HK1

Summary

HK1 (hexokinase 1, HGNC:4922) is a protein-coding gene on chromosome 10q22.1, encoding Hexokinase-1 (P19367). Catalyzes the phosphorylation of various hexoses, such as D-glucose, D-glucosamine, D-fructose, D-mannose and 2-deoxy-D-glucose, to hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate, D-fructose 6-phosphate, D-mannose 6-phosphate and 2-deoxy-D-glucose 6-phospha….

Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. This gene encodes a ubiquitous form of hexokinase which localizes to the outer membrane of mitochondria. Mutations in this gene have been associated with hemolytic anemia due to hexokinase deficiency. Alternative splicing of this gene results in several transcript variants which encode different isoforms, some of which are tissue-specific.

Source: NCBI Gene 3098 — RefSeq curated summary.

At a glance

• Gene–disease (curated): non-spherocytic hemolytic anemia due to hexokinase deficiency (Strong, GenCC) — +4 more curated relationships
• Clinical variants (ClinVar): 855 total — 11 pathogenic, 22 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000188

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4922
Approved symbol	HK1
Name	hexokinase 1
Location	10q22.1
Locus type	gene with protein product
Status	Approved
Aliases	HKI
Ensembl gene	ENSG00000156515
Ensembl biotype	protein_coding
OMIM	142600
Entrez	3098

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 33 protein_coding, 6 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000298649, ENST00000359426, ENST00000421088, ENST00000436817, ENST00000450646, ENST00000464803, ENST00000470050, ENST00000476368, ENST00000479594, ENST00000480047, ENST00000483054, ENST00000483077, ENST00000488644, ENST00000493591, ENST00000494253, ENST00000643399, ENST00000703944, ENST00000703945, ENST00000703946, ENST00000703947, ENST00000703948, ENST00000703949, ENST00000703950, ENST00000703951, ENST00000703952, ENST00000703953, ENST00000703954, ENST00000703955, ENST00000703956, ENST00000703957, ENST00000904596, ENST00000904597, ENST00000904598, ENST00000904599, ENST00000904600, ENST00000934395, ENST00000934396, ENST00000934397, ENST00000970245, ENST00000970246, ENST00000970247, ENST00000970248, ENST00000970249

RefSeq mRNA: 10 — MANE Select: NM_000188 NM_000188, NM_001322364, NM_001322365, NM_001322366, NM_001322367, NM_001358263, NM_033496, NM_033497, NM_033498, NM_033500

CCDS: CCDS7289, CCDS7291, CCDS7292, CCDS91250

Canonical transcript exons

ENST00000359426 — 18 exons

Exon	Start	End
ENSE00001145266	69398595	69398828
ENSE00001145280	69392125	69392308
ENSE00001145304	69384333	69384481
ENSE00001276429	69386323	69386418
ENSE00001276961	69384796	69384915
ENSE00001460188	69318847	69319010
ENSE00001815320	69400991	69401882
ENSE00003280013	69389197	69389296
ENSE00003480607	69382487	69382791
ENSE00003603689	69394950	69395105
ENSE00003606261	69343827	69343989
ENSE00003628564	69369237	69369336
ENSE00003631817	69379862	69380095
ENSE00003664143	69368536	69368631
ENSE00003670975	69359897	69360045
ENSE00003688317	69364783	69364902
ENSE00003692285	69376934	69377089
ENSE00003788075	69369441	69369624

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 98.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 55.4243 / max 1269.5477, expressed in 1815 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
105344	48.7975	1813
105342	3.7515	116
105341	1.4252	92
205887	0.6326	330
105347	0.5670	318
105343	0.1242	78
105337	0.0880	3
105346	0.0168	7
105338	0.0115	3
105339	0.0084	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	98.79	gold quality
pharyngeal mucosa	UBERON:0000355	98.73	gold quality
pons	UBERON:0000988	98.68	gold quality
cardiac muscle of right atrium	UBERON:0003379	98.67	gold quality
body of tongue	UBERON:0011876	98.50	gold quality
dorsal root ganglion	UBERON:0000044	98.40	gold quality
parotid gland	UBERON:0001831	98.34	gold quality
sperm	CL:0000019	98.28	gold quality
left ventricle myocardium	UBERON:0006566	98.26	gold quality
superior vestibular nucleus	UBERON:0007227	98.23	gold quality
substantia nigra pars compacta	UBERON:0001965	98.22	gold quality
tongue	UBERON:0001723	98.17	gold quality
cardiac atrium	UBERON:0002081	98.09	gold quality
right atrium auricular region	UBERON:0006631	98.03	gold quality
parietal lobe	UBERON:0001872	97.97	gold quality
male germ cell	CL:0000015	97.89	gold quality
cervix squamous epithelium	UBERON:0006922	97.87	gold quality
nipple	UBERON:0002030	97.86	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.85	gold quality
postcentral gyrus	UBERON:0002581	97.84	gold quality
superior frontal gyrus	UBERON:0002661	97.83	gold quality
epithelium of esophagus	UBERON:0001976	97.82	gold quality
tongue squamous epithelium	UBERON:0006919	97.77	gold quality
esophagus squamous epithelium	UBERON:0006920	97.75	gold quality
squamous epithelium	UBERON:0006914	97.74	gold quality
gastrocnemius	UBERON:0001388	97.67	gold quality
superior surface of tongue	UBERON:0007371	97.62	gold quality
endothelial cell	CL:0000115	97.59	gold quality
esophagus mucosa	UBERON:0002469	97.54	gold quality
monocyte	CL:0000576	97.50	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	8.14
E-GEOD-137537	yes	4.74
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI2, HIF1A, KLF5, NCOR1, NR1H2, NR1H3

miRNA regulators (miRDB)

59 targeting HK1, 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-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-5689	99.50	71.26	1154
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4696	99.48	67.48	1040
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-150-3P	99.43	70.51	920
HSA-MIR-4284	99.36	65.25	1293

Literature-anchored findings (GeneRIF, showing 40)

• REVIEW: Gene expression and biological significance of HK1 and HKR isoforms of hexokinase in erythroid cells. (PMID:12432216)
• Glucose 6-phosphate binds to human brain hexokinase in mitochondria (PMID:16166083)
• The role of the HK1 interdomain alpha-helix at the interdomain signal transduction was studied. (PMID:17080299)
• Neither human hexokinase-1 nor human inorganic pyrophosphatase expression segregated concordantly with human cytoplasmic glutamic-oxaloacetic transaminase expression. (PMID:17494625)
• single nucleotide polymorphisms on gene involved with glucose metabolism and obesity may be associated with increased susceptibility to spina bifida (PMID:18212354)
• interference with the binding of Hexokinase-I to mitochondria by VDAC1-derived peptides may offer a novel strategy by which to potentiate the efficacy of conventional chemotherapeutic agents (PMID:18308720)
• This protein has been found differentially expressed in the temporal lobe from patients with schizophrenia. (PMID:19034380)
• 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)
• Glycated hemoglobin levels are associated with genetic variation of HK1. (PMID:19096518)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• The comprehensive sequencing analysis and fine mapping approximately 26 kb of fully characterised sequence spanning the upstream exons of Hexokinase 1 (HK1), is reported. (PMID:19536174)
• The expression pattern of HK1 is reported in newly diagnosed esophageal adenocarcinoma by means of immunohistochemistry. (PMID:19554504)
• reduced erythroid transcription of HK1 together with aberrant splicing of both hexokinase-1 and red cell specific-hexokinase results in hexokinase deficiency and mild chronic hemolysis. (PMID:19608687)
• HK1 may influence A1C levels through its anemic effect or its effect on glucose metabolism in erythrocytes, which may have implications for type 2 diabetes diagnosis and care. (PMID:19651813)
• FimA strengthens the VDAC1-hexokinase(I and II) interaction and prevents dissociation of hexokinase from VDAC1 triggered by apoptotic stimuli. (PMID:20347420)
• Abeta-induced cellular redistribution and inactivation of neuronal HKI play important roles in oxidative stress and neurodegeneration in Alzheimer’s disease (PMID:21179577)
• An association is noted between the rs7072268 T-allele in HK1 and an increased blood glucose in non-diabetic individuals and a nominal association with type 2 diabetes prior to Bonferroni correction. (PMID:21781351)
• This study proposed that HK1 mitochondrial detachment could be linked to these disorders through impaired energy metabolism, increased vulnerability to oxidative stress, and impaired brain growth and development. (PMID:22018957)
• Data indicate that the most frequent form is SH3TC2 gene (CMT4C; 57.14%), followed by HK1 gene causative of CMT4G (CMT4G/HMSN-Russe 25%) and NDRG1 p.R148X in CMT type 4D (CMT4D/HMSN-Lom; 17.86%). (PMID:22978647)
• The screening for novel Parkin substrate(s) identified mitochondrial hexokinase I (HKI) as a candidate. (PMID:23068103)
• A key K8/K18 regulation of glucose metabolism in normal and cancerous hepatic cells through differential modulations of mitochondrial hexokinase status and insulin-mediated signaling. (PMID:23164509)
• A genetic association of myelomeningocele in Chile found polymorphisms for HK1. (PMID:23427181)
• Dominant, diazoxide-responsive HI in this family maps to a novel locus on Chr10q21-22. Disease-associated variants were found in non-coding regions of HK1 (PMID:23859901)
• We detected mutation in the NDRG1 gene in two families and mutation in the HK1 gene in the other two families. These mutations cause Charcot-Marie-Tooth Disease, Type 4D and Charcot-Marie-Tooth disease, type 4g, respectively. (PMID:23996628)
• Hexokinase 1 (HK1) is a mitochondrial protein that controls the tramsmembrane potential and blocks apoptotic signals at the mitochondria. (PMID:24018046)
• An increased ratio of HK1 protein in the extrasynaptic membrane/mitochondrial fraction of prefronal cortex was found in subjects with schizophrenia, suggesting that HK1 protein is abnormally partitioned in this illness (PMID:24560881)
• HK1 is expressed in retina, with two abundant isoforms expressed at similar levels. The Glu847Lys mutation is located at a highly conserved position in the protein, outside the catalytic domains. (PMID:25190649)
• Here, we identified HK1 as a novel causative gene for adRP. This is the first report that associates the glucose metabolic pathway with human retinal degenerative disease, suggesting a potential new disease mechanism. (PMID:25316723)
• The present study was designed to evaluate the involvement of hexokinase and CPT-1 in the cell growth and proliferation of human prostate cancer cell lines, PC3, and LNCaP-FGC-10. (PMID:25501281)
• HK-1 plays a non-metabolic role in HIV-1 infected macrophages by binding to mitochondria thereby maintaining mitochondrial integrity. (PMID:25602755)
• The transport of glucose across the cell membrane by glucose transporters (GLUTs) and intracellular phosphorylation by hexokinases (HKs) are the initial steps of the glycolytic pathway. (PMID:25766729)
• HK1 expression is highly enriched in neurons compared to astrocytes in the cerebral cortex. (PMID:25904018)
• Data indicate a missense mutation in hexokinase 1 (HK1) c.2539G > A, p.Glu847Lys, tracking with disease in all affected family members. (PMID:26427411)
• Our results suggest that overexpression of PKM2 and HK1, especially the latter, significantly associates with lymphatic metastasis, advanced clinical staging and unfavorable prognosis in gastric cancer. (PMID:26464675)
• Data suggest that overexpression of hexokinase 1 (HK1) may act as a significant biomarker of poor prognosis for patients with colorectal cancer (CRC). (PMID:26476538)
• Russe type hereditary motor and sensory neuropathy belongs to the most frequent types of hereditary neuropathy in the Czech Republic, which affects Roma and is caused by a HK1 mutation. (PMID:26822750)
• HK1 and HK2 expression alterations were detected, that could be explained by common deregulation mechanisms of these genes in colorectal tumors. The HK3 expression level was significantly increased in 60% of samples. (PMID:26855992)
• STAT3 expression is upregulated in both HBV- and HCV-related hepatocellular carcinoma (HCC), while hexokinase II (HK-II) is predominantly upregulated and correlated to STAT3 in HBV-related HCC (PMID:26889748)
• 4-hydroxytamoxifen resistance in breast cancer cells is suppressed by curcumin, which targets the SLUG/Hexokinase 2 pathway (PMID:27012210)
• The pathogenic nature of the identified missense mutations was confirmed by biochemical and 3-dimensional structural analysis. The effects of the novel splice site mutation c.873-2A>G were studied at the level of pre-mRNA processing, and confirmed at the protein level. Four of the 6 mutations studied were new. (PMID:27282571)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hk1	ENSDARG00000039452
mus_musculus	Hk1	ENSMUSG00000037012
rattus_norvegicus	Hk1	ENSRNOG00000046891

Paralogs (4): GCK (ENSG00000106633), HKDC1 (ENSG00000156510), HK2 (ENSG00000159399), HK3 (ENSG00000160883)

Protein

Protein identifiers

Hexokinase-1 — P19367 (reviewed: P19367)

Alternative names: Brain form hexokinase, Hexokinase type I, Hexokinase-A

All UniProt accessions (20): P19367, A0A2R8Y626, A0A2R8Y7T9, A0A2R8YEE7, A0A994J428, A0A994J432, A0A994J495, A0A994J499, A0A994J4A4, A0A994J4P6, A0A994J4Q0, A0A994J4Q4, A0A994J6Q7, A0A994J6R1, A0A994J6R6, A0A994J753, A0A994J758, A0A994J761, B1AR62, P78542

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the phosphorylation of various hexoses, such as D-glucose, D-glucosamine, D-fructose, D-mannose and 2-deoxy-D-glucose, to hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate, D-fructose 6-phosphate, D-mannose 6-phosphate and 2-deoxy-D-glucose 6-phosphate, respectively). Does not phosphorylate N-acetyl-D-glucosamine. Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate. Involved in innate immunity and inflammation by acting as a pattern recognition receptor for bacterial peptidoglycan. When released in the cytosol, N-acetyl-D-glucosamine component of bacterial peptidoglycan inhibits the hexokinase activity of HK1 and causes its dissociation from mitochondrial outer membrane, thereby activating the NLRP3 inflammasome.

Subunit / interactions. Monomer. Interacts with RABL2/RABL2A; binds preferentially to GTP-bound RABL2. Interacts with VDAC1. The HK1-VDAC1 complex interacts with ATF2. Interacts (via N-terminal spermatogenic cell-specific region) with PFKM (via C-terminus). Interacts with SMAD5.

Subcellular location. Mitochondrion outer membrane. Cytoplasm. Cytosol.

Tissue specificity. Isoform 2: Erythrocyte specific (Ref.6). Isoform 3: Testis-specific. Isoform 4: Testis-specific.

Disease relevance. Anemia, congenital, non-spherocytic hemolytic, 5 (CNSHA5) [MIM:235700] An autosomal recessive disorder characterized by hemolytic anemia as the predominant clinical feature, and decreased red cell hexokinase activity. The disease is caused by variants affecting the gene represented in this entry. Neuropathy, hereditary motor and sensory, Russe type (HMSNR) [MIM:605285] An autosomal recessive progressive complex peripheral neuropathy characterized by onset in the first decade of distal lower limb weakness and muscle atrophy resulting in walking difficulties. Distal impairment of the upper limbs usually occurs later, as does proximal lower limb weakness. There is distal sensory impairment, with pes cavus and areflexia. Laboratory studies suggest that it is a myelinopathy resulting in reduced nerve conduction velocities in the demyelinating range as well as a length-dependent axonopathy. The disease is caused by variants affecting the gene represented in this entry. Retinitis pigmentosa 79 (RP79) [MIM:617460] A form of retinitis pigmentosa, a retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. RP79 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry. Neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA) [MIM:618547] A disorder characterized by global developmental delay, speech delay, intellectual disability, structural brain abnormalities, and visual impairments including retinitis pigmentosa and optic atrophy. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Hexokinase is an allosteric enzyme inhibited by its product D-glucose 6-phosphate. Hexokinase activity is inhibited by N-acetyl-D-glucosamine.

Domain organisation. The N- and C-terminal halves of this hexokinase contain a hexokinase domain. The catalytic activity is associated with the C-terminus while regulatory function is associated with the N-terminus. Each domain can bind a single D-glucose and D-glucose 6-phosphate molecule.

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

Similarity. Belongs to the hexokinase family.

Isoforms (4)

UniProt ID	Names	Canonical?
P19367-1	1, Common	yes
P19367-2	2, Erythrocyte, R
P19367-3	3, TA, TB
P19367-4	4, TD

RefSeq proteins (10): NP_000179, NP_001309293, NP_001309294, NP_001309295, NP_001309296, NP_001345192, NP_277031, NP_277032, NP_277033, NP_277035 (=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), 5 shown:

• D-glucosamine + ATP = D-glucosamine 6-phosphate + ADP + H(+) (RHEA:10948)
• D-mannose + ATP = D-mannose 6-phosphate + ADP + H(+) (RHEA:11028)
• 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 (126 total): helix 37, binding site 31, strand 24, turn 11, sequence variant 9, region of interest 5, splice variant 3, domain 2, modified residue 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
1CZA	X-RAY DIFFRACTION	1.9
1QHA	X-RAY DIFFRACTION	2.25
4FOI	X-RAY DIFFRACTION	2.4
4FPA	X-RAY DIFFRACTION	2.48
4F9O	X-RAY DIFFRACTION	2.65
4FOE	X-RAY DIFFRACTION	2.7
1DGK	X-RAY DIFFRACTION	2.8
1HKB	X-RAY DIFFRACTION	2.8
1HKC	X-RAY DIFFRACTION	2.8
4FPB	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P19367-F1	94.68	0.89

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 (31): 84–89; 155; 172–173; 208–209; 209; 232; 235; 260; 291–294; 345; 413–415; 425–426 …

Post-translational modifications (2): 1, 337

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-446205	Synthesis of GDP-mannose
R-HSA-5619056	Defective HK1 causes hexokinase deficiency (HK deficiency)
R-HSA-70171	Glycolysis

MSigDB gene sets: 519 (showing top): GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, HARRIS_HYPOXIA, GOBP_INFLAMMATORY_RESPONSE, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION_INVOLVED_IN_IMMUNE_RESPONSE, GOZGIT_ESR1_TARGETS_DN, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, GOBP_MONOSACCHARIDE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_PHOSPHORYLATION, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, KEGG_GLYCOLYSIS_GLUCONEOGENESIS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS

GO Biological Process (21): intracellular glucose homeostasis (GO:0001678), positive regulation of cytokine production involved in immune response (GO:0002720), fructose 6-phosphate metabolic process (GO:0006002), glucose metabolic process (GO:0006006), mannose metabolic process (GO:0006013), glycolytic process (GO:0006096), inflammatory response (GO:0006954), GDP-mannose biosynthetic process (GO:0009298), positive regulation of interleukin-1 beta production (GO:0032731), innate immune response (GO:0045087), carbohydrate phosphorylation (GO:0046835), glucose 6-phosphate metabolic process (GO:0051156), canonical glycolysis (GO:0061621), obsolete GDP-mannose biosynthetic process from mannose (GO:0061728), obsolete establishment of protein localization to mitochondrion (GO:0072655), maintenance of protein location in mitochondrion (GO:0072656), immune system process (GO:0002376), carbohydrate metabolic process (GO:0005975), hexose metabolic process (GO:0019318), organophosphate metabolic process (GO:0019637), carbohydrate derivative metabolic process (GO:1901135)

GO Molecular Function (14): glucokinase activity (GO:0004340), hexokinase activity (GO:0004396), ATP binding (GO:0005524), D-glucose binding (GO:0005536), fructokinase activity (GO:0008865), mannokinase activity (GO:0019158), peptidoglycan binding (GO:0042834), glucosamine kinase activity (GO:0047931), 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), cytosol (GO:0005829), membrane raft (GO:0045121), cytoplasm (GO:0005737), membrane (GO:0016020), mitochondrial membrane (GO:0031966)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Synthesis of substrates in N-glycan biosythesis	1
SLC transporter disorders	1
Glucose metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
hexokinase activity	3
cellular anatomical structure	3
organophosphate metabolic process	2
carbohydrate derivative metabolic process	2
hexose metabolic process	2
mitochondrion	2
phosphotransferase activity, alcohol group as acceptor	2
transferase activity, transferring phosphorus-containing groups	2
cytoplasm	2
glucose homeostasis	1
intracellular chemical homeostasis	1
positive regulation of cytokine production	1
cytokine production involved in immune response	1
positive regulation of production of molecular mediator of immune response	1
regulation of cytokine production involved in immune response	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
defense response	1
phosphomannomutase activity	1
nucleotide-sugar biosynthetic process	1
GDP-mannose metabolic process	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
positive regulation of interleukin-1 production	1
immune response	1
defense response to symbiont	1
carbohydrate metabolic process	1
phosphorylation	1
glucokinase activity	1

Protein interactions and networks

STRING

1908 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HK1	VDAC1	P21796	984
HK1	PFKP	Q01813	948
HK1	PFKM	P08237	887
HK1	TPI1	P00938	757
HK1	PFKL	P17858	753
HK1	SLC2A3	P11169	730
HK1	PKM	P14618	692
HK1	GAPDH	P00354	688
HK1	ALDOA	P04075	685
HK1	LDHA	P00338	682
HK1	J3KPS3	J3KPS3	670
HK1	GPI	P06744	664
HK1	KRAS	P01116	655
HK1	SMAD5	Q99717	646
HK1	H6PD	O95479	644

IntAct

118 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
IFT27	IFT56	psi-mi:“MI:0914”(association)	0.690
Src	HK1	psi-mi:“MI:0915”(physical association)	0.640
Src	HK1	psi-mi:“MI:0403”(colocalization)	0.640
Src	HK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.640
Src	HK1	psi-mi:“MI:0914”(association)	0.640
ATF2	HK1	psi-mi:“MI:0915”(physical association)	0.580
HK1	ATF2	psi-mi:“MI:0915”(physical association)	0.580
VDAC1	HK1	psi-mi:“MI:0914”(association)	0.560
HK1	VDAC1	psi-mi:“MI:0915”(physical association)	0.560
HK1	HK1	psi-mi:“MI:0915”(physical association)	0.540
TUBB3	POTEF	psi-mi:“MI:0914”(association)	0.530
HK3	HK1	psi-mi:“MI:0914”(association)	0.530
HK1	HK2	psi-mi:“MI:0914”(association)	0.530
SUN2	PIP	psi-mi:“MI:0914”(association)	0.530
SRC	HK1	psi-mi:“MI:0915”(physical association)	0.520
HK1	CFTR	psi-mi:“MI:0915”(physical association)	0.520
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
HK1	BRAF	psi-mi:“MI:2364”(proximity)	0.470
BRAF	HK1	psi-mi:“MI:0915”(physical association)	0.470
	HK1	psi-mi:“MI:0407”(direct interaction)	0.440
EEF1A1	HK1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (272): ASPDH (Co-fractionation), HK1 (Co-fractionation), HK1 (Affinity Capture-MS), HK1 (Reconstituted Complex), HK1 (Proximity Label-MS), HK1 (Proximity Label-MS), HK1 (Proximity Label-MS), HK1 (Affinity Capture-MS), HK1 (Affinity Capture-MS), HKDC1 (Affinity Capture-MS), HK2 (Affinity Capture-MS), CAV1 (Affinity Capture-MS), SNCA (Affinity Capture-MS), ASPSCR1 (Affinity Capture-MS), HK1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0K0JFP3, A2PYL6, A2PYL7, A2PYL8, O08528, O64390, P05708, P17710, P17712, P19367, P27595, P27881, P27926, P33284, P35557, P50506, P50521, P52789, P52790, P52792, P80581, P83776, P93834, Q04409, Q09756, Q1W674, Q1WM15, Q1WM16, Q26609, Q2KNB4, Q2KNB7, Q2KNB9, Q2TB90, Q3TRM8, Q42525, Q5RC71, Q5W676, Q69TF4, Q6CUZ3, Q6Q8A5

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

11 interactions.

A	Effect	B	Mechanism
AKT	up-regulates	HK1	binding
AKT1	up-regulates	HK1	binding
HK1	“up-regulates quantity”	“alpha-D-glucose 6-phosphate(2-)”	“chemical modification”
HK1	“down-regulates quantity”	α-D-glucose	“chemical modification”
“HIF-1 complex”	“up-regulates quantity by expression”	HK1	“transcriptional regulation”
ULK1	“up-regulates activity”	HK1	phosphorylation
ULK2	“up-regulates activity”	HK1	phosphorylation
SRC	“up-regulates activity”	HK1	phosphorylation
SRC	“down-regulates activity”	HK1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 112 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
PINK1-PRKN Mediated Mitophagy	5	21.2×	1e-03
FLT3 Signaling	5	20.6×	1e-03
Signaling by BRAF and RAF1 fusions	5	10.2×	8e-03
Mitochondrial protein import	5	10.0×	8e-03
VEGFA-VEGFR2 Pathway	5	8.3×	8e-03
ESR-mediated signaling	5	7.6×	1e-02
Signaling by Receptor Tyrosine Kinases	8	4.9×	8e-03
Cell Cycle	9	3.9×	1e-02

GO biological processes:

GO term	Partners	Fold	FDR
obsolete protein targeting to mitochondrion	5	29.9×	4e-04
epidermal growth factor receptor signaling pathway	5	12.8×	7e-03
MAPK cascade	6	9.5×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	22
Uncertain significance	427
Likely benign	297
Benign	31

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1417253	NM_000188.3(HK1):c.1907_1910del (p.Thr635_Leu636insTer)	Pathogenic
1442714	NM_000188.3(HK1):c.2380C>T (p.Arg794Ter)	Pathogenic
14915	NM_000188.3(HK1):c.497_591+1del	Pathogenic
14916	NM_000188.3(HK1):c.1586T>C (p.Leu529Ser)	Pathogenic
2038014	NM_000188.3(HK1):c.267del (p.Arg91fs)	Pathogenic
2115913	NM_000188.3(HK1):c.442_473dup (p.Gln159fs)	Pathogenic
2664015	NM_000188.3(HK1):c.991C>T (p.Arg331Ter)	Pathogenic
3608703	NM_000188.3(HK1):c.919C>T (p.Arg307Ter)	Pathogenic
4766093	NM_000188.3(HK1):c.2305C>T (p.Arg769Ter)	Pathogenic
55851	NM_000188.3(HK1):c.2039C>G (p.Thr680Ser)	Pathogenic
855341	NM_000188.3(HK1):c.1456del (p.Glu486fs)	Pathogenic
1320105	NM_000188.3(HK1):c.796G>A (p.Asp266Asn)	Likely pathogenic
1465743	NM_000188.3(HK1):c.1240G>C (p.Gly414Arg)	Likely pathogenic
1685345	NM_001358263.1(HK1):c.1A>T (p.Met1Leu)	Likely pathogenic
2024756	NM_000188.3(HK1):c.226+2T>A	Likely pathogenic
2105231	NM_000188.3(HK1):c.691+1G>A	Likely pathogenic
2422554	NC_000010.10:g.(?71103563)(71103765_?)dup	Likely pathogenic
2506469	NM_000188.3(HK1):c.1370C>A (p.Thr457Lys)	Likely pathogenic
2581721	NM_000188.3(HK1):c.613del (p.Ala205fs)	Likely pathogenic
3028181	NM_000188.3(HK1):c.409T>A (p.Phe137Ile)	Likely pathogenic
3544385	NM_000188.3(HK1):c.1370C>G (p.Thr457Arg)	Likely pathogenic
4057299	NM_001358263.1(HK1):c.2T>C (p.Met1Thr)	Likely pathogenic
4081443	NM_000188.3(HK1):c.891dup (p.Ser298fs)	Likely pathogenic
4532805	Single allele	Likely pathogenic
4687917	NM_000188.3(HK1):c.1542del (p.Phe515fs)	Likely pathogenic
4718497	NM_000188.3(HK1):c.876-2A>T	Likely pathogenic
4755525	NM_000188.3(HK1):c.2354A>T (p.Lys785Met)	Likely pathogenic
4823068	NM_000188.3(HK1):c.226+4919T>G	Likely pathogenic
4845902	NM_000188.3(HK1):c.1114C>T (p.Gln372Ter)	Likely pathogenic
599646	NM_000188.3(HK1):c.1252A>G (p.Lys418Glu)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

6065 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:69368551:T:A	W171R	1.000
10:69368551:T:C	W171R	1.000
10:69369271:A:T	D209V	1.000
10:69369460:C:G	C237W	1.000
10:69369530:T:A	W261R	1.000
10:69369530:T:C	W261R	1.000
10:69379963:T:A	V378D	1.000
10:69380059:T:A	V410D	1.000
10:69380071:G:A	G414E	1.000
10:69384354:T:C	L531P	1.000
10:69384357:A:C	D532A	1.000
10:69384357:A:G	D532G	1.000
10:69384357:A:T	D532V	1.000
10:69384360:T:C	L533P	1.000
10:69384362:G:A	G534R	1.000
10:69384362:G:C	G534R	1.000
10:69384363:G:A	G534E	1.000
10:69384363:G:T	G534V	1.000
10:69384365:G:A	G535R	1.000
10:69384365:G:C	G535R	1.000
10:69384366:G:A	G535E	1.000
10:69384384:T:C	L541P	1.000
10:69384829:T:C	F585L	1.000
10:69384831:C:A	F585L	1.000
10:69384831:C:G	F585L	1.000
10:69384875:T:C	F600S	1.000
10:69384886:T:C	F604L	1.000
10:69384888:T:A	F604L	1.000
10:69384888:T:G	F604L	1.000
10:69386338:T:A	W619R	1.000

dbSNP variants (sampled 300 via entrez): RS1000033416 (10:69379408 C>A), RS1000036258 (10:69294919 C>A), RS1000039806 (10:69398948 T>C), RS1000060891 (10:69377249 C>G,T), RS1000071293 (10:69301528 C>T), RS1000073547 (10:69307549 G>A), RS1000150698 (10:69401343 A>C), RS1000183541 (10:69299863 T>C), RS1000238863 (10:69391619 G>A), RS1000253414 (10:69373668 G>A), RS1000255145 (10:69326994 T>C), RS1000261853 (10:69343773 C>T), RS1000262243 (10:69268212 G>T), RS1000294556 (10:69343627 G>A,T), RS1000301933 (10:69305485 A>G)

Disease associations

OMIM: gene MIM:142600 | disease phenotypes: MIM:605285, MIM:618547, MIM:235700, MIM:617460, MIM:268000

GenCC curated gene-disease

Disease	Classification	Inheritance
non-spherocytic hemolytic anemia due to hexokinase deficiency	Strong	Autosomal recessive
Charcot-Marie-Tooth disease type 4G	Strong	Autosomal recessive
retinitis pigmentosa 79	Strong	Autosomal dominant
neurodevelopmental disorder with visual defects and brain anomalies	Strong	Autosomal dominant
hyperinsulinism	Strong	Autosomal dominant

Mondo (9): Charcot-Marie-Tooth disease type 4G (MONDO:0011534), neurodevelopmental disorder with visual defects and brain anomalies (MONDO:0032807), inherited retinal dystrophy (MONDO:0019118), non-spherocytic hemolytic anemia due to hexokinase deficiency (MONDO:0009340), retinitis pigmentosa 79 (MONDO:0044320), neurodevelopmental disorder (MONDO:0700092), retinitis pigmentosa (MONDO:0019200), autism spectrum disorder (MONDO:0005258), hyperinsulinism (MONDO:0002177)

Orphanet (5): Charcot-Marie-Tooth disease type 4G (Orphanet:99953), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Non-spherocytic hemolytic anemia due to hexokinase deficiency (Orphanet:90031), Retinitis pigmentosa (Orphanet:791), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000556	Retinal dystrophy

GWAS associations

0 associations (top):

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D006946	Hyperinsulinism	C18.452.394.968
D065886	Neurodevelopmental Disorders	F03.625
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C562995	Hexokinase Deficiency Hemolytic Anemia (supp.)
C535813	Neuropathy, hereditary motor and sensory, Russe type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2688 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 13,237 (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
CHEMBL51085	EBSELEN	3	13,237

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

Binding affinities (BindingDB)

79 measured of 92 human assays (101 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
cid_3005734	EC50	615 nM
(phenylmethyl) N-(1-pyridin-2-ylethylideneamino)carbamodithioate	EC50	1610 nM
MLS001002736	IC50	1610 nM
3-[[phenyl(pyridin-2-yl)methylidene]amino]-1,1-bis(pyridin-2-ylmethyl)thiourea	EC50	1780 nM
N-[1-(1,3-thiazol-2-yl)ethylideneamino]-3-azabicyclo[3.2.2]nonane-3-carbothioamide	EC50	1830 nM
MLS000565792	EC50	1980 nM
N’-[1-(1-isoquinolinyl)ethyl]-4-(2-pyridinyl)-1-piperazinecarbothiohydrazide	EC50	2190 nM
SMR000294066	EC50	2200 nM
MLS000769398	EC50	2230 nM
MLS002702209	EC50	2270 nM
3-chloranyl-N-(3,3-dimethylbutan-2-yl)-6-nitro-1-benzothiophene-2-carboxamide	EC50	2470 nM
1-(2-methoxyphenyl)-3-[1-(2-pyridinyl)ethylideneamino]thiourea	EC50	3030 nM
(4E)-5-methyl-2-phenyl-4-[[(5-phenyl-1,2,4-triazin-3-yl)hydrazo]methylidene]-3-pyrazolone	IC50	3500 nM
N-[[[[3-(4-methoxyphenyl)-1H-pyrazol-5-yl]-oxomethyl]hydrazo]-sulfanylidenemethyl]-5-methyl-3-phenyl-4-isoxazolecarboxamide	EC50	3620 nM
cid_11958865	IC50	5460 nM
4-bromo-N-[[(5-methyl-3-phenyl-1,2-oxazole-4-carbonyl)amino]carbamothioyl]benzamide	EC50	6580 nM
1-(1,3-diphenylpropan-2-ylideneamino)-3-[4-(4-morpholinylsulfonyl)phenyl]thiourea	EC50	7650 nM
SMR001565418	IC50	7770 nM
cid_5130254	EC50	8140 nM
SMR000048155	EC50	8740 nM
MLS002477170	EC50	9100 nM
MLS000772545	EC50	10000 nM
MLS001195521	IC50	10100 nM
3-[[5-(4-ethylphenyl)-6H-1,3,4-thiadiazin-2-yl]amino]-N,N-dimethylbenzenesulfonamide	EC50	10300 nM
SMR000219116	EC50	11500 nM
N-(2-piperazin-1-yl-1,2-dihydroacenaphthylen-1-yl)benzenesulfonamide	EC50	11700 nM
SMR000556071	IC50	12900 nM
Pentanoic acid [(4-diethylamino-phenyl)-(8-hydroxy-quinolin-7-yl)-methyl]-amide	EC50	13300 nM
MLS002702391	EC50	13300 nM
MLS002701915	EC50	14200 nM
4-chloranyl-N-(5-chloranylpyridin-2-yl)-1,2,3-dithiazol-5-imine	IC50	14300 nM
4-fluoro-N-{[2-(2-pyrazinylcarbonyl)hydrazino]carbonothioyl}benzamide	EC50	14500 nM
N-[1-(6-methylpyridin-2-yl)ethylideneamino]piperidine-1-carbothioamide	EC50	14500 nM
3-[1-methyl-5-[(1-methyl-5-pyridin-3-yl-pyrrol-2-yl)disulfanyl]pyrrol-2-yl]pyridine	EC50	14800 nM
SMR000253852	EC50	15000 nM
(4-chloro-2,5-dimethoxy-phenyl)-(4-chlorodithiazol-5-ylidene)amine	IC50	15200 nM
1-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxoethyl]-8-methyl-4-[1]benzopyrano[4,3-c]pyrazolone	EC50	16000 nM
cid_3032310	EC50	18000 nM
N-{2-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-acenaphthen-1-yl}-benzenesulfonamide	EC50	18100 nM
The compound has not trivial name.	EC50	18300 nM
3-[[5-(2,4-dimethoxyphenyl)-6H-1,3,4-thiadiazin-2-yl]amino]-N,N,4-trimethylbenzenesulfonamide	EC50	18500 nM
SMR000254526	EC50	19400 nM
SMR000364573	EC50	19500 nM
SMR000236766	IC50	19600 nM
SMR000377241	EC50	20200 nM
3-[1,3-bis(oxidanylidene)benzo[de]isoquinolin-2-yl]propyl-[6-[3-[1,3-bis(oxidanylidene)benzo[de]isoquinolin-2-yl]propyl-dimethyl-azaniumyl]hexyl]-dimethyl-azanium;bromide	EC50	20400 nM
(4-chlorodithiazol-5-ylidene)-(3,4,5-trimethoxyphenyl)amine	IC50	20400 nM
MLS000565740	EC50	23200 nM
MLS000556098	EC50	23900 nM
MLS000335157	EC50	24300 nM

ChEMBL bioactivities

28 potent at pChembl≥5 of 92 total, top 28 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.26	Kd	5.549	nM	CHEMBL3752910
8.26	ED50	5.549	nM	CHEMBL3752910
8.10	IC50	7.9	nM	CHEMBL3806069
8.10	IC50	7.9	nM	CHEMBL3804841
7.80	IC50	16	nM	CHEMBL3805148
7.70	IC50	20	nM	CHEMBL3805398
7.70	IC50	20	nM	CHEMBL3805205
7.60	IC50	25	nM	CHEMBL3805734
7.50	IC50	32	nM	CHEMBL3805905
7.40	IC50	40	nM	CHEMBL3804930
6.80	IC50	160	nM	CHEMBL3805753
6.80	IC50	160	nM	CHEMBL3805598
6.10	IC50	790	nM	CHEMBL3805460
6.00	IC50	1000	nM	CHEMBL3806103
5.97	EC50	1060	nM	CHEMBL1734083
5.80	IC50	1600	nM	CHEMBL3806028
5.70	IC50	2000	nM	CHEMBL3805703
5.70	IC50	2000	nM	CHEMBL3805765
5.70	IC50	2000	nM	CHEMBL3806250
5.70	IC50	2000	nM	CHEMBL3806132
5.42	IC50	3760	nM	CHEMBL1347253
5.30	IC50	5000	nM	CHEMBL3805653
5.28	EC50	5200	nM	CHEMBL1790033
5.18	EC50	6540	nM	CHEMBL1312377
5.12	EC50	7650	nM	CHEMBL1576392
5.09	EC50	8100	nM	CHEMBL1478479
5.08	EC50	8260	nM	CHEMBL1461738
5.00	IC50	1e+04	nM	CHEMBL3804874

PubChem BioAssay actives

20 with measured affinity, of 36 total; 20 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148513: Binding affinity to human HK1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0055	uM
N-[(3R,4R,5S,6R)-6-[[(4-cyanophenyl)sulfonylamino]methyl]-2,4,5-trihydroxyoxan-3-yl]-3-phenylbenzamide	1299801: Inhibition of His-tagged human HK1 (11 to 917 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
3-(4-cyanophenyl)-N-[(3R,4R,5S,6R)-6-[[(2,3-dichlorophenyl)sulfonylamino]methyl]-2,4,5-trihydroxyoxan-3-yl]-5-methoxybenzamide	1299801: Inhibition of His-tagged human HK1 (11 to 917 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
N-[(3R,4R,5S,6R)-6-[[(2-chlorophenyl)sulfonylamino]methyl]-2,4,5-trihydroxyoxan-3-yl]-3-phenylbenzamide	1299801: Inhibition of His-tagged human HK1 (11 to 917 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.0160	uM
N-[(3R,4R,5S,6R)-6-[[(4-chloro-3-pyridinyl)sulfonylamino]methyl]-2,4,5-trihydroxyoxan-3-yl]-3-phenylbenzamide	1299801: Inhibition of His-tagged human HK1 (11 to 917 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.0200	uM
5-[[(2R,3S,4R,5R)-5-[(3-bromobenzoyl)amino]-3,4,6-trihydroxyoxan-2-yl]methylsulfamoyl]-2-methylfuran-3-carboxylic acid	1299801: Inhibition of His-tagged human HK1 (11 to 917 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.0200	uM
3-[[(2R,3S,4R,5R)-3,4,6-trihydroxy-5-[(3-phenylbenzoyl)amino]oxan-2-yl]methylsulfamoyl]benzoic acid	1299801: Inhibition of His-tagged human HK1 (11 to 917 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	1299801: Inhibition of His-tagged human HK1 (11 to 917 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.0320	uM
3-(4-cyanophenyl)-5-(trifluoromethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]benzamide	1299801: Inhibition of His-tagged human HK1 (11 to 917 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
N-[(3R,4R,5S,6R)-6-[[(3-chlorophenyl)sulfonylamino]methyl]-2,4,5-trihydroxyoxan-3-yl]-3-phenylbenzamide	1299801: Inhibition of His-tagged human HK1 (11 to 917 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.1600	uM
N-[(3R,4R,5S,6R)-6-(benzenesulfonamidomethyl)-2,4,5-trihydroxyoxan-3-yl]-3-phenylbenzamide	1299801: Inhibition of His-tagged human HK1 (11 to 917 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	0.1600	uM
3-phenyl-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]benzamide	1299801: Inhibition of His-tagged human HK1 (11 to 917 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
2,3-dichloro-N-[[(2R,3S,4R,5R)-5-[[3-(4-chlorophenyl)phenyl]sulfonylamino]-3,4,6-trihydroxyoxan-2-yl]methyl]benzenesulfonamide	1299801: Inhibition of His-tagged human HK1 (11 to 917 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	1.0000	uM
methyl 5-[[(2R,3S,4R,5R)-5-[(3-bromobenzoyl)amino]-3,4,6-trihydroxyoxan-2-yl]methylsulfamoyl]-2-methylfuran-3-carboxylate	1299801: Inhibition of His-tagged human HK1 (11 to 917 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	1.6000	uM
5-chloro-N-[(3R,4R,5S,6R)-6-[[(2,3-dichlorophenyl)sulfonylamino]methyl]-2,4,5-trihydroxyoxan-3-yl]thiophene-2-carboxamide	1299801: Inhibition of His-tagged human HK1 (11 to 917 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-[[(4-methylphenyl)sulfonylamino]methyl]oxan-3-yl]prop-2-enamide	1299801: Inhibition of His-tagged human HK1 (11 to 917 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	1299801: Inhibition of His-tagged human HK1 (11 to 917 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	1299801: Inhibition of His-tagged human HK1 (11 to 917 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
2,3-dichloro-N-[[(2R,3S,4R,5R)-3,4,6-trihydroxy-5-[(3-phenylphenyl)sulfonylamino]oxan-2-yl]methyl]benzenesulfonamide	1299801: Inhibition of His-tagged human HK1 (11 to 917 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	5.0000	uM
2,3-dichloro-N-[[(2R,3S,4R,5R)-3,4,6-trihydroxy-5-[(3-nitrophenyl)sulfonylamino]oxan-2-yl]methyl]benzenesulfonamide	1299801: Inhibition of His-tagged human HK1 (11 to 917 residues) expressed in Escherichia coli BL21(DE3) using glucose as substrate after 45 mins by ADP-glo assay in presence of MgATP	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, increases methylation	7
trichostatin A	affects cotreatment, increases expression	3
Arsenic Trioxide	affects binding, decreases reaction, decreases expression, increases reaction, increases expression (+1 more)	3
sodium arsenite	increases expression	2
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Arsenic	affects methylation	2
Ascorbic Acid	decreases expression, increases reaction, affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	2
Aflatoxin B1	decreases methylation, increases expression, increases methylation	2
aristolochic acid I	decreases expression, increases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
titanium dioxide	increases expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization, increases expression	1
decabromobiphenyl ether	decreases expression	1
alpha-naphthoflavone	decreases reaction, increases expression, decreases expression	1
tetrahydropalmatine	decreases expression, increases expression	1
arsenite	affects binding, increases reaction	1
1,10-phenanthroline	increases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	increases expression	1
dinophysistoxin 1	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
yessotoxin	increases expression	1
hydroxysafflor yellow A	decreases reaction, increases activity, increases cleavage, increases secretion, increases expression (+2 more)	1
azoxystrobin	decreases expression	1

ChEMBL screening assays

12 unique, capped per target: 9 binding, 3 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1738619	Functional	PUBCHEM_BIOASSAY: Dose Response confirmation of activators of hexokinase domain containing I (HKDC1) in the hexokinase 1 selectivity assay. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID493187, AID493207]	PubChem BioAssay data set
CHEMBL2166286	Binding	Activation of human hexokinase 1 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

2 cell lines: 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2YQ	Abcam HEK293T HK1 KO	Transformed cell line	Female
CVCL_E1FR	Abcam HEK293 HK1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT00004700	PHASE2	COMPLETED	Phase II Long Term, Randomized Study of Recombinant Human Insulin-like Growth Factor I in Children With Hyperinsulinism
NCT00151684	PHASE2	COMPLETED	Diazoxide-Mediated Insulin Suppression in Hyperinsulinemic Obese Men
NCT00674440	PHASE2	COMPLETED	Utility of [F-18] fluoroDOPA for Neonatal Hyperinsulinism
NCT03053284	PHASE2	WITHDRAWN	Pasireotide in Hyperinsulinemic Hypoglycemia
NCT04062890	PHASE2	WITHDRAWN	Inhibiting GABA Transaminase to Relieve Obesity Induced Hyperinsulinemia and Insulin Resistance
NCT05088798	PHASE2	RECRUITING	Utility of 18FDOPA PET/MRI for Focal Hyperinsulinism
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT05989347	PHASE1	RECRUITING	Study to Evaluate Biomarkers and Safety of Dapagliflozin Concomitant With Neoadjuvant Therapy
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants