TK2

Summary

TK2 (thymidine kinase 2, HGNC:11831) is a protein-coding gene on chromosome 16q21, encoding Thymidine kinase 2, mitochondrial (O00142). Phosphorylates thymidine, deoxycytidine, and deoxyuridine in the mitochondrial matrix.

This gene encodes a deoxyribonucleoside kinase that specifically phosphorylates thymidine, deoxycytidine, and deoxyuridine. The encoded enzyme localizes to the mitochondria and is required for mitochondrial DNA synthesis. Mutations in this gene are associated with a myopathic form of mitochondrial DNA depletion syndrome. Alternate splicing results in multiple transcript variants encoding distinct isoforms, some of which lack transit peptide, so are not localized to mitochondria.

Source: NCBI Gene 7084 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 566 total — 47 pathogenic, 31 likely-pathogenic
• Phenotypes (HPO): 102
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004614

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11831
Approved symbol	TK2
Name	thymidine kinase 2
Location	16q21
Locus type	gene with protein product
Status	Approved
Aliases	SCA31
Ensembl gene	ENSG00000166548
Ensembl biotype	protein_coding
OMIM	188250
Entrez	7084

Gene structure

Transcript identifiers

Ensembl transcripts: 55 — 27 protein_coding, 14 protein_coding_CDS_not_defined, 11 nonsense_mediated_decay, 3 retained_intron

ENST00000299697, ENST00000417693, ENST00000451102, ENST00000525974, ENST00000527284, ENST00000527800, ENST00000544898, ENST00000545043, ENST00000561905, ENST00000562484, ENST00000562552, ENST00000563099, ENST00000563369, ENST00000563478, ENST00000564792, ENST00000564917, ENST00000565729, ENST00000567357, ENST00000568170, ENST00000569718, ENST00000620035, ENST00000676536, ENST00000676538, ENST00000676718, ENST00000676904, ENST00000677117, ENST00000677124, ENST00000677296, ENST00000677319, ENST00000677379, ENST00000677412, ENST00000677420, ENST00000677497, ENST00000677535, ENST00000677541, ENST00000677555, ENST00000677715, ENST00000677739, ENST00000677961, ENST00000678015, ENST00000678099, ENST00000678190, ENST00000678205, ENST00000678219, ENST00000678297, ENST00000678314, ENST00000678336, ENST00000678639, ENST00000678746, ENST00000678861, ENST00000678864, ENST00000679154, ENST00000679271, ENST00000679306, ENST00000679327

RefSeq mRNA: 7 — MANE Select: NM_004614 NM_001172643, NM_001172644, NM_001172645, NM_001271934, NM_001271935, NM_001272050, NM_004614

CCDS: CCDS10805, CCDS54016, CCDS54017, CCDS54018, CCDS61955, CCDS92169

Canonical transcript exons

ENST00000544898 — 10 exons

Exon	Start	End
ENSE00001329349	66508003	66512066
ENSE00002608475	66549938	66550122
ENSE00003461951	66531380	66531469
ENSE00003537426	66541879	66541953
ENSE00003566648	66513731	66513811
ENSE00003569045	66548978	66549009
ENSE00003644858	66517789	66517877
ENSE00003660633	66517136	66517215
ENSE00003674645	66536964	66537017
ENSE00003680074	66528994	66529067

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 97.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.7301 / max 209.5631, expressed in 1804 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157701	11.8596	1719
157700	3.2868	1263
157704	1.7075	721
157702	0.9587	678
157703	0.7460	494
157698	0.7163	435
207914	0.4553	247

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	97.64	gold quality
sural nerve	UBERON:0015488	95.64	gold quality
adrenal tissue	UBERON:0018303	94.79	gold quality
monocyte	CL:0000576	94.32	gold quality
colonic epithelium	UBERON:0000397	93.99	gold quality
mononuclear cell	CL:0000842	93.68	gold quality
left testis	UBERON:0004533	93.55	gold quality
right testis	UBERON:0004534	93.55	gold quality
leukocyte	CL:0000738	93.45	gold quality
adipose tissue	UBERON:0001013	93.10	gold quality
right adrenal gland	UBERON:0001233	92.88	gold quality
subcutaneous adipose tissue	UBERON:0002190	92.77	gold quality
stromal cell of endometrium	CL:0002255	92.75	gold quality
right adrenal gland cortex	UBERON:0035827	92.70	gold quality
nerve	UBERON:0001021	92.69	gold quality
tibial nerve	UBERON:0001323	92.69	gold quality
connective tissue	UBERON:0002384	92.57	gold quality
left ovary	UBERON:0002119	92.46	gold quality
left adrenal gland	UBERON:0001234	92.43	gold quality
body of pancreas	UBERON:0001150	92.41	gold quality
left adrenal gland cortex	UBERON:0035825	92.29	gold quality
right lobe of liver	UBERON:0001114	92.22	gold quality
testis	UBERON:0000473	92.18	gold quality
adrenal gland	UBERON:0002369	92.02	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.02	gold quality
omental fat pad	UBERON:0010414	91.95	gold quality
peritoneum	UBERON:0002358	91.93	gold quality
tendon	UBERON:0000043	91.90	gold quality
adrenal cortex	UBERON:0001235	91.83	gold quality
parotid gland	UBERON:0001831	91.70	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.04
E-MTAB-2983	no	453.75

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

116 targeting TK2, 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-7110-3P	100.00	73.18	2486
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111

Literature-anchored findings (GeneRIF, showing 40)

• dS6K activity is dependent on the Drosophila homologue of the phosphoinositide-dependent protein kinase 1, dPDK1, demonstrating that both dPDK1, as well as dTOR, mediated dS6K activation is phosphatidylinositide-3,4,5-trisphosphate (PIP3)-independent. (PMID:11862217)
• Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. (PMID:12766775)
• S6K activity becomes resistant to amino acid starvation upon loss of Tsc1 and Tsc2 or ectopic activation of Rheb. (PMID:12771962)
• S6 kinase (dS6K) and a single 4E-BP (d4E-BP) are phosphorylated via the insulin and target of rapamycin (TOR) signaling pathways. (PMID:14645523)
• Reaults show that S6K is required for increased Rheb-TOR signaling to sensitize the whole organism to oxidative stress and promote the senescence of locomotor activity. (PMID:17038544)
• ATG1 is a negative regulator of the target of rapamycin (TOR)/S6 kinase (S6K) pathway. (PMID:17347671)
• Results indicate that PP2A, but not other members of this subfamily, is likely to be a major S6K phosphatase in intact cells and is consistent with an important role for this phosphatase in the TOR pathway. (PMID:17570358)
• DHR3 modulates dS6 kinase-dependent growth in Drosophila. (PMID:20463884)
• Data show that female Drosophila melanogaster undergo a dietary switch following mating and that S6 kinase and serotonin production are involved in this switch. (PMID:20471266)
• Data show that mating status modulates food choice in females, that it relies on the action of the sex peptide receptor in sensory neurons, and that neuronal TOR/S6K function affects this decision, possibly signaling the fly’s current nutritional status. (PMID:20471268)
• the effect of allelic variation at S6k on a range of phenotypes associated with metabolism and fitness in an age-, diet-, and sex-specific manner (PMID:20491566)
• S6 kinase localizes to the presynaptic active zone and functions with PDK1 to control synapse development (PMID:21930778)
• our results indicate that S6K1 has an inhibitory effect on autophagic activity under normal nutritional conditions (PMID:23532117)
• MYC and S6K cooperate through coordinate activation of the essential Pol I transcription initiation factor TIF-1A. (PMID:26215099)
• This study showed that p70 S6 kinase (S6k), acting downstream of the insulin receptor (InR) and the small GTPase Arf6, is a key mediator of ethanol-induced sedation in Drosophila (PMID:26586826)
• Findings indicate that Archipelago (Ago)/FBXW7 controls S6kinase (dS6K) protein levels, but do not impinge on the transcript level. (PMID:30656413)
• mTOR-S6K1 pathway mediates cytoophidium assembly (PMID:30857853)
• Identification of PP2A and S6 Kinase as Modifiers of Leucine-Rich Repeat Kinase-Induced Neurotoxicity. (PMID:31664682)
• The S6k/4E-BP mediated growth promoting sub-pathway of insulin signalling cascade is essential to restrict pathogenesis of poly(Q) disorders in Drosophila. (PMID:33744321)
• Glutamine stimulates the S6K/4E-BP branch of insulin signalling pathway to mitigate human poly(Q) disorders in Drosophila disease models. (PMID:37658796)
• Inhibition of S6K lowers age-related inflammation and increases lifespan through the endolysosomal system. (PMID:38413780)
• TK2 mutations have been identified in four patients from two families with myopathic mitochondrial DNA depletion and spinal muscular atrophy. (PMID:12391347)
• human thymidine kinase 2 has a role in mitochondrial DNA depletion myopathy as demonstrated by kinetic analysis (PMID:12493767)
• TK2 deficiency associated with myopathy and apparent reversion of mtDNA depletion noted in a 14-year-old patient in whom pathogenic mutations were identified in the TK2 gene (PMID:12682338)
• exon 5 is a “hot spot” for TK2 mutations in patients with myopathic mitochondrial DNA depletion syndrome (PMID:12873860)
• Long-term treatment of H9 human lymphoid cells in the presence of dideoxycytidine down-regulated TK2 gene expression and reduced the expression and activity of TK in resistant cells. (PMID:14659972)
• 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)
• import of cytosolic dNTPs in mitochondria of proliferating cells can compensate a TK2 induced imbalance of the mitochondrial dNTP pool (PMID:17065084)
• Using (124)I-FIAU, (18)F-FIAU, or (18)F-FEAU, it should be possible to image DeltahTK2 reporter gene expression with PET in preclinical and clinical studies. (PMID:17468435)
• activity of TK2 is curbed by thymidine phosphorylase, which degrades thymidine in the cytoplasm, thus limiting the availability of thymidine for phosphorylation by TK2 in mitochondria (PMID:17913703)
• A 12-year-old patient with mitochondrial DNA (mtDNA) depletion syndrome due to TK2 gene mutations has been evaluated serially over the last 10 years. We observed progressive muscle atrophy with selective loss of type 2 muscle fibers. (PMID:18021809)
• FMAU is preferably phosphorylated by TK2 and can track TK2 activity and mitochondrial mass in cellular stress. FMAU may provide an early marker of treatment effects. (PMID:18265975)
• Mutations in TK2, necessary for mtDNA biogenesis, increased risk for defective mtDNA replication, leading to LV hypertrophy. (PMID:18446447)
• Novel mutations(p.Q87X and p.N100S) in the TK2 gene associated with fatal mitochondrial DNA depletion myopathy. (PMID:18508266)
• Normal fibroblasts apparently contain more TK2 than needed to maintain dTTP during quiescence, which would explain why TK2-mutated fibroblasts do not manifest mtDNA depletion despite their reduced TK2 activity. (PMID:19154348)
• Gene mutations in TK2 resulting in MDS syndrome was studied. (PMID:19265691)
• Sequence analysis of the TK2 gene revealed two novel heterozygous mutations: the frame shift mutation, c.255_c.258delAGAA, and the heterozygous missense mutation, c.515G>A, (p.R172Q). (PMID:19736010)
• TK2-deficient cells showed severe mtDNA depletion. (PMID:21382338)
• R225W and T230A mutation of TK2 leads to a significant reduction activity in autosomal recessive progressive external ophthalmoplegia patients. (PMID:21937588)
• Results strongly suggest that oxidative damage-induced S-glutathionylation and degradation of TK2 have significant impact on mitochondrial DNA precursor synthesis. (PMID:22661713)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tk2	ENSDARG00000046127
mus_musculus	Tk2	ENSMUSG00000035824
rattus_norvegicus	Tk2	ENSRNOG00000012853
drosophila_melanogaster	dnk	FBGN0022338

Paralogs (3): DGUOK (ENSG00000114956), NDUFA10 (ENSG00000130414), DCK (ENSG00000156136)

Protein

Protein identifiers

Thymidine kinase 2, mitochondrial — O00142 (reviewed: O00142)

Alternative names: 2’-deoxyuridine kinase TK2, Deoxycytidine kinase TK2, Mt-TK

All UniProt accessions (24): A0A0A0MSY7, A0A7I2V2L8, A0A7I2V304, A0A7I2V3A3, A0A7I2V3V1, O00142, A0A7I2V406, A0A7I2V408, A0A7I2V465, A0A7I2V471, A0A7I2V4A1, A0A7I2V557, A0A7I2V5P3, A0A7I2V5S4, A0A7I2YQY6, A0A7P0MLU2, A0A7P0PE46, A0A7P0SB82, H3BP77, H3BV57, J3KS73, J3KSZ2, J3QL12, J3QRP0

UniProt curated annotations — full annotation on UniProt →

Function. Phosphorylates thymidine, deoxycytidine, and deoxyuridine in the mitochondrial matrix. In non-replicating cells, where cytosolic dNTP synthesis is down-regulated, mtDNA synthesis depends solely on TK2 and DGUOK. Widely used as target of antiviral and chemotherapeutic agents.

Subunit / interactions. Monomer.

Subcellular location. Mitochondrion.

Tissue specificity. Predominantly expressed in liver, pancreas, muscle, and brain.

Disease relevance. Mitochondrial DNA depletion syndrome 2 (MTDPS2) [MIM:609560] A disorder due to mitochondrial dysfunction characterized by childhood onset of muscle weakness associated with depletion of mtDNA in skeletal muscle. There is wide clinical variability; some patients have onset in infancy and show a rapidly progressive course with early death due to respiratory failure, whereas others have later onset of a slowly progressive myopathy. The disease is caused by variants affecting the gene represented in this entry. Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 (PEOB3) [MIM:617069] A form of progressive external ophthalmoplegia, a mitochondrial myopathy characterized by progressive paralysis of the levator palpebrae, orbicularis oculi, and extraocular muscles. PEOB3 patients manifest adult-onset progressive external ophthalmoplegia and progressive proximal muscle weakness associated with muscle atrophy. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the DCK/DGK family.

Isoforms (6)

UniProt ID	Names	Canonical?
O00142-1	1	yes
O00142-2	2
O00142-3	3
O00142-4	4
O00142-5	5
O00142-6	6

RefSeq proteins (7): NP_001166114, NP_001166115, NP_001166116, NP_001258863, NP_001258864, NP_001258979, NP_004605* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002624	DCK/DGK	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR031314	DNK_dom	Domain
IPR050566	Deoxyribonucleoside_kinase	Family

Pfam: PF01712

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), 3 shown:

• thymidine + ATP = dTMP + ADP + H(+) (RHEA:19129)
• 2’-deoxyuridine + ATP = dUMP + ADP + H(+) (RHEA:28206)
• 2’-deoxycytidine + ATP = dCMP + ADP + H(+) (RHEA:46040)

UniProt features (28 total): sequence variant 10, sequence conflict 7, splice variant 5, transit peptide 1, chain 1, region of interest 1, compositionally biased region 1, active site 1, binding site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00142-F1	85.01	0.73

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): 133 (proton acceptor)

Ligand- & substrate-binding residues (1): 57–65

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-73614	Pyrimidine salvage
R-HSA-1430728	Metabolism
R-HSA-15869	Metabolism of nucleotides
R-HSA-8956321	Nucleotide salvage

MSigDB gene sets: 371 (showing top): ZHAN_MULTIPLE_MYELOMA_PR_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, SENESE_HDAC1_AND_HDAC2_TARGETS_DN, BROWNE_HCMV_INFECTION_48HR_DN, CAIRO_HEPATOBLASTOMA_CLASSES_DN, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GROSS_HYPOXIA_VIA_HIF1A_DN, GROSS_HYPOXIA_VIA_ELK3_AND_HIF1A_DN

GO Biological Process (8): nucleobase-containing compound metabolic process (GO:0006139), pyrimidine nucleoside salvage (GO:0043097), deoxycytidine metabolic process (GO:0046092), thymidine metabolic process (GO:0046104), DNA biosynthetic process (GO:0071897), deoxyribonucleoside monophosphate biosynthetic process (GO:0009157), nucleotide biosynthetic process (GO:0009165), carbohydrate derivative metabolic process (GO:1901135)

GO Molecular Function (9): deoxycytidine kinase activity (GO:0004137), thymidine kinase activity (GO:0004797), ATP binding (GO:0005524), deoxynucleoside kinase activity (GO:0019136), nucleoside kinase activity (GO:0019206), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (3): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Nucleotide salvage	1
Metabolism	1
Metabolism of nucleotides	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
pyrimidine deoxyribonucleoside metabolic process	2
deoxynucleoside kinase activity	2
nucleobase-containing compound kinase activity	2
primary metabolic process	1
pyrimidine-containing compound salvage	1
nucleoside salvage	1
pyrimidine nucleoside biosynthetic process	1
DNA metabolic process	1
nucleic acid biosynthetic process	1
nucleoside monophosphate biosynthetic process	1
nucleotide metabolic process	1
nucleoside phosphate biosynthetic process	1
metabolic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
deoxyribonucleoside monophosphate biosynthetic process	1
nucleotide biosynthetic process	1
phosphotransferase activity, alcohol group as acceptor	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

1990 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TK2	TK1	P04183	938
TK2	TYMS	P04818	876
TK2	DTYMK	P23919	851
TK2	GALK1	P51570	844
TK2	DHFR2	Q86XF0	842
TK2	DHFR	P00374	820
TK2	TYMP	P19971	820
TK2	RRM2B	Q7LG56	713
TK2	MPV17	P39210	713
TK2	HPRT1	P00492	668
TK2	SUCLA2	Q9P2R7	668
TK2	TWNK	Q96RR1	667
TK2	CTH	P32929	650
TK2	CMPK1	P30085	643
TK2	UPRT	Q96BW1	636

IntAct

20 interactions, top by confidence:

A	B	Type	Score
GSTK1	TK2	psi-mi:“MI:0914”(association)	0.560
TK2	GSTK1	psi-mi:“MI:0915”(physical association)	0.560
	TK2	psi-mi:“MI:0915”(physical association)	0.400
rep	TK2	psi-mi:“MI:0914”(association)	0.350
CTNNBIP1	TK2	psi-mi:“MI:0914”(association)	0.350
DKK1	TK2	psi-mi:“MI:0914”(association)	0.350
LIG3	TK2	psi-mi:“MI:0914”(association)	0.350
CDCA8	LILRA5	psi-mi:“MI:0914”(association)	0.350
NUBP2	TK2	psi-mi:“MI:0914”(association)	0.350
NHLRC1	TK2	psi-mi:“MI:0914”(association)	0.350
SLC39A12	ESYT2	psi-mi:“MI:0914”(association)	0.350
ATF3	TMEM223	psi-mi:“MI:0914”(association)	0.350
FOS	TMEM223	psi-mi:“MI:0914”(association)	0.350
FOS	MYO1G	psi-mi:“MI:0914”(association)	0.350

BioGRID (21): TK2 (Affinity Capture-MS), TK2 (Synthetic Lethality), TK2 (Affinity Capture-MS), TK2 (Affinity Capture-MS), TK2 (Affinity Capture-MS), TK2 (Affinity Capture-MS), TK2 (Affinity Capture-MS), TK2 (Affinity Capture-MS), TK2 (Affinity Capture-MS), TK2 (Affinity Capture-MS), TK2 (Affinity Capture-RNA), TK2 (Affinity Capture-MS), TK2 (Affinity Capture-MS), TK2 (Affinity Capture-MS), TK2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1W2PQ27, A0A1W2PQ64, A0A1W2PQC6, A0A1W2PQD8, A0A1W2PQJ5, A0A1W2PR75, A2AV36, A4QN59, A6QQV6, D4A1F2, F1RA39, G5E8F4, J9SQF3, O00142, O42868, O55239, O95050, O95932, O97972, P0CR76, P0CR77, P10938, P40261, P40936, P53538, Q01841, Q22453, Q32LP9, Q4R7D0, Q566Y1, Q5M9G7, Q5RFR7, Q5U4E8, Q5XG58, Q62160, Q6C195, Q6CQ61, Q6DE00, Q6FMU7, Q6PCI6

Diamond homologs: A0A1L8HV70, O00142, P21974, P27707, P43346, P48769, Q16854, Q3MHR2, Q5ZJM7, Q5ZMF3, Q6DD33, Q6GPW6, Q9J579, Q9N0C5, Q9QX60, Q9R088, Q9XZT6, Q8FKZ1, P28855, Q6GZP0, Q197D1, Q54YL2, A1W1K1, A3N3W1, A7H5U9, A8FNR1, B3GZG9, B8D708, B8D8Q4, O25531, P06987, P10368, P46452, P57203, P59454, P62455, P63228, P63229, P63230, P9WMV2

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
TK2	“down-regulates quantity”	ATP(4-)	“chemical modification”
TK2	“up-regulates quantity”	ADP(3-)	“chemical modification”
TK2	“down-regulates quantity”	2’-deoxycytidine	“chemical modification”
TK2	“up-regulates quantity”	“2’-deoxycytosine 5’-monophosphate(2-)”	“chemical modification”
TK2	“down-regulates quantity”	thymidine	“chemical modification”
TK2	“up-regulates quantity”	dTMP(2-)	“chemical modification”
TK2	“down-regulates quantity”	2’-deoxyuridine	“chemical modification”
TK2	“up-regulates quantity”	dUMP(2-)	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	47
Likely pathogenic	31
Uncertain significance	171
Likely benign	220
Benign	34

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
12708	NM_004614.5(TK2):c.361C>A (p.His121Asn)	Pathogenic
12709	NM_004614.5(TK2):c.635T>A (p.Ile212Asn)	Pathogenic
12710	NM_004614.5(TK2):c.323C>T (p.Thr108Met)	Pathogenic
1414250	NM_004614.5(TK2):c.447_448dup (p.Ser150fs)	Pathogenic
1496034	NM_004614.5(TK2):c.1A>T (p.Met1Leu)	Pathogenic
1686262	NM_004614.5(TK2):c.414C>A (p.Ser138Arg)	Pathogenic
2137836	NM_004614.5(TK2):c.404C>T (p.Ser135Leu)	Pathogenic
2425184	NC_000016.9:g.(?66575762)(66575876_?)del	Pathogenic
2570945	NM_004614.5(TK2):c.150dup (p.Ser51fs)	Pathogenic
265614	NM_004614.5(TK2):c.372_373delinsCT (p.Gln125Ter)	Pathogenic
2707265	NM_004614.5(TK2):c.355del (p.Asp119fs)	Pathogenic
2716150	NM_004614.5(TK2):c.713_723del (p.Asp238fs)	Pathogenic
280624	NM_004614.5(TK2):c.583A>T (p.Lys195Ter)	Pathogenic
2810054	NM_004614.5(TK2):c.500G>A (p.Trp167Ter)	Pathogenic
2814604	NM_004614.5(TK2):c.473_474del (p.Tyr158fs)	Pathogenic
2839755	NM_004614.5(TK2):c.743_744del (p.Leu247_Phe248insTer)	Pathogenic
2844746	NM_004614.5(TK2):c.568del (p.Tyr190fs)	Pathogenic
2910404	NM_004614.5(TK2):c.469_470insTGGG (p.Asp157fs)	Pathogenic
3243639	NC_000016.9:g.(?66583821)(66583964_?)del	Pathogenic
3243640	NC_000016.9:g.(?66582861)(66583964_?)del	Pathogenic
3243641	NC_000016.9:g.(?66562877)(66565392_?)del	Pathogenic
3243642	NC_000016.9:g.(?66545871)(66547734_?)del	Pathogenic
3682154	NM_004614.5(TK2):c.583_584del (p.Lys195fs)	Pathogenic
3686708	NM_004614.5(TK2):c.125-1G>A	Pathogenic
3778843	NM_004614.5(TK2):c.142dup (p.Glu48fs)	Pathogenic
3778844	NM_004614.5(TK2):c.83_85delinsAT (p.Gly28fs)	Pathogenic
3778846	NM_004614.5(TK2):c.503del (p.Ile168fs)	Pathogenic
3778850	NM_004614.5(TK2):c.36_40dup (p.Leu14fs)	Pathogenic
3778852	NM_004614.5(TK2):c.1A>G (p.Met1Val)	Pathogenic
3778865	NM_004614.5(TK2):c.218_219dup (p.Thr74fs)	Pathogenic

SpliceAI

2001 predictions. Top by Δscore:

Variant	Effect	Δscore
16:66511982:T:TA	donor_gain	1.0000
16:66513725:ACTT:A	donor_loss	1.0000
16:66513726:CTT:C	donor_loss	1.0000
16:66513729:A:AC	donor_gain	1.0000
16:66513729:ACC:A	donor_loss	1.0000
16:66513729:ACCA:A	donor_loss	1.0000
16:66513730:C:A	donor_loss	1.0000
16:66513730:C:CC	donor_gain	1.0000
16:66517216:C:CC	acceptor_gain	1.0000
16:66517874:CCCA:C	acceptor_gain	1.0000
16:66517875:CCAC:C	acceptor_gain	1.0000
16:66517878:C:CC	acceptor_gain	1.0000
16:66529064:ACACC:A	acceptor_loss	1.0000
16:66529065:CACCT:C	acceptor_loss	1.0000
16:66529066:ACCT:A	acceptor_loss	1.0000
16:66529067:CCTAA:C	acceptor_loss	1.0000
16:66529068:CT:C	acceptor_loss	1.0000
16:66529069:T:A	acceptor_loss	1.0000
16:66531376:CTACC:C	donor_loss	1.0000
16:66531377:TA:T	donor_loss	1.0000
16:66531378:ACCTG:A	donor_loss	1.0000
16:66531379:C:CT	donor_loss	1.0000
16:66531468:CC:C	acceptor_gain	1.0000
16:66531469:CC:C	acceptor_gain	1.0000
16:66513809:TTC:T	acceptor_gain	0.9900
16:66513810:TCC:T	acceptor_loss	0.9900
16:66513812:C:CC	acceptor_gain	0.9900
16:66513812:C:T	acceptor_loss	0.9900
16:66513813:T:A	acceptor_loss	0.9900
16:66517135:CCAG:C	donor_gain	0.9900

AlphaMissense

1730 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:66529014:A:C	F143L	0.996
16:66529014:A:T	F143L	0.996
16:66529016:A:G	F143L	0.996
16:66536993:A:G	W86R	0.996
16:66536993:A:T	W86R	0.996
16:66517215:A:T	V180D	0.995
16:66536991:C:A	W86C	0.995
16:66536991:C:G	W86C	0.995
16:66529029:G:C	S138R	0.993
16:66529029:G:T	S138R	0.993
16:66529031:T:G	S138R	0.993
16:66517187:A:C	C189W	0.992
16:66529045:T:A	E133V	0.992
16:66517837:A:G	W164R	0.991
16:66517837:A:T	W164R	0.991
16:66541927:A:C	S61R	0.991
16:66541927:A:T	S61R	0.991
16:66541929:T:G	S61R	0.991
16:66541936:A:C	N58K	0.991
16:66541936:A:T	N58K	0.991
16:66531411:A:G	L115P	0.990
16:66531442:A:G	W105R	0.990
16:66531442:A:T	W105R	0.990
16:66541941:C:G	G57R	0.990
16:66541946:A:T	V55D	0.990
16:66517832:A:C	F165L	0.988
16:66517832:A:T	F165L	0.988
16:66517834:A:G	F165L	0.988
16:66541914:A:G	C66R	0.988
16:66541921:C:A	K63N	0.988

dbSNP variants (sampled 300 via entrez): RS1000060461 (16:66532691 G>A), RS1000116243 (16:66515162 T>A), RS1000387100 (16:66529529 A>G), RS1000444547 (16:66529229 G>C), RS1000454288 (16:66511757 G>T), RS1000627351 (16:66512844 G>T), RS1000667647 (16:66531210 A>C,T), RS1000839882 (16:66526068 T>A), RS1000893598 (16:66525781 C>A), RS1000973774 (16:66513122 A>C), RS1001089078 (16:66519053 C>T), RS1001133829 (16:66519101 A>G), RS1001190352 (16:66512709 G>T), RS1001289698 (16:66524498 G>C), RS1001331177 (16:66529839 C>T)

Disease associations

OMIM: gene MIM:188250 | disease phenotypes: MIM:603041, MIM:609560, MIM:617069

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial DNA depletion syndrome, myopathic form	Definitive	Autosomal recessive
autosomal recessive progressive external ophthalmoplegia	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (7): mitochondrial DNA depletion syndrome (MONDO:0018158), mitochondrial disease (MONDO:0044970), mitochondrial DNA depletion syndrome, myopathic form (MONDO:0012301), progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 3 (MONDO:0014898), myopathy (MONDO:0005336), inborn mitochondrial myopathy (MONDO:0009637), autosomal recessive progressive external ophthalmoplegia (MONDO:0016810)

Orphanet (5): Mitochondrial DNA depletion syndrome (Orphanet:35698), Mitochondrial disease (Orphanet:68380), Mitochondrial DNA depletion syndrome, myopathic form (Orphanet:254875), Autosomal recessive progressive external ophthalmoplegia (Orphanet:254886), Mitochondrial myopathy (Orphanet:206966)

HPO phenotypes

102 total (30 of 102 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000298	Mask-like facies
HP:0000365	Hearing impairment
HP:0000479	Abnormal retinal morphology
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000544	External ophthalmoplegia
HP:0000590	Progressive external ophthalmoplegia
HP:0000597	Ophthalmoparesis
HP:0000648	Optic atrophy
HP:0000716	Depression
HP:0000737	Irritability
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001283	Bulbar palsy
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001324	Muscle weakness
HP:0001349	Facial diplegia
HP:0001488	Bilateral ptosis
HP:0001531	Failure to thrive in infancy
HP:0001621	Weak voice
HP:0001638	Cardiomyopathy
HP:0002015	Dysphagia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009391_851	Metabolite levels	8.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010398	sphingomyelin 24:1 measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D017240	Mitochondrial Myopathies	C05.651.460; C10.668.491.500; C18.452.660.560
C563698	Mitochondrial DNA Depletion Syndrome, Myopathic Form (supp.)
C564926	Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4580 (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: 3,507 (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
CHEMBL70046	SORIVUDINE	4	3,507

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3826160	TK2		0.00	0

ChEMBL bioactivities

39 potent at pChembl≥5 of 57 total, top 35 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.92	Ki	12	nM	CHEMBL1091988
7.44	IC50	36	nM	CHEMBL1091988
7.38	IC50	42	nM	CHEMBL1090868
7.34	IC50	46	nM	CHEMBL1089867
6.82	IC50	150	nM	CHEMBL1090134
6.82	Ki	150	nM	CHEMBL1089836
6.82	IC50	150	nM	CHEMBL1091873
6.64	IC50	230	nM	CHEMBL1089805
6.60	IC50	250	nM	CHEMBL1091931
6.54	Ki	290	nM	CHEMBL220459
6.52	IC50	300	nM	CHEMBL1090133
6.50	IC50	320	nM	CHEMBL1090132
6.41	IC50	390	nM	CHEMBL219299
6.40	IC50	400	nM	CHEMBL1091872
6.39	Ki	410	nM	CHEMBL1091988
6.33	IC50	470	nM	CHEMBL220459
6.30	IC50	500	nM	CHEMBL216998
6.30	Ki	500	nM	CHEMBL101135
5.96	IC50	1100	nM	CHEMBL1090869
5.89	IC50	1300	nM	CHEMBL1091719
5.82	IC50	1500	nM	CHEMBL101135
5.75	IC50	1800	nM	CHEMBL373998
5.72	IC50	1900	nM	CHEMBL385954
5.72	IC50	1900	nM	CHEMBL219960
5.62	IC50	2400	nM	CHEMBL373997
5.60	IC50	2500	nM	CHEMBL216997
5.42	IC50	3800	nM	CHEMBL400232
5.40	IC50	4000	nM	CHEMBL1091210
5.33	IC50	4700	nM	CHEMBL219367
5.33	IC50	4700	nM	CHEMBL1092729
5.28	IC50	5200	nM	CHEMBL219458
5.20	IC50	6300	nM	CHEMBL238635
5.19	IC50	6400	nM	CHEMBL240716
5.17	IC50	6800	nM	CHEMBL400618
5.01	IC50	9700	nM	CHEMBL219905

PubChem BioAssay actives

39 with measured affinity, of 96 total; 31 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-[(E)-2-bromoethenyl]-1-[(2R,4S,5S)-4-[4-(4-chlorophenyl)triazol-1-yl]-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione	476623: Competitive inhibition of human recombinant mitochondrial thymidine kinase 2 using ATP as substrate by Lineweaver-Burke plotting	ki	0.0120	uM
1-[(2R,4S,5S)-4-[4-(3,4-dichlorophenyl)triazol-1-yl]-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione	476619: Inhibition of human recombinant mitochondrial thymidine kinase 2 assessed as inhibition of [methyl-3H]dThd phosphorylation after 30 mins by scintillation counting	ic50	0.0420	uM
1-[(2R,4S,5S)-4-[4-(4-chlorophenyl)triazol-1-yl]-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione	476619: Inhibition of human recombinant mitochondrial thymidine kinase 2 assessed as inhibition of [methyl-3H]dThd phosphorylation after 30 mins by scintillation counting	ic50	0.0460	uM
N-[(2S,3S,5R)-2-(hydroxymethyl)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]hexanamide	476617: Inhibition of thymidine kinase 2	ki	0.1500	uM
1-[4-chloro-3-(trifluoromethyl)phenyl]-3-[(2S,3S,5R)-2-(hydroxymethyl)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]thiourea	476619: Inhibition of human recombinant mitochondrial thymidine kinase 2 assessed as inhibition of [methyl-3H]dThd phosphorylation after 30 mins by scintillation counting	ic50	0.1500	uM
1-[(2R,4S,5S)-4-[4-(cyclopentylmethyl)triazol-1-yl]-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione	476619: Inhibition of human recombinant mitochondrial thymidine kinase 2 assessed as inhibition of [methyl-3H]dThd phosphorylation after 30 mins by scintillation counting	ic50	0.1500	uM
1-[(2R,4S,5S)-4-(4-butyltriazol-1-yl)-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione	476619: Inhibition of human recombinant mitochondrial thymidine kinase 2 assessed as inhibition of [methyl-3H]dThd phosphorylation after 30 mins by scintillation counting	ic50	0.2300	uM
5-[(E)-2-bromoethenyl]-1-[(2R,4S,5S)-5-(hydroxymethyl)-4-(4-phenyltriazol-1-yl)oxolan-2-yl]pyrimidine-2,4-dione	476619: Inhibition of human recombinant mitochondrial thymidine kinase 2 assessed as inhibition of [methyl-3H]dThd phosphorylation after 30 mins by scintillation counting	ic50	0.2500	uM
1-[6-[diphenyl(pyridin-4-yl)methoxy]hexyl]-5-methylpyrimidine-2,4-dione	274893: Inhibition of TK2	ki	0.2900	uM
1-[(2R,4S,5S)-4-(4-benzyltriazol-1-yl)-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione	476619: Inhibition of human recombinant mitochondrial thymidine kinase 2 assessed as inhibition of [methyl-3H]dThd phosphorylation after 30 mins by scintillation counting	ic50	0.3000	uM
1-[(2R,4S,5S)-5-(hydroxymethyl)-4-(4-phenyltriazol-1-yl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione	476619: Inhibition of human recombinant mitochondrial thymidine kinase 2 assessed as inhibition of [methyl-3H]dThd phosphorylation after 30 mins by scintillation counting	ic50	0.3200	uM
N-methyl-4-[6-(5-methyl-2,4-dioxopyrimidin-1-yl)hexoxy-diphenylmethyl]benzamide	274890: Inhibition of [3H]methyl dThd phosphorylation by TK2	ic50	0.3900	uM
N-methyl-4-[8-(5-methyl-2,4-dioxopyrimidin-1-yl)octoxy-diphenylmethyl]benzamide	476617: Inhibition of thymidine kinase 2	ic50	0.4000	uM
5-methyl-1-(6-trityloxyhexyl)pyrimidine-2,4-dione	274890: Inhibition of [3H]methyl dThd phosphorylation by TK2	ic50	0.5000	uM
5-methyl-1-[(Z)-4-trityloxybut-2-enyl]pyrimidine-2,4-dione	274893: Inhibition of TK2	ki	0.5000	uM
1-[(2R,4S,5S)-5-(hydroxymethyl)-4-(5-phenyltriazol-1-yl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione	476619: Inhibition of human recombinant mitochondrial thymidine kinase 2 assessed as inhibition of [methyl-3H]dThd phosphorylation after 30 mins by scintillation counting	ic50	1.1000	uM
1-[(2R,4S,5S)-5-(hydroxymethyl)-4-(4-pyridin-2-yltriazol-1-yl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione	476619: Inhibition of human recombinant mitochondrial thymidine kinase 2 assessed as inhibition of [methyl-3H]dThd phosphorylation after 30 mins by scintillation counting	ic50	1.3000	uM
1-[(Z)-4-[diphenyl(pyridin-4-yl)methoxy]but-2-enyl]-5-methylpyrimidine-2,4-dione	274890: Inhibition of [3H]methyl dThd phosphorylation by TK2	ic50	1.8000	uM
N-methyl-4-[[(Z)-4-(5-methyl-2,4-dioxopyrimidin-1-yl)but-2-enoxy]-diphenylmethyl]benzamide	274890: Inhibition of [3H]methyl dThd phosphorylation by TK2	ic50	1.9000	uM
1-[6-[(4-chlorophenyl)-diphenylmethoxy]hexyl]-5-methylpyrimidine-2,4-dione	274890: Inhibition of [3H]methyl dThd phosphorylation by TK2	ic50	1.9000	uM
1-[(Z)-4-[(4-chlorophenyl)-diphenylmethoxy]but-2-enyl]-5-methylpyrimidine-2,4-dione	274890: Inhibition of [3H]methyl dThd phosphorylation by TK2	ic50	2.4000	uM
5-methyl-1-(5-trityloxypentyl)pyrimidine-2,4-dione	274890: Inhibition of [3H]methyl dThd phosphorylation by TK2	ic50	2.5000	uM
[(2R,3S,4R,5R)-2-[5-[(E)-2-bromoethenyl]-2,4-dioxopyrimidin-1-yl]-4-hydroxy-5-(hydroxymethyl)oxolan-3-yl] 12-[(2-methylpropan-2-yl)oxycarbonylamino]dodecanoate	306719: Inhibition of human TK2 assessed as [methyl-3H]dThd phosphorylation	ic50	3.8000	uM
1-[(2R,4S,5S)-4-[5-(4-chlorophenyl)triazol-1-yl]-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione	476619: Inhibition of human recombinant mitochondrial thymidine kinase 2 assessed as inhibition of [methyl-3H]dThd phosphorylation after 30 mins by scintillation counting	ic50	4.0000	uM
5-methyl-1-(7-trityloxyheptyl)pyrimidine-2,4-dione	274890: Inhibition of [3H]methyl dThd phosphorylation by TK2	ic50	4.7000	uM
1-[(2R,4S,5S)-5-(hydroxymethyl)-4-(triazol-1-yl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione	476619: Inhibition of human recombinant mitochondrial thymidine kinase 2 assessed as inhibition of [methyl-3H]dThd phosphorylation after 30 mins by scintillation counting	ic50	4.7000	uM
1-[2-[2-[(4-chlorophenyl)-diphenylmethoxy]ethoxy]ethyl]-5-methylpyrimidine-2,4-dione	274890: Inhibition of [3H]methyl dThd phosphorylation by TK2	ic50	5.2000	uM
[(2R,3S,4R,5R)-2-[5-[(E)-2-bromoethenyl]-2,4-dioxopyrimidin-1-yl]-4-hydroxy-5-(hydroxymethyl)oxolan-3-yl] octanoate	210896: Inhibitory concentration against mitochondrial thymidine kinase (TK-2)	ic50	6.3000	uM
[(2R,3S,4R,5R)-2-[5-[(E)-2-bromoethenyl]-2,4-dioxopyrimidin-1-yl]-4-hydroxy-5-(hydroxymethyl)oxolan-3-yl] 8-[(2-methylpropan-2-yl)oxycarbonylamino]octanoate	306719: Inhibition of human TK2 assessed as [methyl-3H]dThd phosphorylation	ic50	6.4000	uM
[(2R,3S,4R,5R)-2-[5-[(E)-2-bromoethenyl]-2,4-dioxopyrimidin-1-yl]-4-hydroxy-5-(hydroxymethyl)oxolan-3-yl] decanoate	210896: Inhibitory concentration against mitochondrial thymidine kinase (TK-2)	ic50	6.8000	uM
5-methyl-1-[2-(2-trityloxyethoxy)ethyl]pyrimidine-2,4-dione	274890: Inhibition of [3H]methyl dThd phosphorylation by TK2	ic50	9.7000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	4
bisphenol A	affects cotreatment, decreases methylation, decreases expression, increases expression	3
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	3
trichostatin A	affects cotreatment, decreases expression	2
potassium chromate(VI)	affects cotreatment, decreases expression	2
Benzo(a)pyrene	decreases expression, affects methylation	2
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
hydroquinone	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
fialuridine	affects response to substance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
chromium hexavalent ion	decreases expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	affects expression, affects methylation	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
jinfukang	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	decreases expression	1
Air Pollutants, Occupational	decreases expression	1
Vehicle Emissions	affects expression, increases abundance	1
Carbamazepine	affects expression	1

ChEMBL screening assays

17 unique, capped per target: 17 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1064157	Binding	Activity of thymidine kinase 2 up to 1 mM	The mechanism of action of beta-D-2’-deoxy-2’-fluoro-2’-C-methylcytidine involves a second metabolic pathway leading to beta-D-2’-deoxy-2’-fluoro-2’-C-methyluridine 5’-triphosphate, a potent inhibitor of the hepatitis C virus RNA-dependent RNA polymerase. — Antimicrob Agents Chemother

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A2VI	GM26117	Transformed cell line	Female
CVCL_B5RL	UNIZARi001-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT04581733	PHASE3	WITHDRAWN	A Study of the Efficacy and Safety of MT1621 in Thymidine Kinase 2 (TK2) Deficiency (Treatment naïve)
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT03845712	PHASE2	ACTIVE_NOT_RECRUITING	An Open-Label Study of Continuation Treatment With Combination Pyrimidine Nucleosides in Patients With TK2 Deficiency
NCT06754098	PHASE2	RECRUITING	Doxecitin and Doxribthymine in Adult Subjects With Thymidine Kinase 2 (TK2) Deficiency
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT03639701	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Treatment of TK2 Deficiency With Thymidine and Deoxycytidine
NCT05017818	Not specified	COMPLETED	A Retrospective Study of Subjects With Thymidine Kinase 2 Deficiency
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01642056	PHASE1/PHASE2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT03384420	PHASE1/PHASE2	COMPLETED	A Study to Evaluate the Safety and Therapeutic Effects of Transplantation of MNV-BM-BLD in Pediatric Patients With Pearson Syndrome
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT01252979	EARLY_PHASE1	COMPLETED	Ketones & Mitochondrial Heteroplasmy