (Reconstituted Complex), APEH (Co-fractionation), ARFIP1 (Co-fractionation), CTH (Co-fractionation), EEF1A1 (Co-fractionation), MCFD2 (Co-fractionation), PFKM (Co-fractionation), PFKM (Co-fractionation), PFKM (Co-fractionation), PFKM (Co-fractionation), PFKM (Co-fractionation)

ESM2 similar proteins: A1A4J1, A2E9H3, A2EF58, C4QXA5, O42938, O61068, O83146, O94200, O94201, P00511, P08237, P12382, P16862, P17858, P30835, P47857, P47858, P47859, P47860, P51553, P52034, P52784, P59680, P78985, Q01813, Q03216, Q0IIG5, Q27483, Q27665, Q27705, Q27778, Q2HYU2, Q2RNU4, Q4W9B8, Q5R636, Q5R7V5, Q5RAG9, Q60HD9, Q867C9, Q8TGA0

Diamond homologs: A0PYC8, A0RJJ6, A1A4J1, A5I798, A5IKL2, A6TVD3, A7FYW7, A7GIW9, A7GTP4, A7Z7K6, A8FG55, A8MLY0, A9VJR1, B0K6L2, B0K7U7, B1IFV9, B1L266, B1L9U3, B2A6Y0, B7GGT1, B7HFB3, B7HRN9, B7IJZ8, B7JRX2, B8D1K5, B9DN94, B9J099, B9K6R9, C0Z7W7, C1EUU3, C1FM55, C3KV06, C3L8X8, C3PAI8, C4K7E1, C4LEQ5, C4QXA5, C5D663, O34529, O42938

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
PFKM	“down-regulates quantity”	“β-D-fructose 6-phosphate”	“chemical modification”
PFKM	“up-regulates quantity”	“beta-D-fructofuranose 1,6-bisphosphate(4-)”	“chemical modification”
“beta-D-fructofuranose 2,6-bisphosphate”	“up-regulates activity”	PFKM	binding
OGT	“down-regulates activity”	PFKM	glycosylation
OGA	“up-regulates activity”	PFKM	deglycosylation
ULK1	“down-regulates activity”	PFKM	phosphorylation
ULK2	“down-regulates activity”	PFKM	phosphorylation
MYC	“up-regulates quantity”	PFKM	“transcriptional regulation”
CyclinD3/CDK6	“down-regulates activity”	PFKM	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 157 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
Assembly and cell surface presentation of NMDA receptors	12	30.8×	1e-12
Ras activation upon Ca2+ influx through NMDA receptor	5	28.8×	7e-05
Unblocking of NMDA receptors, glutamate binding and activation	5	27.5×	7e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	27.5×	7e-05
Dopamine Neurotransmitter Release Cycle	5	25.1×	9e-05
Long-term potentiation	5	24.0×	9e-05
Neurexins and neuroligins	11	21.9×	5e-10
Protein-protein interactions at synapses	7	18.8×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	42.7×	2e-11
protein localization to synapse	6	33.8×	5e-06
receptor clustering	7	32.1×	8e-07
regulation of postsynaptic membrane neurotransmitter receptor levels	6	21.9×	4e-05
bicellular tight junction assembly	5	12.2×	3e-03
mitotic spindle organization	6	12.0×	1e-03
Rho protein signal transduction	6	10.9×	1e-03
protein-containing complex assembly	10	8.4×	4e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

1117 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	31
Likely pathogenic	84
Uncertain significance	279
Likely benign	600
Benign	57

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1074467	NM_000289.6(PFKM):c.165T>A (p.Tyr55Ter)	Pathogenic
1152	NM_000289.6(PFKM):c.1341+1G>T	Pathogenic
1153	NM_000289.6(PFKM):c.428-2A>C	Pathogenic
1157	NM_000289.6(PFKM):c.116G>T (p.Arg39Leu)	Pathogenic
1159	NM_000289.6(PFKM):c.2058G>T (p.Trp686Cys)	Pathogenic
1381155	NM_000289.6(PFKM):c.646dup (p.Ala216fs)	Pathogenic
1398900	NM_000289.6(PFKM):c.74del (p.Gly25fs)	Pathogenic
1422945	NM_000289.6(PFKM):c.1761del (p.Ala588fs)	Pathogenic
1429205	NM_000289.6(PFKM):c.1704del (p.Phe568fs)	Pathogenic
1453463	NM_000289.6(PFKM):c.237+1G>C	Pathogenic
1455763	NM_000289.6(PFKM):c.2075_2076del (p.Lys692fs)	Pathogenic
2004770	NM_000289.6(PFKM):c.21dup (p.Ala8fs)	Pathogenic
2018449	NM_000289.6(PFKM):c.1053del (p.Cys351fs)	Pathogenic
2030770	NM_000289.6(PFKM):c.1828_1834del (p.Glu610fs)	Pathogenic
2125307	NM_000289.6(PFKM):c.290del (p.Gly97fs)	Pathogenic
2413895	NM_000289.6(PFKM):c.780_783del (p.Ile260fs)	Pathogenic
2419015	NM_000289.6(PFKM):c.1656del (p.Cys553fs)	Pathogenic
2703596	NM_000289.6(PFKM):c.1827del (p.Glu610fs)	Pathogenic
2704310	NM_000289.6(PFKM):c.1426A>T (p.Lys476Ter)	Pathogenic
2707072	NM_000289.6(PFKM):c.1091del (p.Glu364fs)	Pathogenic
2813983	NM_000289.6(PFKM):c.1159del (p.Leu387fs)	Pathogenic
2820211	NM_000289.6(PFKM):c.1344_1345insAA (p.Glu449fs)	Pathogenic
2824187	NM_000289.6(PFKM):c.589C>T (p.Gln197Ter)	Pathogenic
2901901	NM_000289.6(PFKM):c.103dup (p.Arg35fs)	Pathogenic
3244230	NC_000012.11:g.(?48535509)(48538245_?)del	Pathogenic
3646350	NM_000289.6(PFKM):c.732T>A (p.Cys244Ter)	Pathogenic
4735550	NM_000289.6(PFKM):c.1471C>T (p.Gln491Ter)	Pathogenic
632192	NM_000289.6(PFKM):c.2003del (p.Pro668fs)	Pathogenic
660611	NM_000289.6(PFKM):c.1929_1933del (p.Leu643_Tyr644insTer)	Pathogenic
7777	NM_000289.6(PFKM):c.237+1G>T	Pathogenic

SpliceAI

3485 predictions. Top by Δscore:

Variant	Effect	Δscore
12:48122762:TCTA:T	acceptor_loss	1.0000
12:48122763:CTA:C	acceptor_loss	1.0000
12:48122765:A:AG	acceptor_gain	1.0000
12:48122765:A:T	acceptor_loss	1.0000
12:48122765:AGAGT:A	acceptor_gain	1.0000
12:48122766:G:GT	acceptor_gain	1.0000
12:48122766:GA:G	acceptor_gain	1.0000
12:48122766:GAGT:G	acceptor_gain	1.0000
12:48122766:GAGTG:G	acceptor_gain	1.0000
12:48122858:AGG:A	donor_loss	1.0000
12:48122859:GGTAA:G	donor_loss	1.0000
12:48122860:G:GA	donor_loss	1.0000
12:48122861:T:G	donor_loss	1.0000
12:48130358:TTCA:T	acceptor_loss	1.0000
12:48130361:AGGT:A	acceptor_loss	1.0000
12:48130432:ATGAG:A	donor_loss	1.0000
12:48130434:GAGG:G	donor_loss	1.0000
12:48130435:AGGT:A	donor_loss	1.0000
12:48130436:GGTT:G	donor_loss	1.0000
12:48130437:G:A	donor_loss	1.0000
12:48130438:T:G	donor_loss	1.0000
12:48132864:A:AG	acceptor_gain	1.0000
12:48132864:AAAG:A	acceptor_gain	1.0000
12:48132865:A:G	acceptor_gain	1.0000
12:48132866:A:AG	acceptor_gain	1.0000
12:48132866:AG:A	acceptor_gain	1.0000
12:48132867:G:A	acceptor_gain	1.0000
12:48132867:G:GG	acceptor_gain	1.0000
12:48133054:GCAG:G	donor_gain	1.0000
12:48133058:G:C	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000035826 (12:48129486 T>C), RS1000109846 (12:48108148 T>A), RS1000305851 (12:48117181 T>C), RS1000378249 (12:48134361 A>G), RS1000431893 (12:48134575 C>G,T), RS1000472192 (12:48138371 C>T), RS1000503634 (12:48144897 A>G), RS1000636607 (12:48128198 C>A,G), RS1000739581 (12:48121493 C>T), RS1000791971 (12:48121803 G>A,T), RS1000824503 (12:48138068 G>A), RS1000899346 (12:48115925 A>G), RS1000914654 (12:48124822 A>G), RS1000984637 (12:48112830 G>A), RS1001037808 (12:48106396 C>T)

Disease associations

OMIM: gene MIM:610681 | disease phenotypes: MIM:232800, MIM:232200

GenCC curated gene-disease

Disease	Classification	Inheritance
glycogen storage disease VII	Definitive	Autosomal recessive

Mondo (2): glycogen storage disease VII (MONDO:0009295), disorder of glycogen metabolism (MONDO:0002412)

Orphanet (2): Glycogen storage disease due to muscle phosphofructokinase deficiency (Orphanet:371), Glycogen storage disease (Orphanet:79201)

HPO phenotypes

30 total (30 of 30 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000790	Hematuria
HP:0000952	Jaundice
HP:0001081	Cholelithiasis
HP:0001324	Muscle weakness
HP:0001878	Hemolytic anemia
HP:0001903	Anemia
HP:0001923	Reticulocytosis
HP:0001997	Gout
HP:0002149	Hyperuricemia
HP:0002486	Myotonia
HP:0003202	Skeletal muscle atrophy
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003326	Myalgia
HP:0003388	Easy fatigability
HP:0003546	Exercise intolerance
HP:0003557	Increased variability in muscle fiber diameter
HP:0003573	Increased total bilirubin
HP:0003621	Juvenile onset
HP:0003710	Exercise-induced muscle cramps
HP:0003738	Exercise-induced myalgia
HP:0008305	Exercise-induced myoglobinuria
HP:0008967	Exercise-induced muscle stiffness
HP:0009020	Exercise-induced muscle fatigue
HP:0009051	Increased muscle glycogen content
HP:0011463	Childhood onset
HP:0012544	Elevated circulating aldolase concentration
HP:0025435	Increased circulating lactate dehydrogenase concentration
HP:0030271	Reduced erythrocyte 2,3-diphosphoglycerate concentration
HP:6000359	Reduced muscle 6-phosphofructokinase activity

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST002599_6	Longevity (90 years and older)	8.000000e-06
GCST004604_55	Hematocrit	4.000000e-34
GCST004615_91	Hemoglobin concentration	1.000000e-26
GCST007272_44	Pulse pressure	7.000000e-51
GCST009391_560	Metabolite levels	7.000000e-06
GCST010083_326	Hemoglobin levels	5.000000e-61
GCST90002383_4	Hematocrit	5.000000e-58
GCST90002384_308	Hemoglobin	3.000000e-45
GCST90002385_227	High light scatter reticulocyte count	4.000000e-13
GCST90002387_121	Immature fraction of reticulocytes	1.000000e-11
GCST90002391_206	Mean corpuscular hemoglobin concentration	3.000000e-09
GCST90002392_380	Mean corpuscular volume	5.000000e-18
GCST90002397_425	Mean spheric corpuscular volume	4.000000e-21
GCST90002403_449	Red blood cell count	6.000000e-18

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0005763	pulse pressure measurement
EFO:0009769	histidine measurement
EFO:0007986	reticulocyte count
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004305	erythrocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D006008	Glycogen Storage Disease	C16.320.565.202.449; C18.452.648.202.449
D006014	Glycogen Storage Disease Type VII	C05.651.534.500.149; C10.668.491.175.500.112; C16.320.565.202.449.600; C16.320.577.149; C18.452.648.202.449.600

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3291 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation, increases expression	5
bisphenol A	decreases expression, increases expression	4
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	2
Acetaminophen	decreases expression	2
Acrolein	affects cotreatment, increases oxidation, increases abundance	2
Air Pollutants	decreases expression, affects cotreatment, increases abundance, increases oxidation	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Ivermectin	decreases expression, decreases reaction	2
Ozone	affects cotreatment, increases oxidation, increases abundance	2
Aflatoxin B1	increases expression, decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
FR900359	decreases phosphorylation	1
TAK-243	increases sumoylation	1
4-methyl-7-diethylaminocoumarin	increases expression	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pirinixic acid	affects binding, decreases expression, increases activity	1
decabromobiphenyl ether	increases expression	1
alpha-naphthoflavone	decreases expression, decreases reaction, increases expression	1
sodium arsenite	decreases expression	1
fructose 2,6-diphosphate	decreases activity, decreases reaction	1
arsenic trichloride	affects cotreatment, decreases expression	1
dinophysistoxin 1	decreases expression	1
CGP 52608	affects binding, increases reaction	1
bardoxolone methyl	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
abrine	decreases 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
CHEMBL1037330	Binding	Inhibition of phosphofructokinase AMP binding site	Fructose-1,6-bisphosphatase Inhibitors. 2. Design, synthesis, and structure-activity relationship of a series of phosphonic acid containing benzimidazoles that function as 5’-adenosinemonophosphate (AMP) mimics. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E0K1	Ubigene HeLa PFKM KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02782741	PHASE3	COMPLETED	Study to Compare the Efficacy and Safety of Enzyme Replacement Therapies Avalglucosidase Alfa and Alglucosidase Alfa Administered Every Other Week in Patients With Late-onset Pompe Disease Who Have Not Been Previously Treated for Pompe Disease
NCT04808505	PHASE3	RECRUITING	A Study to Evaluate the Safety, Efficacy, PK, PD and Immunogenicity of Cipaglucosidase Alfa/Miglustat in IOPD Subjects Aged 0 to <18
NCT03642860	PHASE2	COMPLETED	The Effect of Triheptanoin on Fatty Acid Oxidation and Exercise Tolerance in Patients With Glycogenoses
NCT00765414	PHASE2	COMPLETED	Extension Study of Long-term Safety and Efficacy of Myozyme for a Single Patient With Pompe Disease Who Were Previously Enrolled in Genzyme Sponsored ERT Studies.
NCT02032524	PHASE2	COMPLETED	Avalglucosidase Alfa Extension Study
NCT03019406	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Assess Safety and Efficacy of Avalglucosidase Alfa Administered Every Other Week in Pediatric Patients With Infantile-onset Pompe Disease Previously Treated With Alglucosidase Alfa
NCT06130228	PHASE2	UNKNOWN	Nutritional Therapy in Late-onset Pompe Disease
NCT00001331	Not specified	COMPLETED	Genetic and Family Studies of Inherited Muscle Diseases
NCT02385162	Not specified	WITHDRAWN	Biomarker for Glycogen Storage Diseases (BioGlycogen)
NCT06795152	Not specified	RECRUITING	Rare Glycogen Storage Diseases Natural History Study
NCT05095727	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study of mRNA-3745 in Adult and Pediatric Participants With Glycogen Storage Disease Type 1a (GSD1a)
NCT00001342	Not specified	COMPLETED	Study of Glycogen Storage Disease and Associated Disorders
NCT00566878	Not specified	COMPLETED	Pompe Lactation Sub-Registry
NCT01461304	Not specified	NO_LONGER_AVAILABLE	Compassionate Use of Triheptanoin (C7) for Inherited Disorders of Energy Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02057731	Not specified	COMPLETED	Study of Glycogen Storage Disease Expression in Carriers
NCT02176096	Not specified	COMPLETED	Comparison of the Effect of a Novel Starch (Glycosade) Versus Gastrostomy Tube-Dextrose Infusion on Overnight Euglycaemia Control in Children With Glycogen Storage Disease Type I: Open Label Demonstration Trial
NCT02318966	Not specified	COMPLETED	Glycosade v UCCS in the Dietary Management of Hepatic GSD
NCT02338817	Not specified	TERMINATED	Clinical Evaluation of a Non-Invasive Hypoglycemia Detector in a Glycogen Storage Disease Population
NCT03255213	Not specified	COMPLETED	Lingual Muscle Training in Late-Onset Pompe Disease (LOPD)
NCT03564561	Not specified	RECRUITING	Natural History of Pompe Disease
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04292938	Not specified	COMPLETED	McArdle Disease Treatment by Ketogenic Diet
NCT04399694	Not specified	COMPLETED	Identification and Characterization of Novel Non-Coding Variants That Contribute to Genetic Disorders
NCT04929002	Not specified	ACTIVE_NOT_RECRUITING	Carbon-13 Magnetic Resonance Spectroscopy in Glycogen Storage Diseases
NCT05199246	Not specified	COMPLETED	Assessment of Safety and Acute Effects of a Lower-limb Powered Dermoskeleton in Patients With Neuromuscular Disorders
NCT05200702	Not specified	COMPLETED	Assessment of Safety and Acute Effects of a Knee-hip Powered Soft Exoskeleton in Patients With Neuromuscular Disorders
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06396546	Not specified	RECRUITING	‘Glycogen Storage Diseases (GSDs) in Indian Children- Establishing an Indian GSD (I-GSD) Registry’
NCT06813443	Not specified	RECRUITING	Characterization of Patients With Cardiomyopathy to Identify Critical Patients Candidates for Cardiac Transplantation
NCT07136844	Not specified	RECRUITING	Gait Analysis Parameter and Upper Limb Evaluation in Adult Patients With Neurological or Metabolic Pathology
NCT07336394	Not specified	RECRUITING	Precision Diagnosis and Risk Stratification of Rare Cardiomyopathies Based on Novel Cardiac Magnetic Resonance Techniques
NCT07614139	Not specified	COMPLETED	Continuous Glucose Monitoring Alerts, Accuracy, and Patient Outcomes in Adults With Inherited Metabolic Disorders