HK2

Summary

HK2 (hexokinase 2, HGNC:4923) is a protein-coding gene on chromosome 2p12, encoding Hexokinase-2 (P52789). Catalyzes the phosphorylation of hexose, such as D-glucose and D-fructose, to hexose 6-phosphate (D-glucose 6-phosphate and D-fructose 6-phosphate, respectively).

Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. This gene encodes hexokinase 2, the predominant form found in skeletal muscle. It localizes to the outer membrane of mitochondria. Expression of this gene is insulin-responsive, and studies in rat suggest that it is involved in the increased rate of glycolysis seen in rapidly growing cancer cells.

Source: NCBI Gene 3099 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 175 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000189

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4923
Approved symbol	HK2
Name	hexokinase 2
Location	2p12
Locus type	gene with protein product
Status	Approved
Aliases	HKII
Ensembl gene	ENSG00000159399
Ensembl biotype	protein_coding
OMIM	601125
Entrez	3099

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000290573, ENST00000409174, ENST00000472302, ENST00000912519, ENST00000967919

RefSeq mRNA: 2 — MANE Select: NM_000189 NM_000189, NM_001371525

CCDS: CCDS1956, CCDS92787

Canonical transcript exons

ENST00000290573 — 18 exons

Exon	Start	End
ENSE00001072304	74889245	74889478
ENSE00001072308	74885494	74885589
ENSE00001072312	74834127	74834643
ENSE00001072314	74882120	74882239
ENSE00001072315	74877166	74877321
ENSE00001072316	74878688	74878921
ENSE00001072317	74886490	74886673
ENSE00001072318	74873276	74873371
ENSE00001072319	74867636	74867784
ENSE00001072320	74886294	74886393
ENSE00001072321	74881711	74881859
ENSE00001072325	74872300	74872419
ENSE00001177379	74880265	74880569
ENSE00001579786	74890797	74893359
ENSE00002433120	74873844	74873943
ENSE00002495817	74887903	74888058
ENSE00002533308	74874266	74874449
ENSE00003615600	74854293	74854455

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 97.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.4322 / max 239.8198, expressed in 1771 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21071	18.8150	1767
21072	2.6173	907

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	97.62	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.38	gold quality
colonic mucosa	UBERON:0000317	97.21	gold quality
body of tongue	UBERON:0011876	96.02	gold quality
cartilage tissue	UBERON:0002418	95.55	gold quality
esophagus squamous epithelium	UBERON:0006920	94.86	gold quality
pericardium	UBERON:0002407	94.85	gold quality
secondary oocyte	CL:0000655	94.79	gold quality
oocyte	CL:0000023	93.87	gold quality
tongue	UBERON:0001723	93.57	gold quality
epithelium of esophagus	UBERON:0001976	93.46	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.21	gold quality
mucosa of transverse colon	UBERON:0004991	92.89	gold quality
rectum	UBERON:0001052	92.74	gold quality
epididymis	UBERON:0001301	92.30	gold quality
lower esophagus mucosa	UBERON:0035834	92.28	gold quality
monocyte	CL:0000576	91.78	gold quality
mononuclear cell	CL:0000842	91.55	gold quality
squamous epithelium	UBERON:0006914	91.49	gold quality
pharyngeal mucosa	UBERON:0000355	91.44	gold quality
oviduct epithelium	UBERON:0004804	91.39	gold quality
leukocyte	CL:0000738	91.33	gold quality
biceps brachii	UBERON:0001507	91.15	gold quality
caput epididymis	UBERON:0004358	90.71	gold quality
tongue squamous epithelium	UBERON:0006919	90.36	gold quality
buccal mucosa cell	CL:0002336	90.31	gold quality
superior surface of tongue	UBERON:0007371	90.13	gold quality
penis	UBERON:0000989	90.10	gold quality
parotid gland	UBERON:0001831	89.88	gold quality
blood	UBERON:0000178	89.84	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-7	yes	779.00
E-ENAD-21	yes	578.16
E-GEOD-125970	yes	24.66
E-ANND-3	yes	10.59
E-MTAB-9801	yes	8.40

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

111 targeting HK2, 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-8485	100.00	77.57	4731
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4803	99.98	71.99	3117
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-7162-3P	99.89	68.16	1682

Literature-anchored findings (GeneRIF, showing 40)

• hypoxia-induced gene in pancreatic cancer cell lines (PMID:11688991)
• Both HIF-1 alpha and HK II protein expressions were co-localized in the cancer cells near necrosis, and the intensity of HIF-1 alpha protein expression was significantly correlated with HK II mRNA expression in both tumors. (PMID:14672622)
• SRE binding protein-1c is involved in the effect of insulin on HKII gene transcription. (PMID:14747281)
• Hexokinase II induction may participate in hepatocellular carcinoma progrssion and the blockage of this enzyme may therapeutically be efficacious. (PMID:15710218)
• Glut-1, HK-II, and PCNA expression are related to uptake of 18F-FDG uptake in lung cancer (PMID:15967114)
• cyclophilin D suppresses apoptotic cell death via a mitochondrial hexokinase II-dependent mechanism in cancer cells (PMID:16551620)
• HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2 and pyruvate dehydrogenase kinase 1. (PMID:17785433)
• hexokinase 2 contributes to the increased metabolism of glucose, especially in moderately and poorly differentiated Cholangiocellular carcinoma. (PMID:18271924)
• hexokinase II gene inhibits human colon cancer LoVo cell growth (PMID:18535403)
• The NR5A1 gene expression was activated in mesenchymal stem cells by siRNA directed against hexokinase 2. (PMID:18579725)
• targeting HK II may be beneficial for patients with colon cancer treated with 5-FU (PMID:18772588)
• PIM-1 and hK2 were expressed higher in prostate cancer than those in benign prostatic glandular hyperplasia and normal prostate tissues, the differences among which had statistic significance (P < 0.05). (PMID:19003546)
• neuroprotective effect of HKII may be relevant to neurodegenerative diseases in which glucose hypometabolism and mitochondrial dysfunction are prominent features (PMID:19033437)
• results point to HK-I and HK-II as promoting tumor cell survival through binding to VDAC1, thereby inhibiting cytochrome c release and apoptotic cell death. (PMID:19049977)
• The expression pattern of HK2 is reported in newly diagnosed esophageal neoplasms by means of immunohistochemistry. (PMID:19554504)
• each domain of HK II possesses enzyme activity, unlike HK I, with the N-terminal half showing higher enzyme activity than the C-terminal half. (PMID:19558793)
• Down-reg of HK2 gene of LoVo cells resulted decreased IC50 value of fluorouracil and increased apoptosis. Silencing HK2 of LoVo cells induced loss of mitochondrial membrane potential, activation of caspase-3,inhibition of thymidylate synthase expression. (PMID:19579598)
• HKII is the predominant isoform in rat hepatocarcinoma AS-30D and HeLa cells. (PMID:19681047)
• HK2 overexpression is associated with metastasis to the brain in breast cancer and it may be a therapeutic target (PMID:19723875)
• Disruption in the binding of hexokinase II to the mitochondria was to promote mitochondrial injury provoked by pro-apoptotic proteins. (PMID:19770592)
• Regulated translocation of HXKII to the nucleus of mammalian cells could represent a previously unknown glucose-sensing mechanism. (PMID:20346347)
• FimA strengthens the VDAC1-hexokinase (I and II) interaction and prevents dissociation of hexokinase from VDAC1 triggered by apoptotic stimuli. (PMID:20347420)
• Interleukin 6 enhances glycolysis through expression of the glycolytic enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3. (PMID:20453422)
• Overexpression of hexokinase-2 is associated with gastric adenocarcinoma. (PMID:20845004)
• The results suggested that there was a close association between expression of hOGG1, HK-2 and early cervical cancer. (PMID:20846459)
• 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)
• Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. (PMID:21242296)
• High hexokinase II is associated with hepatocellular carcinoma. (PMID:21279699)
• HK2 R844K GA/AA genotype was associated pancreatic cancer. (PMID:21411499)
• Data indicate that PSA, PSMA, hK2, PSCA, DD3, and their combinations, combined analysis of PSA and/or hK2 expression in pelvic lymph nodes could predict biochemical recurrence free survival (BRFS) following radical prostatectomy (RP). (PMID:21600799)
• proliferative states including the developing embryo and malignant gliomas, which rely on aerobic glycolysis, preferentially express the HK2 isoform (PMID:21726646)
• High Hexokinase II is associated with hepatoma. (PMID:21909686)
• Two genes, HK2 and CD28, emerged as potential culprits in diabetes-increased tuberculosis susceptibility. (PMID:22230325)
• PPARgamma contributes to PKM2 and HK2 expression in fatty liver (PMID:22334075)
• Via targeting C/EBPbeta (a transcriptional activator for mir-143), miR-155 represses mir-143, a negative regulator of hk2, thus resulting in upregulation of hk2 expression at the post-transcriptional level. (PMID:22354042)
• Overexpression of hexokinase 2 may be related to 2-deoxy-2-F18-fluoro-D-glucose uptake in false-positive cervical cancer tissues on PET/CT. (PMID:22398711)
• We demonstrate that miR143 inhibits HK2 expression both in primary keratinocytes and in head and neck squamous cell carcinoma (HNSCC)-derived cell lines. (PMID:22469988)
• We identified miR-143 as an essential regulator of cancer glycolysis via targeting HK2. (PMID:22593586)
• We have identified and validated HK2 as a miR-143 target. miR-143 mediated down-regulation of HK2 affects glucose metabolism in colon cancer cells. (PMID:22691140)
• The increased glucose consumption of many tumor cells depends to a large extent on the overexpression of HK-2, including giant cell tumor of bone. (PMID:22825642)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hk2	ENSDARG00000101482
mus_musculus	Hk2	ENSMUSG00000000628
rattus_norvegicus	Hk2	ENSRNOG00000006116

Paralogs (4): GCK (ENSG00000106633), HKDC1 (ENSG00000156510), HK1 (ENSG00000156515), HK3 (ENSG00000160883)

Protein

Protein identifiers

Hexokinase-2 — P52789 (reviewed: P52789)

Alternative names: Hexokinase type II, Hexokinase-B, Muscle form hexokinase

All UniProt accessions (2): P52789, E9PB90

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the phosphorylation of hexose, such as D-glucose and D-fructose, to hexose 6-phosphate (D-glucose 6-phosphate and D-fructose 6-phosphate, respectively). Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate. Plays a key role in maintaining the integrity of the outer mitochondrial membrane by preventing the release of apoptogenic molecules from the intermembrane space and subsequent apoptosis.

Subunit / interactions. Monomer. Interacts with TIGAR; the interaction increases hexokinase activity in a hypoxia- and HIF1A-dependent manner.

Subcellular location. Mitochondrion outer membrane. Cytoplasm. Cytosol.

Tissue specificity. Predominant hexokinase isozyme expressed in insulin-responsive tissues such as skeletal muscle.

Activity regulation. Hexokinase activity is specifically inhibited by 2,6-disubstituted glucosamines.

Domain organisation. The N- and C-terminal halves of the protein contain a hexokinase domain. In contrast to hexokinase-1 and -3 (HK1 and HK3, respectively), both hexokinase domains display catalytic activity. The region connecting the two hexokinase domains is required for the catalytic activity of the N-terminal hexokinase domain. The N-terminal half regulates stability of the whole enzyme.

Pathway. Carbohydrate metabolism; hexose metabolism. Carbohydrate degradation; glycolysis; D-glyceraldehyde 3-phosphate and glycerone phosphate from D-glucose: step 1/4.

Polymorphism. Although found in NIDDM patients, genetic variations of HK2 do not contribute to the disease.

Similarity. Belongs to the hexokinase family.

RefSeq proteins (2): NP_000180, NP_001358454 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001312	Hexokinase	Family
IPR019807	Hexokinase_BS	Binding_site
IPR022672	Hexokinase_N	Domain
IPR022673	Hexokinase_C	Domain
IPR043129	ATPase_NBD	Homologous_superfamily

Pfam: PF00349, PF03727

Enzyme classification (BRENDA):

• EC 2.7.1.1 — hexokinase (BRENDA: 77 organisms, 225 substrates, 336 inhibitors, 483 Km, 134 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ATP	—	184
D-GLUCOSE	0.003–45	112
D-FRUCTOSE	0.025–1510	46
D-MANNOSE	0.014–25.41	36
2-DEOXY-D-GLUCOSE	0.033–19.2	24
D-GLUCOSAMINE	0.06–2	12
UTP	0.288–30	7
ITP	1.9–16.6	6
CTP	0.52–5	5
GTP	0.231–0.788	4
N-ACETYL-D-GLUCOSAMINE	0.32–41.6	2
1,5-ANHYDRO-D-GLUCITOL	20	1
1-THIO-D-GLUCOSE	5	1
2-DEOXY-2-FLUORO-D-GLUCOSE	0.2	1
2-DEOXYGLUCOSE	18	1

Catalyzed reactions (Rhea), 3 shown:

• D-fructose + ATP = D-fructose 6-phosphate + ADP + H(+) (RHEA:16125)
• D-glucose + ATP = D-glucose 6-phosphate + ADP + H(+) (RHEA:17825)
• a D-hexose + ATP = a D-hexose 6-phosphate + ADP + H(+) (RHEA:22740)

UniProt features (135 total): helix 40, binding site 30, strand 28, sequence variant 13, turn 10, region of interest 5, mutagenesis site 3, domain 2, sequence conflict 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2NZT	X-RAY DIFFRACTION	2.45
5HEX	X-RAY DIFFRACTION	2.73
5HG1	X-RAY DIFFRACTION	2.76
5HFU	X-RAY DIFFRACTION	2.92

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P52789-F1	92.07	0.77

Functional residue map

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

Ligand- & substrate-binding residues (30): 84–88; 155–156; 172–173; 208–209; 209; 232; 235; 260; 291–294; 413–415; 425–426; 449 …

Post-translational modifications (1): 1

Mutagenesis-validated functional residues (3):

Position	Phenotype
209	decreased hexokinase activity.
468	induces a rapid dissociation of d-glucose.
657	decreased hexokinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-70171	Glycolysis

MSigDB gene sets: 490 (showing top): AHRARNT_01, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, HARRIS_HYPOXIA, GOBP_RESPONSE_TO_PEPTIDE, ATACCTC_MIR202, GOBP_NEGATIVE_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS, MENSE_HYPOXIA_UP, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, GOBP_MONOSACCHARIDE_CATABOLIC_PROCESS

GO Biological Process (24): response to hypoxia (GO:0001666), intracellular glucose homeostasis (GO:0001678), response to ischemia (GO:0002931), fructose 6-phosphate metabolic process (GO:0006002), glucose metabolic process (GO:0006006), glycolytic process (GO:0006096), lactation (GO:0007595), apoptotic mitochondrial changes (GO:0008637), negative regulation of mitochondrial membrane permeability (GO:0035795), positive regulation of angiogenesis (GO:0045766), regulation of D-glucose import across plasma membrane (GO:0046324), glucose 6-phosphate metabolic process (GO:0051156), canonical glycolysis (GO:0061621), obsolete establishment of protein localization to mitochondrion (GO:0072655), maintenance of protein location in mitochondrion (GO:0072656), positive regulation of type 2 mitophagy (GO:1905091), cellular response to leukemia inhibitory factor (GO:1990830), negative regulation of reactive oxygen species metabolic process (GO:2000378), carbohydrate metabolic process (GO:0005975), glucose catabolic process (GO:0006007), hexose metabolic process (GO:0019318), organophosphate metabolic process (GO:0019637), carbohydrate phosphorylation (GO:0046835), carbohydrate derivative metabolic process (GO:1901135)

GO Molecular Function (11): glucokinase activity (GO:0004340), hexokinase activity (GO:0004396), ATP binding (GO:0005524), D-glucose binding (GO:0005536), fructokinase activity (GO:0008865), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), phosphotransferase activity, alcohol group as acceptor (GO:0016773)

GO Cellular Component (7): mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), centrosome (GO:0005813), cytosol (GO:0005829), membrane (GO:0016020), sarcoplasmic reticulum (GO:0016529), 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	3
response to stress	2
organophosphate metabolic process	2
carbohydrate derivative metabolic process	2
hexokinase activity	2
transferase activity, transferring phosphorus-containing groups	2
cytoplasm	2
response to decreased oxygen levels	1
glucose homeostasis	1
intracellular chemical homeostasis	1
hexose metabolic 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
body fluid secretion	1
mammary gland development	1
milk ejection reflex	1
apoptotic process	1
mitochondrion organization	1
regulation of mitochondrial membrane permeability	1
negative regulation of membrane permeability	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
regulation of D-glucose transmembrane transport	1
D-glucose import across plasma membrane	1
glucokinase activity	1
glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity	1
glucose catabolic process	1
glycolytic process through glucose-6-phosphate	1

Protein interactions and networks

STRING

2426 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HK2	VDAC1	P21796	980
HK2	TIGAR	Q9NQ88	904
HK2	LDHA	P00338	828
HK2	PKM	P14618	818
HK2	SLC2A1	P11166	798
HK2	AKT1	P31749	768
HK2	PFKM	P08237	763
HK2	PDK1	Q15118	739
HK2	HIF1A	Q16665	729
HK2	PFKFB3	Q16875	722
HK2	PPIF	P30405	713
HK2	H6PD	O95479	709
HK2	TP53	P04637	706
HK2	SLC2A4	P14672	703
HK2	SLC2A3	P11169	692

IntAct

111 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
UBQLN1	HK2	psi-mi:“MI:0915”(physical association)	0.670
HK2	UBQLN1	psi-mi:“MI:0915”(physical association)	0.670
Src	HK2	psi-mi:“MI:0915”(physical association)	0.600
HK2	Src	psi-mi:“MI:0217”(phosphorylation reaction)	0.600
HK2	MAGEA12	psi-mi:“MI:0915”(physical association)	0.560
UBQLN1	HK2	psi-mi:“MI:0915”(physical association)	0.560
MAGEA12	HK2	psi-mi:“MI:0915”(physical association)	0.560
HK2	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
VDAC1	HK1	psi-mi:“MI:0914”(association)	0.560
TMA16	TNPO2	psi-mi:“MI:0914”(association)	0.530
HK3	HK1	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
HK3	HK2	psi-mi:“MI:0914”(association)	0.530
HK1	HK2	psi-mi:“MI:0914”(association)	0.530
TIGAR	HK2	psi-mi:“MI:0915”(physical association)	0.520
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
Tor1aip1	PEX10	psi-mi:“MI:0914”(association)	0.350
RAD18	SRGAP3	psi-mi:“MI:0914”(association)	0.350

BioGRID (171): MAGEA12 (Two-hybrid), UBQLN1 (Two-hybrid), UBQLN1 (Two-hybrid), CNBP (Co-fractionation), HK2 (Co-fractionation), HK2 (Co-fractionation), HK2 (Co-fractionation), HK2 (Co-fractionation), HK2 (Co-fractionation), HK2 (Co-fractionation), MARS (Co-fractionation), SEPT10 (Co-fractionation), SEPT6 (Co-fractionation), HK2 (Affinity Capture-MS), HK2 (Affinity Capture-MS)

ESM2 similar proteins: A0A072TK64, A0A072ULZ1, A0A6P8HC43, A2PYL6, A2PYL7, A2PYL8, A2XE45, A2XEA0, A2Y6J9, A5A3E0, B5DUH6, E9Q0N2, F4HWL4, F4JCB2, O04309, O08528, O24521, O95744, P0CG38, P0CG39, P25071, P27881, P28316, P29127, P35753, P37842, P52789, Q1W674, Q29428, Q6S8J3, Q70SU7, Q70SU8, Q75II4, Q84JE8, Q8L727, Q8LRK8, Q8RXK2, Q8VC49, Q90WJ7, Q93Y92

Diamond homologs: A0A0K0JFP3, A2PYL6, A2PYL7, A2PYL8, O08528, O64390, P04806, P04807, P05708, P17709, P17710, P17712, P19367, P27595, P27881, P27926, P33284, P35557, P50506, P52789, P52790, P52792, P80581, P83776, P93834, Q04409, Q09756, Q1W674, Q1WM15, Q1WM16, Q26609, Q2KNB4, Q2KNB5, Q2KNB7, Q2KNB9, Q2TB90, Q3TRM8, Q42525, Q56XE8, Q5RC71

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
BACH1	“up-regulates quantity”	HK2	“transcriptional regulation”
HK2	“up-regulates activity”	Glycolysis
AKT1	“up-regulates activity”	HK2	phosphorylation
AKT	“up-regulates activity”	HK2	phosphorylation
MYC	“up-regulates quantity”	HK2	“transcriptional regulation”
TRAF6	“down-regulates quantity”	HK2	ubiquitination
“Chaperone-mediated autophagy”	“down-regulates quantity by destabilization”	HK2
FLT3	“up-regulates activity”	HK2
glucose	“up-regulates quantity by stabilization”	HK2
HK2	“up-regulates quantity”	“alpha-D-glucose 6-phosphate(2-)”	“chemical modification”
HK2	“down-regulates quantity”	α-D-glucose	“chemical modification”
“HIF-1 complex”	“up-regulates quantity by expression”	HK2	“transcriptional regulation”
TP53	“down-regulates quantity by repression”	HK2	“transcriptional regulation”
SRC	“up-regulates activity”	HK2	phosphorylation
HK2	“down-regulates activity”	Cell_death

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	123
Likely benign	24
Benign	12

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

6081 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:74872390:T:C	F156L	1.000
2:74872392:C:A	F156L	1.000
2:74872392:C:G	F156L	1.000
2:74873291:T:A	W171R	1.000
2:74873291:T:C	W171R	1.000
2:74873299:G:C	K173N	1.000
2:74873299:G:T	K173N	1.000
2:74873877:G:C	D209H	1.000
2:74873878:A:C	D209A	1.000
2:74873878:A:G	D209G	1.000
2:74873878:A:T	D209V	1.000
2:74874285:C:G	C237W	1.000
2:74874355:T:A	W261R	1.000
2:74874355:T:C	W261R	1.000
2:74881735:A:C	D532A	1.000
2:74881735:A:T	D532V	1.000
2:74881738:T:C	L533P	1.000
2:74882199:T:C	F600S	1.000
2:74882210:T:C	F604L	1.000
2:74882212:C:A	F604L	1.000
2:74882212:C:G	F604L	1.000
2:74885509:T:A	W619R	1.000
2:74885509:T:C	W619R	1.000
2:74885511:G:C	W619C	1.000
2:74885511:G:T	W619C	1.000
2:74885516:A:T	K621I	1.000
2:74885517:A:C	K621N	1.000
2:74885517:A:T	K621N	1.000
2:74886327:G:C	D657H	1.000
2:74886328:A:C	D657A	1.000

dbSNP variants (sampled 300 via entrez): RS1000000977 (2:74845386 C>T), RS1000034228 (2:74892881 A>G), RS1000036793 (2:74888176 A>G,T), RS1000132043 (2:74870825 T>C), RS1000145026 (2:74888345 T>G), RS1000163078 (2:74851090 C>T), RS1000163582 (2:74840233 T>C), RS1000186392 (2:74850502 T>A), RS1000275973 (2:74846116 G>T), RS1000366219 (2:74856712 T>C), RS1000378963 (2:74834706 C>T), RS1000428695 (2:74855938 G>A,C,T), RS1000574755 (2:74867083 G>A), RS1000596651 (2:74883915 G>T), RS1000597212 (2:74861062 G>C)

Disease associations

OMIM: gene MIM:601125 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2640 (SINGLE PROTEIN), CHEMBL5465210 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 9,306 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1096979	BENSERAZIDE	3	9,306

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

ChEMBL bioactivities

31 potent at pChembl≥5 of 36 total, top 31 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.10	IC50	7.9	nM	CHEMBL3806103
8.00	IC50	10	nM	CHEMBL3805205
7.60	IC50	25	nM	CHEMBL3805905
7.60	IC50	25	nM	CHEMBL3804841
7.60	IC50	25	nM	CHEMBL3805653
7.40	IC50	40	nM	CHEMBL3806132
7.30	IC50	50	nM	CHEMBL3805734
7.30	IC50	50	nM	CHEMBL3806095
7.00	IC50	100	nM	CHEMBL3805148
7.00	IC50	100	nM	CHEMBL3805398
6.89	IC50	130	nM	CHEMBL3806069
6.89	IC50	130	nM	CHEMBL3804874
6.89	IC50	130	nM	CHEMBL3805459
6.70	IC50	200	nM	CHEMBL3805905
6.50	IC50	320	nM	CHEMBL3805598
6.33	IC50	470	nM	CHEMBL3805653
6.28	IC50	520	nM	CHEMBL3805459
6.20	IC50	630	nM	CHEMBL3806028
6.10	IC50	790	nM	CHEMBL3804930
6.10	IC50	790	nM	CHEMBL3805753
5.81	IC50	1560	nM	CHEMBL6145089
5.70	IC50	2000	nM	CHEMBL3805765
5.70	IC50	2000	nM	CHEMBL3806250
5.54	Ki	2900	nM	CHEMBL3805703
5.50	IC50	3200	nM	CHEMBL3805460
5.32	IC50	4800	nM	CHEMBL4474580
5.29	Kd	5120	nM	CHEMBL4466819
5.26	IC50	5520	nM	BENSERAZIDE
5.20	IC50	6300	nM	CHEMBL3805703
5.03	IC50	9360	nM	CHEMBL4466819
5.01	IC50	9800	nM	CHEMBL4447523

PubChem BioAssay actives

31 with measured affinity, of 94 total; 26 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
2,3-dichloro-N-[[(2R,3S,4R,5R)-5-[[3-(4-chlorophenyl)phenyl]sulfonylamino]-3,4,6-trihydroxyoxan-2-yl]methyl]benzenesulfonamide	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.0079	uM
5-[[(2R,3S,4R,5R)-5-[(3-bromobenzoyl)amino]-3,4,6-trihydroxyoxan-2-yl]methylsulfamoyl]-2-methylfuran-3-carboxylic acid	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.0100	uM
2,3-dichloro-N-[[(2R,3S,4R,5R)-3,4,6-trihydroxy-5-[(3-phenylphenyl)sulfonylamino]oxan-2-yl]methyl]benzenesulfonamide	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.0250	uM
N-[(3R,4R,5S,6R)-6-[[(2,3-dichlorophenyl)sulfonylamino]methyl]-2,4,5-trihydroxyoxan-3-yl]-3-phenylbenzamide	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.0250	uM
3-(4-cyanophenyl)-N-[(3R,4R,5S,6R)-6-[[(2,3-dichlorophenyl)sulfonylamino]methyl]-2,4,5-trihydroxyoxan-3-yl]-5-methoxybenzamide	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.0250	uM
5-chloro-N-[(3R,4R,5S,6R)-6-[[(2,3-dichlorophenyl)sulfonylamino]methyl]-2,4,5-trihydroxyoxan-3-yl]thiophene-2-carboxamide	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.0400	uM
2,3-dichloro-N-[[(2R,3S,4R,5R)-5-[(3,4-dichlorophenyl)sulfonylamino]-3,4,6-trihydroxyoxan-2-yl]methyl]benzenesulfonamide	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.0500	uM
3-[[(2R,3S,4R,5R)-3,4,6-trihydroxy-5-[(3-phenylbenzoyl)amino]oxan-2-yl]methylsulfamoyl]benzoic acid	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.0500	uM
N-[(3R,4R,5S,6R)-6-[[(4-chloro-3-pyridinyl)sulfonylamino]methyl]-2,4,5-trihydroxyoxan-3-yl]-3-phenylbenzamide	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.1000	uM
N-[(3R,4R,5S,6R)-6-[[(2-chlorophenyl)sulfonylamino]methyl]-2,4,5-trihydroxyoxan-3-yl]-3-phenylbenzamide	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.1000	uM
2,3-dichloro-N-[[(2R,3S,4R,5R)-3,4,6-trihydroxy-5-[(3-nitrophenyl)sulfonylamino]oxan-2-yl]methyl]benzenesulfonamide	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.1300	uM
5-chloro-N-[(3R,4R,5S,6R)-6-[[(2,3-dichlorophenyl)sulfonylamino]methyl]-2,4,5-trihydroxyoxan-3-yl]thiophene-2-sulfonamide	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.1300	uM
N-[(3R,4R,5S,6R)-6-[[(4-cyanophenyl)sulfonylamino]methyl]-2,4,5-trihydroxyoxan-3-yl]-3-phenylbenzamide	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.1300	uM
(E)-3-(3,4-dichlorophenyl)-N-[(2R,3R,4R,5S,6R)-2,4,5-trihydroxy-6-[[(4-methylphenyl)sulfonylamino]methyl]oxan-3-yl]prop-2-enamide	1167909: Inhibition of hexokinase 2 (unknown origin)	ic50	0.3162	uM
N-[(3R,4R,5S,6R)-6-[[(3-chlorophenyl)sulfonylamino]methyl]-2,4,5-trihydroxyoxan-3-yl]-3-phenylbenzamide	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.3200	uM
methyl 5-[[(2R,3S,4R,5R)-5-[(3-bromobenzoyl)amino]-3,4,6-trihydroxyoxan-2-yl]methylsulfamoyl]-2-methylfuran-3-carboxylate	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.6300	uM
3-(4-cyanophenyl)-5-(trifluoromethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]benzamide	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.7900	uM
N-[(3R,4R,5S,6R)-6-(benzenesulfonamidomethyl)-2,4,5-trihydroxyoxan-3-yl]-3-phenylbenzamide	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.7900	uM
(E)-3-(3,4-dichlorophenyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-[[(4-methylphenyl)sulfonylamino]methyl]oxan-3-yl]prop-2-enamide	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	2.0000	uM
3,5-dinitro-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]benzamide	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	2.0000	uM
(E)-3-(3,4-dichlorophenyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]prop-2-enamide	1299807: Competitive inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) assessed as formation of G6P by continuous G6P dehydrogenase coupled assay in presence of glucose	ki	2.9000	uM
3-phenyl-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]benzamide	1299802: Inhibition of His-tagged human HK2 (17 to 916 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	3.2000	uM
[(1R,5aS,6R,9aS)-1,5a-dimethyl-7-methylidene-3-oxo-6-[(E)-2-(5-oxo-2H-furan-4-yl)ethenyl]-4,5,6,8,9,9a-hexahydro-2H-benzo[c]azepin-1-yl]methyl (2R)-2-amino-3-phenylpropanoate	1551815: Inhibition of recombinant human HK2 expressed in Escherichia coli BL21(DE3) using glucose as substrate preincubated for 10 mins followed by substrate addition in presence of ATP by G6PDH/NADP coupled assay	ic50	4.8000	uM
[(1R,5aS,6R,9aS)-1,5a-dimethyl-7-methylidene-3-oxo-6-[(E)-2-(5-oxo-2H-furan-4-yl)ethenyl]-4,5,6,8,9,9a-hexahydro-2H-benzo[c]azepin-1-yl]methyl 5-[(3R)-dithiolan-3-yl]pentanoate	1551836: Binding affinity to recombinant human HK2 expressed in Escherichia coli BL21(DE3) assessed as dissociation constant measured after 15 mins by microscale thermophoresis assay	kd	5.1200	uM
2-amino-3-hydroxy-N’-[(2,3,4-trihydroxyphenyl)methyl]propanehydrazide	1525106: Inhibition of HK2 (unknown origin) using glucose-6-phosphate dehydrogenase as substrate preincubated for 10 mins followed by substrate addition	ic50	5.5200	uM
(6R)-6-hydroxy-3-methoxy-6-(2-oxopropyl)-2,5-diphenylcyclohexa-2,4-dien-1-one	1525106: Inhibition of HK2 (unknown origin) using glucose-6-phosphate dehydrogenase as substrate preincubated for 10 mins followed by substrate addition	ic50	9.8000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Oxygen	decreases reaction, increases activity, increases expression, affects expression, affects reaction	7
Valproic Acid	decreases reaction, increases expression, affects expression, decreases expression, increases methylation	6
sodium arsenite	affects reaction, increases expression, decreases reaction, affects cotreatment, increases abundance (+1 more)	5
3-methyladenine	increases abundance, increases expression, increases activity, decreases expression, increases reaction (+1 more)	5
Cadmium	affects reaction, decreases reaction, increases abundance, increases expression, affects cotreatment	5
Deoxyglucose	increases expression, affects localization, decreases expression, decreases activity, affects cotreatment (+2 more)	5
Estradiol	affects cotreatment, decreases expression, increases expression	5
bisphenol A	affects cotreatment, decreases expression, affects expression, increases expression	4
cobaltous chloride	decreases reaction, increases expression	4
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases reaction	4
Cadmium Chloride	decreases reaction, increases abundance, increases expression, affects cotreatment, affects reaction	4
trichostatin A	affects cotreatment, increases expression, decreases expression	3
nickel chloride	decreases reaction, increases expression	3
Arsenic	increases abundance, increases expression, affects cotreatment, decreases expression	3
Benzo(a)pyrene	increases methylation, affects expression, decreases expression	3
Doxorubicin	decreases reaction, increases expression, decreases expression	3
Formaldehyde	decreases reaction, increases expression, decreases expression	3
Quercetin	decreases expression, decreases reaction, increases expression, increases reaction	3
Silicon Dioxide	affects expression, decreases expression	3
Particulate Matter	affects expression, decreases expression, increases abundance, increases expression	3
methylmercuric chloride	decreases expression	2
arsenite	increases expression, affects binding, decreases reaction	2
potassium chromate(VI)	affects cotreatment, increases expression	2
epigallocatechin gallate	affects cotreatment, increases expression	2
chromium hexavalent ion	increases expression	2
4-phenylbutyric acid	increases expression, decreases reaction	2
dorsomorphin	decreases expression, increases reaction, affects cotreatment, increases expression	2
4,6-dimorpholino-N-(4-nitrophenyl)-1,3,5-triazin-2-amine	decreases expression, decreases reaction	2
Vorinostat	increases expression, decreases expression, affects cotreatment	2
Leflunomide	increases expression	2

ChEMBL screening assays

45 unique, capped per target: 45 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2166287	Binding	Activation of human hexokinase 2 at 500 times EC50 concentration	Discovery of (S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid as a hepatoselective glucokinase activator clinical candidate for treating type 2 diabetes mellitus. — J Med Chem

Cellosaurus cell lines

6 cell lines: 4 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1AZ	Abcam HEK293 HK2 KO	Transformed cell line	Female
CVCL_B1DQ	Abcam HCT 116 HK2 KO	Cancer cell line	Male
CVCL_C0Q7	143B-GFP-HK2	Cancer cell line	Female
CVCL_C0Q8	U2OS-GFP-HK2	Cancer cell line	Female
CVCL_D8ME	Ubigene HCT 116 HK2 KO	Cancer cell line	Male
CVCL_D9GA	Ubigene HEK293 HK2 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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