TK1

Summary

TK1 (thymidine kinase 1, HGNC:11830) is a protein-coding gene on chromosome 17q25.3, encoding Thymidine kinase, cytosolic (P04183). Cell-cycle-regulated enzyme of importance in nucleotide metabolism.

The protein encoded by this gene is a cytosolic enzyme that catalyzes the addition of a gamma-phosphate group to thymidine. This creates dTMP and is the first step in the biosynthesis of dTTP, which is one component required for DNA replication. The encoded protein, whose levels fluctuate depending on the cell cycle stage, can act as a low activity dimer or a high activity tetramer. High levels of this protein have been used as a biomarker for diagnosing and categorizing many types of cancers.

Source: NCBI Gene 7083 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 46 total
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003258

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11830
Approved symbol	TK1
Name	thymidine kinase 1
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000167900
Ensembl biotype	protein_coding
OMIM	188300
Entrez	7083

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 11 protein_coding, 1 retained_intron

ENST00000301634, ENST00000586613, ENST00000588734, ENST00000590430, ENST00000590862, ENST00000592126, ENST00000853515, ENST00000935504, ENST00000935505, ENST00000935506, ENST00000944214, ENST00000944215

RefSeq mRNA: 3 — MANE Select: NM_003258 NM_001346663, NM_001363848, NM_003258

CCDS: CCDS11754, CCDS86642, CCDS86643

Canonical transcript exons

ENST00000301634 — 7 exons

Exon	Start	End
ENSE00001118176	78186787	78186818
ENSE00001118182	78175050	78175169
ENSE00001274786	78174091	78174950
ENSE00003480668	78185055	78185165
ENSE00003511192	78175529	78175618
ENSE00003518826	78182589	78182682
ENSE00003843293	78186929	78187052

Expression profiles

Bgee: expression breadth ubiquitous, 204 present calls, max score 97.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.3577 / max 352.0826, expressed in 1569 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168347	45.3577	1569

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endometrium epithelium	UBERON:0004811	97.60	gold quality
mucosa of transverse colon	UBERON:0004991	95.28	gold quality
metanephros cortex	UBERON:0010533	90.00	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.98	gold quality
stromal cell of endometrium	CL:0002255	88.52	gold quality
esophagus mucosa	UBERON:0002469	87.64	gold quality
ventricular zone	UBERON:0003053	86.66	gold quality
bone marrow	UBERON:0002371	86.60	gold quality
lower esophagus mucosa	UBERON:0035834	86.20	gold quality
esophagus	UBERON:0001043	85.00	gold quality
ganglionic eminence	UBERON:0004023	84.81	gold quality
rectum	UBERON:0001052	84.34	gold quality
bone marrow cell	CL:0002092	84.04	gold quality
oral cavity	UBERON:0000167	83.79	gold quality
gingival epithelium	UBERON:0001949	83.41	gold quality
ileal mucosa	UBERON:0000331	83.24	gold quality
gingiva	UBERON:0001828	83.12	gold quality
vermiform appendix	UBERON:0001154	82.99	gold quality
trabecular bone tissue	UBERON:0002483	82.98	gold quality
lower esophagus	UBERON:0013473	82.61	gold quality
lower esophagus muscularis layer	UBERON:0035833	82.59	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.39	gold quality
transverse colon	UBERON:0001157	82.32	gold quality
lymph node	UBERON:0000029	81.79	gold quality
small intestine Peyer’s patch	UBERON:0003454	81.10	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	81.04	gold quality
squamous epithelium	UBERON:0006914	80.62	silver quality
esophagus squamous epithelium	UBERON:0006920	80.10	gold quality
epithelium of esophagus	UBERON:0001976	80.04	silver quality
body of stomach	UBERON:0001161	79.99	gold quality

Single-cell (SCXA)

Detected in 26 experiment(s), a significant marker in 25.

Experiment	Marker?	Max mean expression
E-GEOD-99795	yes	581.04
E-GEOD-84465	yes	576.29
E-HCAD-24	yes	482.02
E-HCAD-11	yes	407.31
E-HCAD-13	yes	379.81
E-GEOD-114530	yes	351.91
E-HCAD-10	yes	345.01
E-MTAB-8884	yes	329.91
E-ENAD-20	yes	329.24
E-MTAB-10885	yes	324.91
E-MTAB-8530	yes	319.80
E-MTAB-6701	yes	283.01
E-CURD-114	yes	267.96
E-GEOD-125970	yes	252.85
E-MTAB-10485	yes	237.40

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, E2F1, E2F4, MYB, PAX9, POU2AF1, POU2F1, POU2F2, SP1, YY1

miRNA regulators (miRDB)

19 targeting TK1, 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-4493	99.90	66.48	977
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-4635	98.74	67.63	1339
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-6792-5P	98.39	68.16	1330
HSA-MIR-4691-3P	98.11	66.83	1204
HSA-MIR-3132	97.96	67.91	711
HSA-MIR-512-5P	97.47	66.48	591
HSA-MIR-197-5P	97.23	68.10	596
HSA-MIR-7109-3P	94.23	67.19	743
HSA-MIR-6820-5P	94.04	61.13	161

Literature-anchored findings (GeneRIF, showing 40)

• TK1 gene expression together with TS, TP and DPD gene expression may play important roles in influencing the malignant behavior of epithelial ovarian cancer. (PMID:11992400)
• Mutation analysis in the coding sequence of thymidine kinase 1 in breast and colorectal cancer (PMID:12699056)
• Long-term treatment of H9 human lymphoid cells in the presence of dideoxycytidine down-regulated TK1 gene expression and reduced the expression and activity of TK in resistant cells. (PMID:14659972)
• the enzymatic function at the G2/M phase of TK1 depends on its quaternary structure (PMID:14697231)
• activation of the APC/C-Cdh1 complex during mitotic exit controls timing of TK1 destruction (PMID:14701726)
• Activity of thymidine kinase, thymidine phosphorylase and thymidilate synthase in human cancer xenografts to investigate the contribution of these enzymes to the sensitivity of TAS-102. (PMID:14719072)
• The importance of valine 106 for the structure and function of TK1. (PMID:15153115)
• activation of TK1 may be critical to modulate the radiation-induced cell death and cell cycle progression in irradiated K562 cells. (PMID:15353126)
• analysis and comparison of human and mycoplasmic thymidine kinase 1 (PMID:15611477)
• crystal structure of thymidine kinase 1 (PMID:15733844)
• TK1 expression is apparently a reliable marker in patients with non-small cell lung cancer. (PMID:15809747)
• an increased expression of mRNA, specific for TK1, deoxycytidine kinase, and thymidine phosphorylase, may be involved in carcinogenic processes in the human thyroid (PMID:15978330)
• an increase in activity of dCK, TK1 and 2 might be involved in an adaptive response of cultured human squamous lung carcinoma cells to radiation by facilitation of DNA repair (PMID:16969512)
• analysis of the role of C-terminal 20, 40, and 44 amino acids of TK1 in in vitro stability, oligomerization, and enzyme kinetics (PMID:17065087)
• thymidine is not only a substrate of TK1 but also acts as its expression regulator by modulating its proteolytic control during mitotic exit, conferring a feed-forward regulation of dTTP formation (PMID:17227951)
• The structures of hTK1 and of the Thermotoga maritima thymidine kinase (TmTK) in complex with the bisubstrate inhibitor TP4A, is reported. (PMID:17407781)
• Clinical-grade preparation of regulatory T-cells encoding the TK1 suicide gene as a safety gene is reported. (PMID:18615770)
• TK1 concentration was found to have a pivotal effect on catalytic efficiency (PMID:19087190)
• Mice with reduced thymidine Kinase treated neonatally with acrylamide or glycidamide is associated with DNA adduct formation and induction of micronuclei and mutations. (PMID:19123476)
• Increased TK1 is associated with renal cell carcinoma. (PMID:19282758)
• study indicates that the tumour proliferation marker thymidine kinase 1 has a potential as a serum marker in breast cancer (PMID:19396699)
• the relationship between the expression of TK1 and TP as they relate to proliferation (Ki-67 labeling index) and angiogenesis (Chalkley count of CD31-stained blood vessels) in a series of 110 non-small-cell lung cancer (NSCLC) tumors (PMID:19654105)
• cell cycle regulation of TK1 in normal tubule cells differ from that in other type of normal and malignant renal cells. (PMID:19957115)
• The TK1 model presented supports both K and k positive cooperativity. Three-parameter mass action models can and should replace the 3-parameter Hill model. (PMID:20003201)
• TK1 in serum may possess a reference value in the evaluation of treatment and prognosis of non-Hodgkin’s lymphoma following chemotherapy. (PMID:20140744)
• Serum TK1 correlates to clinical stages and clinical reactions and monitors the effect of tumor therapies, not only in controlled clinical trials, but also in routine clinical settings. (PMID:20354751)
• Thymidine kinase-1 and thymidylate synthase expression was markedly different between cancer types, suggesting that response to TAS-102 may differ. (PMID:20372850)
• High levels of HER2 and Ki-67 or TK1 expression correlate with the increase of tumor grades and tumor recurrence in meningiomas. (PMID:20450760)
• Serological thymidine kinase 1 is a useful marker for prognosis in patients with esophageal, cardial and lung carcinomas. (PMID:20479645)
• Results suggest that higher thymidine levels in the TK- cells caused by defect thymidine salvage to dTTP protects against UV irradiation. (PMID:20544518)
• The expression of TK1 in tumor tissues correlated to pathological stages and clinical grades of carcinomas (ca) of esophagus, lung and in premalignancy of breast ductal ca. STK1p could monitor the out-come of tumor therapy. (PMID:20544519)
• more dTTP synthesis via TK1 take place after genotoxic insults in tumor cells, improving DNA repair during G(2) arrest. (PMID:20554529)
• nucleoside recognition mechanisms for TK1 and TK2 are very different. nonpolar nucleosides are likely to be active in the nucleotide salvage pathway in human cells. (PMID:20560637)
• thymidine kinase has a role in progression of lung cancer (PMID:20592392)
• direct involvement of the G-quadruplex motif in transcription of TK1 (PMID:20849417)
• data demonstrate that the Flt3L/TK gene therapeutic approach can induce systemic immunological memory capable of recognizing a brain tumor neoantigen in a model of recurrent GBM (PMID:21505426)
• Elevated serum thymidine kinase 1 is associated with pre/early cancerous progression. (PMID:21545220)
• (18)F-FLT uptake and retention within cells may be complicated by a variety of still undetermined factors in addition to TK1 enzymatic activity (PMID:21764789)
• frequencies of polymorphic mutations in HIV-1 (subtype B) were compared between patients detected with the 69 insertion (n = 17), Q151M (n = 29), >/=2 thymidine analogue mutations (TAM) 1 (n = 400) or >/=2 TAM 2 (n = 249). (PMID:22027876)
• TK1 may be involved in poor survival in patients with pT1 of lung adenocarcinoma (PMID:22143937)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tk1	ENSDARG00000102245
mus_musculus	Tk1	ENSMUSG00000025574
rattus_norvegicus	Tk1	ENSRNOG00000047314
caenorhabditis_elegans		WBGENE00006568

Protein

Protein identifiers

Thymidine kinase, cytosolic — P04183 (reviewed: P04183)

All UniProt accessions (6): A0A384MDV9, P04183, K7ENW5, K7ERJ1, K7ERV3, K7ES52

UniProt curated annotations — full annotation on UniProt →

Function. Cell-cycle-regulated enzyme of importance in nucleotide metabolism. Catalyzes the first enzymatic step in the salvage pathway converting thymidine into thymidine monophosphate. Transcriptional regulation limits expression to the S phase of the cell cycle and transient expression coincides with the oscillation in the intracellular dTTP concentration. Also important for the activation of anticancer and antiviral nucleoside analog prodrugs such as 1-b-d-arabinofuranosylcytosine (AraC) and 3c-azido-3c-deoxythymidine (AZT).

Subunit / interactions. Homotetramer. Tetramerization from dimerization is induced by ATP and increases catalytic efficiency due to a high affinity for thymidine. Tetramerization is inhibited by phosphorylation at Ser-13. Interacts (via the KEN box) with FZR1.

Subcellular location. Cytoplasm.

Post-translational modifications. Phosphorylated on Ser-13 in mitosis. Phosphorylation of Ser-13 by CDK1 during mitosis reduces homotetramerization and catalytic efficiency when DNA replication is complete and intracellular TK1 is still present at a high level. Polyubiquitinated. Postmitosis, ubiquitination leads to proteasomal degradation. The KEN box sequence located at the C-terminal region targets for degradation by the anaphase promoting complex (APC/C) activated and rate-limited by FZR1.

Domain organisation. KEN box sequence located in the C-terminal region is required for its mitotic degradation by the APC/C-FZR1 ubiquitin ligase and interaction capability with FZR1.

Miscellaneous. Two forms have been identified in animal cells, one in cytosol and one in mitochondria. Activity of the cytosolic enzyme is high in proliferating cells and peaks during the S-phase of the cell cycle; it is very low in resting cells.

Similarity. Belongs to the thymidine kinase family.

RefSeq proteins (3): NP_001333592, NP_001350777, NP_003249* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001267	Thymidine_kinase	Family
IPR020633	Thymidine_kinase_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00265

Enzyme classification (BRENDA):

• EC 2.7.1.21 — thymidine kinase (BRENDA: 62 organisms, 199 substrates, 289 inhibitors, 268 Km, 122 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
THYMIDINE	0.0001–6	106
ATP	0.0001–20	48
3’-AZIDO-3’-DEOXYTHYMIDINE	0.0004–2.318	15
DEOXYCYTIDINE	0.003–0.568	10
2’-DEOXYTHYMIDINE	0.0011–0.33	9
GANCICLOVIR	0.0033–0.473	7
CTP	0.049–0.15	6
DEOXYURIDINE	0.0047–0.43	6
GTP	0.041–0.3	6
2’-DEOXYCYTIDINE	0.004–0.025	4
ACYCLOVIR	0.0034–0.417	4
5-FLUORO-2’-DEOXYURIDINE	0.001–0.04	3
2’,3’-DIDEOXY-3’-AZIDOTHYMIDINE	0.0006–0.0087	2
2’-DEOXYURIDINE	0.0015–0.011	2
TTP	0.072–0.127	2

Catalyzed reactions (Rhea), 1 shown:

• thymidine + ATP = dTMP + ADP + H(+) (RHEA:19129)

UniProt features (49 total): binding site 10, strand 10, mutagenesis site 9, helix 9, modified residue 4, turn 2, initiator methionine 1, chain 1, short sequence motif 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
1W4R	X-RAY DIFFRACTION	1.83
2WVJ	X-RAY DIFFRACTION	2.2
2ORV	X-RAY DIFFRACTION	2.3
1XBT	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04183-F1	82.72	0.67

Functional residue map

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

Catalytic / active sites (1): 98 (proton acceptor)

Ligand- & substrate-binding residues (10): 172–176; 181; 185; 188; 26–33; 58–60; 97–100; 128; 153; 156

Post-translational modifications (4): 2, 2, 13, 231

Mutagenesis-validated functional residues (9):

Position	Phenotype
13	loss of phosphorylation. constant expression during cell cycle. no effect on atp-induced tetramerization.
13	perturbes atp-induced tetramerization. retaines the enzymatic function with decreased thymidine affinity and catalytic e
28	300-fold higher km for thymidine.
124	30-fold higher km for thymidine.
163	50-fold higher km for thymidine.
194	no effect on phosphorylation.
203–205	resistant to degradation in the mitotic exit phase.
203–204	resistant to degradation in the mitotic exit phase.
203	resistant to degradation in the mitotic exit phase.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-69205	G1/S-Specific Transcription
R-HSA-73614	Pyrimidine salvage
R-HSA-1430728	Metabolism
R-HSA-15869	Metabolism of nucleotides
R-HSA-1640170	Cell Cycle
R-HSA-453279	Mitotic G1 phase and G1/S transition
R-HSA-69206	G1/S Transition
R-HSA-69278	Cell Cycle, Mitotic
R-HSA-8956321	Nucleotide salvage

MSigDB gene sets: 396 (showing top): BORCZUK_MALIGNANT_MESOTHELIOMA_UP, HORIUCHI_WTAP_TARGETS_DN, KANG_DOXORUBICIN_RESISTANCE_UP, REACTOME_G1_S_SPECIFIC_TRANSCRIPTION, GOBP_PROTEIN_HOMOTETRAMERIZATION, GOBP_CELL_CYCLE_DNA_REPLICATION, CROONQUIST_NRAS_SIGNALING_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, KENNY_CTNNB1_TARGETS_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, CAIRO_PML_TARGETS_BOUND_BY_MYC_UP, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, FRASOR_RESPONSE_TO_SERM_OR_FULVESTRANT_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (7): nucleobase-containing compound metabolic process (GO:0006139), thymidine metabolic process (GO:0046104), thymidine biosynthetic process (GO:0046105), protein homotetramerization (GO:0051289), DNA synthesis involved in mitotic DNA replication (GO:1904860), deoxyribonucleoside monophosphate biosynthetic process (GO:0009157), DNA biosynthetic process (GO:0071897)

GO Molecular Function (9): thymidine kinase activity (GO:0004797), ATP binding (GO:0005524), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleus (GO:0005634), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
G1/S Transition	1
Nucleotide salvage	1
Metabolism	1
Cell Cycle, Mitotic	1
Mitotic G1 phase and G1/S transition	1
Cell Cycle	1
Metabolism of nucleotides	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
primary metabolic process	1
pyrimidine deoxyribonucleoside metabolic process	1
thymidine metabolic process	1
pyrimidine deoxyribonucleoside biosynthetic process	1
protein homooligomerization	1
protein tetramerization	1
DNA synthesis involved in DNA replication	1
mitotic DNA replication	1
mitotic cell cycle process	1
nucleoside monophosphate biosynthetic process	1
DNA metabolic process	1
nucleic acid biosynthetic process	1
deoxynucleoside kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion binding	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2936 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TK1	TK2	O00142	938
TK1	DCK	P27707	887
TK1	GALK1	P51570	870
TK1	TYMS	P04818	855
TK1	DGUOK	P78532	811
TK1	NT5C	Q8TCD5	769
TK1	DTYMK	P23919	766
TK1	TMC8	Q8IU68	750
TK1	SYNGR2	O43760	737
TK1	TYMP	P19971	717
TK1	TMC6	Q7Z403	712
TK1	MADCAM1	Q13477	705
TK1	UCK2	Q9BZX2	692
TK1	CDC20	Q12834	664
TK1	SHMT2	P34897	661

IntAct

233 interactions, top by confidence:

A	B	Type	Score
AKR7A3	AKR7A2	psi-mi:“MI:0914”(association)	0.890
CNOT3	CNOT1	psi-mi:“MI:0914”(association)	0.740
CDH1	CTNND1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
AGRP	TK1	psi-mi:“MI:0914”(association)	0.640
TK1	MAGEA4	psi-mi:“MI:0915”(physical association)	0.560
MAGEA4	TK1	psi-mi:“MI:0915”(physical association)	0.560
BOLA2-SMG1P6	TK1	psi-mi:“MI:0915”(physical association)	0.560
TK1	KAT5	psi-mi:“MI:0915”(physical association)	0.560
TK1	APP	psi-mi:“MI:0915”(physical association)	0.560
CFTR	TK1	psi-mi:“MI:0915”(physical association)	0.550
TK1	APLP1	psi-mi:“MI:0915”(physical association)	0.550
ERG28	TK1	psi-mi:“MI:0915”(physical association)	0.550
TK1	RBM48	psi-mi:“MI:0915”(physical association)	0.550
CCDC90B	TK1	psi-mi:“MI:0915”(physical association)	0.550
TK1	COPS6	psi-mi:“MI:0915”(physical association)	0.550
TK1	CRMP1	psi-mi:“MI:0915”(physical association)	0.550
TK1	GAPDH	psi-mi:“MI:0915”(physical association)	0.550
TK1	GDF9	psi-mi:“MI:0915”(physical association)	0.550
PTPRK	TK1	psi-mi:“MI:0915”(physical association)	0.550
TK1	SETDB1	psi-mi:“MI:0915”(physical association)	0.550
PLA2G10	CHEK1	psi-mi:“MI:0914”(association)	0.530
NCS1	NMT2	psi-mi:“MI:0914”(association)	0.530

BioGRID (281): TK1 (Two-hybrid), TK1 (Affinity Capture-RNA), TK1 (Affinity Capture-MS), TK1 (Affinity Capture-MS), TK1 (Affinity Capture-MS), TK1 (Affinity Capture-MS), TK1 (Affinity Capture-MS), TK1 (Affinity Capture-MS), TK1 (Affinity Capture-MS), TK1 (Affinity Capture-MS), TK1 (Affinity Capture-MS), TK1 (Affinity Capture-MS), TK1 (Affinity Capture-MS), TK1 (Affinity Capture-MS), TK1 (Affinity Capture-MS)

ESM2 similar proteins: A1L251, A3KPF2, A5D7R8, A7SLX5, A9XLE1, A9XLG1, B5ZCA9, B8ARK7, O13648, O81263, O81395, O96720, P04047, P04183, P04184, P09768, P0C8I4, P18555, P27158, P38025, P45350, P51820, Q04149, Q07379, Q07422, Q10313, Q23695, Q27564, Q27783, Q27793, Q2QRX6, Q3T7C9, Q5R864, Q5XI69, Q6GPQ5, Q6PE54, Q6T7E8, Q754C9, Q7S8A6, Q7XWV4

Diamond homologs: A0A7H0DN73, A0RLB6, A4ITL0, A5D7R8, A5HY32, A6L1E7, A7FQF9, A7G9N9, A7GV80, A8FID5, A9VSC8, A9WGI6, B0K1F4, B0K7G9, B0R5S5, B1IE18, B1KSQ8, B2RJJ6, B3PM40, B5YDB0, B5ZCA9, B7GMH4, B7HFM8, B7HY90, B7IQY3, B7JHF2, B8E001, B8G6Y1, B9E8G2, B9IRW3, B9LJ65, C1D0Z6, C1F0Q7, C1FQ94, C3KYH2, C3LFK4, C3P292, C5D9N8, F4KBF5, O57203

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
CDK1	down-regulates	TK1	phosphorylation
CDK2	down-regulates	TK1	phosphorylation
TK1	“down-regulates quantity”	thymidine	“chemical modification”
TK1	“down-regulates quantity”	ATP(4-)	“chemical modification”
TK1	“up-regulates quantity”	dTMP(2-)	“chemical modification”
TK1	“up-regulates quantity”	ADP(3-)	“chemical modification”
FZR1	“down-regulates quantity by destabilization”	TK1	binding
APC-c	“down-regulates quantity by destabilization”	TK1	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 197 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
Chromatin organization	10	5.9×	7e-03
Chromatin modifying enzymes	10	5.2×	9e-03
Hemostasis	14	3.6×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	35
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1114 predictions. Top by Δscore:

Variant	Effect	Δscore
17:78175051:T:TA	donor_gain	1.0000
17:78175052:C:A	donor_gain	1.0000
17:78175165:AATGG:A	acceptor_gain	1.0000
17:78175167:TGG:T	acceptor_gain	1.0000
17:78175173:C:CT	acceptor_gain	1.0000
17:78175179:C:CT	acceptor_gain	1.0000
17:78175179:C:T	acceptor_gain	1.0000
17:78175180:A:C	acceptor_gain	1.0000
17:78175180:A:T	acceptor_gain	1.0000
17:78175525:TTA:T	donor_gain	1.0000
17:78175526:T:TG	donor_gain	1.0000
17:78175526:TA:T	donor_loss	1.0000
17:78175527:A:AC	donor_gain	1.0000
17:78175527:A:AT	donor_loss	1.0000
17:78175527:A:T	donor_gain	1.0000
17:78175527:ACCTT:A	donor_gain	1.0000
17:78175528:C:CC	donor_gain	1.0000
17:78175528:CCTT:C	donor_gain	1.0000
17:78175528:CCTTC:C	donor_gain	1.0000
17:78175531:T:A	donor_gain	1.0000
17:78175614:GGGAA:G	acceptor_gain	1.0000
17:78175615:GGAA:G	acceptor_gain	1.0000
17:78175616:GAA:G	acceptor_gain	1.0000
17:78175617:AA:A	acceptor_gain	1.0000
17:78175617:AAC:A	acceptor_loss	1.0000
17:78175619:C:CC	acceptor_gain	1.0000
17:78175619:CT:C	acceptor_loss	1.0000
17:78175629:C:CT	acceptor_gain	1.0000
17:78175631:C:CT	acceptor_gain	1.0000
17:78182582:AACTT:A	donor_loss	1.0000

AlphaMissense

1527 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:78186798:G:C	F29L	1.000
17:78186798:G:T	F29L	1.000
17:78186800:A:G	F29L	1.000
17:78174923:A:G	Y181H	0.999
17:78175068:C:A	R165S	0.999
17:78175068:C:G	R165S	0.999
17:78175069:C:G	R165T	0.999
17:78175104:G:C	C153W	0.999
17:78175106:A:G	C153R	0.999
17:78175164:A:C	F133L	0.999
17:78175164:A:T	F133L	0.999
17:78175166:A:G	F133L	0.999
17:78175538:G:C	F128L	0.999
17:78175538:G:T	F128L	0.999
17:78175540:A:G	F128L	0.999
17:78182589:A:C	F101L	0.999
17:78182589:A:T	F101L	0.999
17:78182591:A:G	F101L	0.999
17:78182599:T:A	E98V	0.999
17:78185092:C:G	D58H	0.999
17:78186790:T:A	K32I	0.999
17:78186808:C:T	G26E	0.999
17:78186809:C:G	G26R	0.999
17:78186809:C:T	G26R	0.999
17:78174911:A:G	C185R	0.998
17:78174922:T:C	Y181C	0.998
17:78175069:C:A	R165M	0.998
17:78175075:G:A	T163I	0.998
17:78175105:C:T	C153Y	0.998
17:78175111:G:T	A151E	0.998

dbSNP variants (sampled 300 via entrez): RS1000085266 (17:78180197 C>A,T), RS1000149054 (17:78183113 A>C), RS1000313285 (17:78175335 A>G), RS1000367993 (17:78186021 G>A), RS1000400678 (17:78180412 T>C), RS1000410002 (17:78180271 C>T), RS1000423771 (17:78175345 C>G), RS1000789988 (17:78176283 G>C,T), RS1001004279 (17:78179480 G>A), RS1001161630 (17:78176077 A>C,G), RS1001192565 (17:78180312 G>T), RS1001223602 (17:78180742 G>A), RS1001351504 (17:78185890 C>A,G,T), RS1001425163 (17:78185699 T>G), RS1001692142 (17:78175681 C>T)

Disease associations

OMIM: gene MIM:188300 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST004602_300	Mean corpuscular volume	1.000000e-12
GCST004621_198	Red cell distribution width	3.000000e-15
GCST004630_222	Mean corpuscular hemoglobin	3.000000e-10
GCST006804_59	Red cell distribution width	5.000000e-12
GCST009856_40	Leukocyte telomere length	5.000000e-06
GCST010396_21	Gut microbiota (bacterial taxa, hurdle binary method)	7.000000e-06
GCST90002390_540	Mean corpuscular hemoglobin	1.000000e-29
GCST90002392_33	Mean corpuscular volume	1.000000e-37
GCST90002396_676	Mean reticulocyte volume	5.000000e-38
GCST90002397_589	Mean spheric corpuscular volume	2.000000e-54
GCST90002404_182	Red cell distribution width	1.000000e-09
GCST90002404_183	Red cell distribution width	1.000000e-55

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0009188	Red cell distribution width
EFO:0004527	mean corpuscular hemoglobin
EFO:0007874	gut microbiome measurement
EFO:0010701	mean reticulocyte volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2883 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

8 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 269,631 (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
CHEMBL129	ZIDOVUDINE	4	4,996
CHEMBL788	IDOXURIDINE	4	24,732
CHEMBL222280	BROXURIDINE	2	21,876
CHEMBL271475	FIALURIDINE	2	2,709
CHEMBL31634	BRIVUDINE	2	4,419
CHEMBL52609	DOXRIBTIMINE	2	210,756
CHEMBL146673	(NORTH)-METHANOCARBATHYMIDINE	1	52
CHEMBL475717	5-METHYL-2’-FLUOROARAURACIL	1	91

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs8071253	AFMID, TK1		0.00	0

ChEMBL bioactivities

56 potent at pChembl≥5 of 107 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.70	IC50	2	nM	CHEMBL132598
8.10	IC50	8	nM	CHEMBL132598
7.81	Kd	15.33	nM	CHEMBL5653589
7.80	IC50	16	nM	DOXRIBTIMINE
7.58	IC50	26	nM	DOXRIBTIMINE
7.56	ED50	27.36	nM	CHEMBL5653589
7.30	Ki	50	nM	CHEMBL406254
7.05	Ki	90	nM	IDOXURIDINE
7.05	Ki	90	nM	CHEMBL1269499
7.00	Ki	100	nM	BRIVUDINE
6.85	Ki	140	nM	FIALURIDINE
6.75	Ki	180	nM	5-METHYL-2’-FLUOROARAURACIL
6.75	IC50	180	nM	CHEMBL101135
6.70	Ki	200	nM	DOXRIBTIMINE
6.68	Ki	210	nM	CHEMBL2311131
6.66	Ki	220	nM	CHEMBL341644
6.64	IC50	230	nM	CHEMBL422810
6.41	IC50	390	nM	CHEMBL422810
6.36	Ki	440	nM	CHEMBL1269499
6.02	Ki	950	nM	FIALURIDINE
5.92	IC50	1200	nM	CHEMBL341163
5.85	Ki	1400	nM	5-METHYL-2’-FLUOROARAURACIL
5.82	IC50	1500	nM	CHEMBL101135
5.75	IC50	1800	nM	DOXRIBTIMINE
5.70	Ki	2000	nM	CHEMBL268232
5.70	Ki	2000	nM	DOXRIBTIMINE
5.70	Ki	2000	nM	CHEMBL289100
5.69	Ki	2060	nM	CHEMBL258513
5.66	IC50	2200	nM	CHEMBL101135
5.64	IC50	2300	nM	CHEMBL322230
5.54	Ki	2900	nM	CHEMBL289441
5.54	Ki	2900	nM	ZIDOVUDINE
5.52	IC50	3000	nM	ZIDOVUDINE
5.52	IC50	3000	nM	CHEMBL289100
5.52	IC50	3000	nM	CHEMBL422810
5.51	IC50	3100	nM	CHEMBL422810
5.51	IC50	3100	nM	CHEMBL136020
5.48	IC50	3300	nM	CHEMBL134471
5.46	IC50	3500	nM	CHEMBL316971
5.44	IC50	3600	nM	CHEMBL341163
5.39	Ki	4100	nM	CHEMBL268232
5.39	IC50	4100	nM	CHEMBL102650
5.37	Ki	4300	nM	CHEMBL41698
5.34	IC50	4600	nM	CHEMBL337264
5.34	IC50	4600	nM	CHEMBL335866
5.33	Ki	4700	nM	CHEMBL1161004
5.30	IC50	5000	nM	CHEMBL289441
5.30	Ki	5060	nM	BROXURIDINE
5.16	Ki	7000	nM	ZIDOVUDINE
5.11	IC50	7800	nM	CHEMBL2403290

PubChem BioAssay actives

49 with measured affinity, of 608 total; 29 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
5-methyl-1-[[2-(trityloxymethyl)phenyl]methyl]pyrimidine-2,4-dione	210701: Inhibitory activity against HSV-1 Thymidine kinase in OST-TK-/HSV-1 TK+ cell line in combination with gancicclovir	ic50	0.0020	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149593: Binding affinity to human TK1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0153	uM
1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione	210702: Inhibitory activity (50 uM) against HSV-1 Thymidine kinase in OST-TK-/HSV-1 TK+ cell line in combination with BVAraU	ic50	0.0160	uM
2-anilino-9-(4-hydroxybutyl)-1H-purin-6-one	210697: Binding affinity towards HSV-1 thymidine kinase was determined	ki	0.0500	uM
5-ethyl-1-[(2R,3S,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione	210534: Compound was evaluated for Kinetic constant for viral thymidine kinase of Herpes simplex virus (HSV) -1	ki	0.0900	uM
Idoxuridine	210688: Binding affinity constant against HSV-1 thymidine kinase	ki	0.0900	uM
5-[(E)-2-bromoethenyl]-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione	210688: Binding affinity constant against HSV-1 thymidine kinase	ki	0.1000	uM
1-[(2R,3S,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-iodopyrimidine-2,4-dione	210534: Compound was evaluated for Kinetic constant for viral thymidine kinase of Herpes simplex virus (HSV) -1	ki	0.1400	uM
5-methyl-1-[(Z)-4-trityloxybut-2-enyl]pyrimidine-2,4-dione	210701: Inhibitory activity against HSV-1 Thymidine kinase in OST-TK-/HSV-1 TK+ cell line in combination with gancicclovir	ic50	0.1800	uM
1-[(2R,3S,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione	210534: Compound was evaluated for Kinetic constant for viral thymidine kinase of Herpes simplex virus (HSV) -1	ki	0.1800	uM
1-[(1R,3S,4R)-3-hydroxy-4-(hydroxymethyl)cyclopentyl]-5-iodopyrimidine-2,4-dione	210688: Binding affinity constant against HSV-1 thymidine kinase	ki	0.2100	uM
5-[(E)-2-bromoethenyl]-1-[(1S,3R,4S)-3-hydroxy-4-(hydroxymethyl)cyclopentyl]pyrimidine-2,4-dione	210688: Binding affinity constant against HSV-1 thymidine kinase	ki	0.2200	uM
5-methyl-1-[(E)-4-trityloxybut-2-enyl]pyrimidine-2,4-dione	210701: Inhibitory activity against HSV-1 Thymidine kinase in OST-TK-/HSV-1 TK+ cell line in combination with gancicclovir	ic50	0.2300	uM
1-(3-hydroxy-4-trityloxybutyl)-5-methylpyrimidine-2,4-dione	210699: Compound was evaluated for inhibitory effect against phosphorylation of [methyl-3H]dThd by HSV-1 Thymidine kinase	ic50	1.2000	uM
1-(4,5-dihydroxyoxolan-2-yl)-5-methylsulfanylpyrimidin-2-one	210533: Compound was tested for the binding affinity to thymidine kinase from HSV-1 infected HeLa Bu	ki	2.0000	uM
2-amino-9-(4-hydroxybutyl)-1H-purin-6-one	210697: Binding affinity towards HSV-1 thymidine kinase was determined	ki	2.0600	uM
5-methyl-1-[(Z)-4-(tritylamino)but-2-enyl]pyrimidine-2,4-dione	213299: Inhibitory concentration on phosphorylation of [methyl-3H]-dTh by human Thymidine Kinase 2	ic50	2.3000	uM
Zidovudine	210881: Inhibitory affect against rabbit thymus thymidine kinase and represented as molt/4F kinase.	ki	2.9000	uM
5-methyl-1-(4-trityloxybut-2-ynyl)pyrimidine-2,4-dione	210699: Compound was evaluated for inhibitory effect against phosphorylation of [methyl-3H]dThd by HSV-1 Thymidine kinase	ic50	3.1000	uM
5-methyl-1-(4-trityloxybutyl)pyrimidine-2,4-dione	213298: Inhibitory effect against phosphorylation of [methyl-3H]dThd by Thymidine Kinase 2 (TK-2)	ic50	3.3000	uM
1-[(Z)-4-(dibenzylamino)but-2-enyl]-5-methylpyrimidine-2,4-dione	213299: Inhibitory concentration on phosphorylation of [methyl-3H]-dTh by human Thymidine Kinase 2	ic50	3.5000	uM
N-[(Z)-4-(5-methyl-2,4-dioxopyrimidin-1-yl)but-2-enyl]-2-(4-phenylphenyl)acetamide	213299: Inhibitory concentration on phosphorylation of [methyl-3H]-dTh by human Thymidine Kinase 2	ic50	4.1000	uM
[(Z)-4-(5-methyl-2,4-dioxopyrimidin-1-yl)but-2-enyl] 2,2-diphenylacetate	213298: Inhibitory effect against phosphorylation of [methyl-3H]dThd by Thymidine Kinase 2 (TK-2)	ic50	4.6000	uM
5-iodo-1-[(Z)-3-trityloxyprop-1-enyl]pyrimidine-2,4-dione	213298: Inhibitory effect against phosphorylation of [methyl-3H]dThd by Thymidine Kinase 2 (TK-2)	ic50	4.6000	uM
[(2S,3R,5R)-3-(aminomethyl)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl dihydrogen phosphate	210899: In Vitro inhibition of Thymidine Monophosphatase Kinase (TMPKh)	ki	4.7000	uM
5-bromo-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione	210689: Binding affinity against HSV-1(KOS) thymidine kinase	ki	5.0600	uM
1-[(2R,4S,5R)-4-hydroxy-5-(trityloxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione	210699: Compound was evaluated for inhibitory effect against phosphorylation of [methyl-3H]dThd by HSV-1 Thymidine kinase	ic50	7.8000	uM
5-methyl-1-[(Z)-4-trityloxybut-2-enyl]-1,3-diazinane-2,4-dione	213298: Inhibitory effect against phosphorylation of [methyl-3H]dThd by Thymidine Kinase 2 (TK-2)	ic50	9.8000	uM
1-[(2R,4S,5R)-4-(2-aminoethyldisulfanyl)-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione	344316: Inhibition of recombinant TK1-mediated phosphorylation of [CH3-3H]deoxythymidine	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, decreases reaction, increases mutagenesis, increases response to substance (+3 more)	8
bisphenol A	increases expression, affects expression, decreases expression	6
Zidovudine	affects transport, increases response to substance, decreases activity, decreases expression, increases expression (+4 more)	6
palbociclib	decreases expression	3
Benzo(a)pyrene	affects cotreatment, increases mutagenesis, decreases expression	3
Cadmium	decreases expression	3
Estradiol	increases expression	3
Fluorouracil	affects expression, decreases expression, increases reaction, affects response to substance	3
Cyclosporine	decreases expression	3
Mitomycin	increases mutagenesis, decreases reaction	3
cobaltous chloride	decreases expression	2
Arsenic Trioxide	affects expression, decreases expression	2
Hydrogen Peroxide	decreases expression, increases expression	2
Methyl Methanesulfonate	increases expression, increases mutagenesis	2
Niclosamide	decreases expression	2
Nitric Oxide	increases mutagenesis	2
Progesterone	decreases expression, increases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Tretinoin	increases expression, decreases expression	2
4-Nitroquinoline-1-oxide	increases mutagenesis	2
Aflatoxin B1	affects expression, increases methylation	2
Vitamin K 3	affects expression, decreases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
beauvericin	affects cotreatment, decreases expression	1
geraniol	decreases expression, increases reaction	1
titanium dioxide	affects binding, decreases expression	1
beta-lapachone	decreases expression	1
arsenite	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1

ChEMBL screening assays

144 unique, capped per target: 127 binding, 16 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1004212	Binding	Binding affinity to TK1 in human H9 cells assessed as conversion of [14C]thyminide to [14C]thymidine monophosphate by scintillation counting	Intracellular metabolism and persistence of the anti-human immunodeficiency virus activity of 2’,3’-didehydro-3’-deoxy-4’-ethynylthymidine, a novel thymidine analog. — Antimicrob Agents Chemother
CHEMBL4617514	ADMET	Substrate activity at human thymidine kinase 1 assessed as Km incubated for 24 hrs	Acetylene Group, Friend or Foe in Medicinal Chemistry. — J Med Chem
CHEMBL674917	Functional	Inhibitory activity against herpes simplex virus type 1 thymidine kinase (HSV-1 TK-) VMW 1837 strain.	Structure-antiviral activity relationship in the series of pyrimidine and purine N-[2-(2-phosphonomethoxy)ethyl] nucleotide analogues. 1. Derivatives substituted at the carbon atoms of the base. — J Med Chem

Cellosaurus cell lines

32 cell lines: 22 cancer cell line, 10 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0561	TK6	Transformed cell line	Male
CVCL_2733	TK6TGR	Transformed cell line	Male
CVCL_4W71	POLK F171A MSH-	Cancer cell line	Male
CVCL_4W72	POLK KO hetero MSH-	Cancer cell line	Male
CVCL_4W73	POLK KO homo MSH-	Cancer cell line	Male
CVCL_6742	WTK-1	Transformed cell line	Male
CVCL_A1RF	NH32	Transformed cell line	Male
CVCL_A1SH	TX545	Transformed cell line	Male
CVCL_AR68	TK6 (IVGT)	Transformed cell line	Male
CVCL_B3JB	Abcam HEK293T TK1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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