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53  structures 3022  species 1  interaction 3293  sequences 11  architectures

Family: TK (PF00265)

Summary: Thymidine kinase

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Thymidine kinase Edit Wikipedia article

Thymidine kinase
Crystal structure of a tetramer of thymidine kinase from U. urealyticum (where the monomers are color cyan, green, red, and magenta respectively) in complex with thymidine (space-filling model, carbon = white, oxygen = red, nitrogen = blue).[1]
EC number
CAS number 9002-06-6
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
Thymidine kinase
Symbol TK
Pfam PF00265
Pfam clan CL0023
InterPro IPR001267
Thymidine kinase 1, soluble
Symbol TK1
Entrez 7083
HUGO 11830
OMIM 188300
RefSeq NM_003258
UniProt P04183
Other data
Locus Chr. 17 q23.2-25.3
Thymidine kinase 2, mitochondrial
Symbol TK2
Entrez 7084
HUGO 11831
OMIM 188250
RefSeq NM_004614
UniProt O00142
Other data
Locus Chr. 16 [1]

Thymidine kinase is an enzyme, a phosphotransferase (a kinase): 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC[2][3] It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Certain viruses also have genetic information for expression of viral thymidine kinases.

Thymidine kinase catalyses the reaction:

  • Thd + ATP → TMP + ADP

where Thd is deoxythymidine, ATP is adenosine 5’-triphosphate, TMP is deoxythymidine 5’-phosphate and ADP is adenosine 5’-diphosphate.

Thymidine kinases have a key function in the synthesis of DNA and thereby in cell division, as they are part of the unique reaction chain to introduce deoxythymidine into the DNA. Deoxythymidine is present in the body fluids as a result of degradation of DNA from food and from dead cells. Thymidine kinase is required for the action of many antiviral drugs. It is used to select hybridoma cell lines in production of monoclonal antibodies. In clinical chemistry it is used as a proliferation marker in the diagnosis, control of treatment and follow-up of malignant disease, mainly of hematological malignancies.


The incorporation of thymidine in DNA was demonstrated around 1950.[4] Somewhat later, it was shown that this incorporation was preceded by phosphorylation,[5] and, around 1960, the enzyme responsible was purified and characterized.[6][7]


Two different classes of thymidine kinases have been identified[8][9] and are included in this super family:

The Prosite pattern recognises only the cellular type of thymidine kinases.


Mammals have two isoenzymes, that are chemically very different, TK1 and TK2. The former was first found in fetal tissue, the second was found to be more abundant in adult tissue, and initially they were termed fetal and adult thymidine kinase. Soon it was shown that TK1 is present in the cytoplasm only in anticipation of cell division (cell cycle-dependent),[10][11] whereas TK2 is located in mitochondria and is cell cycle-independent.[12][13] The genes of the two types were localized in the mid-1970s.[14][15] The gene for TK1 was cloned and sequenced.[16] The corresponding protein has a molecular weight of about 25 kD. Normally, it occurs in tissue as a dimer. It can be activated by ATP. After activation, it has been converted to a tetramer. The recombinant TK1 cannot be activated and converted to a tetramer in this way, showing that the enzyme occurring in cells has been modified after synthesis.[17][18][19] TK1 is synthesized by the cell during the S phase of cell division. After cell division is completed, TK1 is degraded intracelluarly, so that it does not pass to body fluids after normal cell division.[20] There is a feed-back regulation of the action of thymidine kinase in the cell: thymidine triphosphate (TTP), the product of the further phosphorylation of thymidine, acts as an inhibitor to thymidine kinase.[18][21][22][23] This serves to maintain a balanced amount of TTP available for nucleic acid synthesis, not oversaturating the system. 5'-Aminothymidine, a non-toxic analogue of thymidine, interferes with this regulatory mechanism and thereby increases the cytotoxicity of thymidine analogues used as antineoplastic drugs.[24][25][26][27][28][29][30]

Genes for virus specific thymidine kinases have been identified in Herpes simplex virus, Varicella zoster virus and Epstein-Barr virus.[31][32][33][34][35][36][37]
2'-Desoxythymidin.svg + ATP ---> 2'-Desoxythymidinmonophosphat.svg + ADP

Deoxythymidine reacts with ATP to give deoxythymidine monophosphate and ADP.

Physiological context

Deoxythymidine monophosphate, the product of the reaction catalysed by thymidine kinase, is in turn phosphorylated to deoxythymidine diphosphate by the enzyme thymidylate kinase and further to deoxythymidine triphosphate by the enzyme nucleoside diphosphate kinase. The triphosphate is included in a DNA molecule, a reaction catalysed by a DNA polymerase and a complementary DNA molecule (or an RNA molecule in the case of reverse transcriptase, an enzyme present in retrovirus). Deoxythymidine monophosphate is produced by the cell in two different reactions - either by phosphorylation of deoxythymidine as described above or by methylation of deoxyuridine monophosphate, a product of other metabolic pathways unrelated to thymidine, by the enzyme thymidylate synthethase. The second route is used by the cell under normal conditions, and it is sufficient to supply deoxythymidine monophosphate for DNA repair. When a cell prepares to divide, a complete new set-up of DNA is required, and the requirement for building blocks, including deoxythymidine triphosphate, increases. Cells prepare for cell division by making some of the enzymes required during the division. They are not normally present in the cells and are downregulated and degraded afterwards. Such enzymes are called salvage enzymes. Thymidine kinase 1 is such a salvage enzyme, whereas thymidine kinase 2 is not cell cycle-dependent.[38][39][40][41][42][43][44][45][46]


Identification of dividing cells

The first indirect use of thymidine kinase in biochemical research was the identification of dividing cells by incorporation of radiolabeled thymidine and subsequent measurement of the radioactivity or autoradiography to identify the dividing cells. For this purpose tritiated thymidine is included in the growth medium.[47] In spite of errors in the technique, it is still used to determine the growth rate of malignant cells and to study the activation of lymphocytes in immunology.

PET scan of active tumours

3'-Deoxy-3'-[(18)F]fluorothymidine is a thymidine analogue. Its uptake is regulated by thymidine kinase 1, and it is therefore taken up preferentially by rapidly proliferating tumour tissue. The fluorine isotope 18 is a positron emitter that is used in positron emission tomography (PET). This marker is therefore useful for PET imaging of active tumour proliferation, and compares favourably with the more commonly used marker 2-[(18)F]fluoro-2-deoxy-D-glucose.[48][49][50][51][52]

Selection of hybridomas

Hybridomas are cells obtained by fusing tumour cells (which can divide infinitely) and immunoglobulin-producing lymphocytes (plasma cells). Hybridomas can be expanded to produce large quantities of immunoglobulins with a given unique specificity (monoclonal antibodies). One problem is to single out the hybridomas from the large excess of unfused cells after the cell fusion. One common way to solve this is to use thymidine kinase negative (TK-) tumour cell lines for the fusion. The thymidine kinase negative cells are obtained by growing the tumour cell line in the presence of thymidine analogues, that kill the thymidine kinase positive (TK+) cells. The negative cells can then be expanded and used for the fusion with TK+ plasma cells. After fusion, the cells are grown in a medium with methotrexate[53] or aminopterin[54] that inhibit the enzyme dihydrofolate reductase thus blocking the de novo synthesis of thymidine monophosphate. One such medium that is commonly used is HAT medium, which contains hypoxanthine, aminopterin and thymidine. The unfused cells from the thymidine kinase-deficient cell line die because they have no source of thymidine monophosphate. The lymphocytes eventually die because they are not "immortal." Only the hybridomas that have "immortality" from their cell line ancestor and thymidine kinase from the plasma cell survive. Those that produce the desired antibody are then selected and cultured to produce the monoclonal antibody.[55][56][57][58][59]

Hybridoma cells can also be isolated using the same principle as described with respect to another gene the HGPRT, which synthesises IMP necessary for GMP nucleotide synthesis in the salvage pathway.

Clinical chemistry

Thymidine kinase is a salvage enzyme that is only present in anticipation of cell division. The enzyme is not set free from cells undergoing normal division where the cells have a special mechanism to degrade the proteins no longer needed after the cell division.[10] In normal subjects, the amount of thymidine kinase in serum or plasma is therefore very low. Tumour cells release enzyme to the circulation, probably in connection with the disruption of dead or dying tumour cells. The thymidine kinase level in serum therefore serves as a measure of malignant proliferation, indirectly as a measure of the aggressivity of the tumour. It is interesting to note that the form of enzyme present in the circulation does not correspond to the protein as encoded by the gene: the gene corresponds to a protein with molecular weight around 25 kD. It is a dimer with a molecular weight of around 50 kD, if activated by ATP a tetramer with molecular weight around 100 kD.[17] The main fraction of the active enzyme in the circulation has a molecular weight of 730 kD and is probably bound in a complex to other proteins.[60]

The most dramatic increases are seen in hematologic malignancies.[61] The main use of thymidine kinase assay now is in Non-Hodgkin lymphoma. This disease has a wide range of aggressivity, from slow-growing indolent disease that hardly requires treatment to highly aggressive, rapidly growing forms that should be treated urgently. This is reflected in the values of serum thymidine kinase, that range from close to the normal range for slow-growing tumours to very high levels for rapidly growing forms.[62][63][64][65][66][67][68][69]

Also in dogs, lymphomas cause elevations of serum TK levels, indicative of the disease activity and useful for management of the disease.[70][71]

Similar patterns can be seen in other hematological malignancies (leukemia,[72][73][74] myeloma[75][76] myelodysplastic syndrome). A very interesting case is the myelodysplastic syndrome: Some of them rapidly change to acute leukemia, whereas others remain indolent for very long time. Identification of those tending to change to overt leukemia is important for the treatment.[77][78]

Also solid tumours give increased values of thymidine kinase. Reports on this have been published for prostatic carcinoma, where thymidine kinase has been suggested as a supplement to PSA (Prostate Specific Antigen), the tumor marker now most frequently used in prostate cancer. Whereas PSA is considered to give an indication of the tumour mass, thymidine kinase indicates the rate of proliferation.[79][80][81][82] There are also reports of the utility of thymidine kinase measurements in serum in small cell lung cancer,[83][84] in breast cancer [85] and in kidney cancer.[86]

Non-malignant causes for elevation of thymidine kinase in serum are vitamin B12 deficiency, leading to pernicious anemia,[87][88] viral infections (particularly by virus from the herpes group)[88][89][90] and wound healing after trauma and operation.


Some drugs are specifically directed against dividing cells. They can be used against tumours and viral diseases (both against retrovirus and against other virus), as the diseased cells replicate much more frequently than normal cells and also against some non-malignant diseases related to excessively rapid cell replication (for instance psoriasis). There are different classes of drugs to control too fast cell division that are directed against thymidine metabolism and thereby involving thymidine kinase:[91][92][93][94]

Chain terminators are thymidine analogues that are included in the growing DNA chain, but modified so that the chain cannot be further elongated. As analogues of thymidine, they are readily phosphorylated to 5'-monophosphates. The monophosphate is further phosphorylated to the corresponding triphosphate and incorporated in the growing DNA chain. The analogue has been modified so that it does not have the hydroxyl group in the 3'-position that is required for continued chain growth. In zidovudine (AZT; ATC: J05AF01) the 3'-hydroxyl group has been replaced by an azido group,[95][96] in Stavudine (ATC: J05AF04) it has been removed without replacement.[97][98] AZT is used as substrate in one of the methods for determination of thymidine kinase in serum.[99] This implies that AZT interferes with this method and may be a limitation: AZT is a standard component of HAART therapy in HIV infection. One common consequence of AIDS is lymphoma and the most important diagnostic application of thymidine kinase determination is for monitoring of lymphoma.

Chemical structures of thymidine kinase substrate analogs

Other thymidine analogues, for instance Idoxuridine (ATC: J05AB02) act by blocking base pairing during subsequent replication cycles, thereby making the resulting DNA chain defective.[100] This may also be combined with radioactivity to achieve apoptosis of malignant cells.[101]

Some antiviral drugs, such as acyclovir (ATC: J05AB01) and ganciclovir (ATC: J05AB06) as well as other recently developed nucleoside analogs[102] make use of the specificity for viral thymidine kinase, as opposed to human thymidine kinases.[103] These drugs act as prodrugs, which in themselves are not toxic, but are converted to toxic drugs by phosphorylation by viral thymidine kinase. Cells infected with the virus therefore produce highly toxic triphosphates that lead to cell death. Human thymidine kinase, in contrast, with its more narrow specificity, is unable to phosphorylate and activate the prodrug. In this way, only cells infected by the virus are susceptible to the drug. Such drugs are effective only against viruses from the herpes group with their specific thymidine kinase.[104]

After smallpox was declared eradicated by WHO in December 1979, vaccination programs were terminated. A re-emergence of the disease either by accident or as a result of biological warfare would meet an unprotected population and could result in an epidemic that could be difficult to control. Mass vaccination would be unethical, as the only efficient vaccines against smallpox include live vaccinia virus with severe adverse effects on rare occasions. As one protective measure, large amounts of vaccine are kept in stock, but an efficient drug against smallpox has high priority. One possible approach would be to use the specificity of the thymidine kinase of poxvirus for the purpose, in a similar way that it is used for drugs against herpesvirus. One difficulty is that the poxvirus thymidine kinase belongs to the same family of thymidine kinases as the human thymidine kinases and thereby is more similar chemically. The structure of poxvirus thymidine kinases has therefore been determined to find potential antiviral drugs.[105] The search has however not yet resulted in a usable antiviral drug against poxviruses.

The herpesvirus thymidine kinase gene has also been used as a “suicide gene” as a safety system in gene therapy experiments, allowing cells expressing the gene to be killed using ganciclovir. This is desirable in case the recombinant gene causes a mutation leading to uncontrolled cell growth (insertional mutagenesis). The thymidine kinase produced by these modified cells may diffuse to neighboring cells, rendering them similarly susceptible to ganciclovir, a phenomenon known as the "bystander effect." This approach has been used to treat cancer in animal models, and is advantageous in that the tumor may be killed with as few as 10% of malignant cells expressing the gene.[106][107]

A similar use of the thymidine kinase makes use of the presence in some tumor cells of substances not present in normal cells (tumor markers). Such tumor markers are, for instance, CEA (carcinoembryonic antigen) and AFP (alpha fetoprotein). The genes for these tumor markers may be used as promoter genes for thymidine kinase. Thymidine kinase can then be activated in cells expressing the tumor marker but not in normal cells, such that treatment with ganciclovir kills only the tumor cells.[108][109][110][111][112][113] Such gene therapy-based approaches are still experimental, however, as problems associated with gene transfer have not yet been completely solved.

Incorporation of a thymidine analogue with boron has been suggested and tried in animal models for boron neutron capture therapy of brain tumours.[114][115][116][117][118][119][120][121][122][123][124]


In serum

The level of thymidine kinase in serum or plasma is so low that the measurement is best based on the enzymatic activity. In commercial assays, this is done by incubation of a serum sample with a substrate analogue. The oldest commercially available technique uses iodo-deoxyuridine wherein a methyl group in thymidine has been replaced with radioactive iodine.[125][126][127] This substrate is well accepted by the enzyme. The monophosphate of iododeoxyuridine is adsorbed on aluminium oxide that is suspended in the incubation medium. After decantation and washing the radioactivity of the aluminium oxide gives a measure of the amount of thymidine kinase in the sample. Kits using this principle are commercially available from the companies Immunotech/Beckman and DiaSorin.

A non-radioactive assay method has been developed by the company Dia-Sorin. In this technique 3'-azido-2',3'-deoxythymidine (AZT)is first phosphorylated to AZT 5'-monophosphate (AZTMP) by TK1 in the sample. AZTMP is measured in an immunoassay with anti-AZTMP antibodies and AZTMP-labeled peroxidase. The assay runs in a closed system on the laboratory robot from DiaSorin[71][99]

Another newly developed technique uses a thymidine analogue, bromo-deoxyuridine, as substrate to the enzyme. The product of the reaction (in microtiter plates) binds to the bottom of the wells in the plate. There it is detected with ELISA technique: The wells are filled with a solution of a monoclonal antibody to bromo-deoxyuridine. The monoclonal antibody has been bound (conjugated) to alkaline phosphatase (an enzyme). After the unbound antibody with attached alkaline phosphatase has been washed away, a solution of a substrate to the alkaline phosphatase, 4-nitrophenyl phosphate, is added. The product of the reaction, 4-nitrophenol, is yellow at alkaline pH and can be measured by photometry.[128] This assay gives a considerably more sensitive determination. It is commercially available from the company Biovica.

Direct determination of the thymidine kinase protein by immunoassay has also been used.[129][130][131] The amounts of thymidine kinase found by this method did not correlate well with the activities and found to have less clinical significance, and the method has been withdrawn from the market.

In tissue

Thymidine kinase has been determined in tissue samples after extraction of the tissue. No standard method for the extraction or for the assay has been developed and TK determination in extracts from cells and tissues have not been validated in relation to any specific clinical question, see however Romain et al.[132] and Arnér et al.[133] A method has been developed for specific determination of TK2 in cell extracts using the substrate analogue 5-Bromovinyl 2'-deoxyuridine.[134] In the studies referred to below the methods used and the way the results are reported are so different that comparisons between different studies are not possible.

The TK1 levels in fetal tissues during development are higher than those of the corresponding tissues later.[135][136][137]

Certain non-malignant diseases also give rise to dramatic elevation of TK values in cells and tissue: in peripheric lymphocytes during monocytosis[138] and in bone marrow during pernicious anemia.[139][140]

As TK1 is present in cells during cell division, it is reasonable to assume that the TK activity in malignant tissue should be higher than in corresponding normal tissue. This is also confirmed in most studies. A higher TK activity is found in neoplastic than in normal tissue,[135][141][142][143] in brain tumours,[144] in hematological malignancies,[145] in cancer and polyps in colon,[146][147][148][149][150][151] in breast cancer,[152][153][154][155][156][157] in lung cancer,[158][159][160] in gastric cancers,[161] in ovarian cancer,[162] in mesotheliomas,[163] in melanomas[164] and in thyroid tumours.[165][166]

In leukemia[167][168] and in breast cancer [169] therapy that influences the rate of cell proliferation influences the TK values correspondingly.

Immunohistochemical staining for thymidine kinase

Antibodies against thymidine kinase are available for immunohistochemical detection.[170] Staining for thymidine kinase was a reliable technique for identification of patients with stage 2 breast carcinoma. The highest number of patients identified was obtained by combination of thymidine kinase and Ki-67 staining.[171][172]

The technique has also been validated for lung cancer,[171][173] for colorectal carcinima,[174] for lung cancer[175] and for renal cell carcinoma.[176]

See also

Further reading

Three survey articles on different aspcets of thymidine kinase are available from the internet site of Biovica International:


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  130. ^ Kimmel N, Friedman MG, Sarov I (May 1982). "Enzyme-linked immunosorbent assay (ELISA) for detection of herpes simplex virus-specific IgM antibodies". J. Virol. Methods 4 (4–5): 219–27. doi:10.1016/0166-0934(82)90068-4. PMID 6286702. 
  131. ^ Huang, S.; Lin, J.; Guo, N.; Zhang, M.; Yun, X.; Liu, S.; Zhou, J.; He, E.; Skog, S. (2011). "Elevated serum thymidine kinase 1 predicts risk of pre/early cancerous progression". Asian Pacific journal of cancer prevention : APJCP 12 (2): 497–505. PMID 21545220.  edit
  132. ^ Romain S, Spyratos F, Guirou O, Deytieux S, Chinot O, Martin PM (1994). "Technical evaluation of thymidine kinase assay in cytosols from breast cancers. EORTC Receptor Study Group Report". Eur. J. Cancer 30A (14): 2163–5. doi:10.1016/0959-8049(94)00376-G. PMID 7857717. 
  133. ^ Arnér ES, Spasokoukotskaja T, Eriksson S (October 1992). "Selective assays for thymidine kinase 1 and 2 and deoxycytidine kinase and their activities in extracts from human cells and tissues". Biochem. Biophys. Res. Commun. 188 (2): 712–8. doi:10.1016/0006-291X(92)91114-6. PMID 1359886. 
  134. ^ Wang L, Eriksson S (June 2008). "5-Bromovinyl 2'-deoxyuridine phosphorylation by mitochondrial and cytosolic thymidine kinase (TK2 and TK1) and its use in selective measurement of TK2 activity in crude extracts". Nucleosides Nucleotides Nucleic Acids 27 (6): 858–62. doi:10.1080/15257770802146510. PMID 18600552. 
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  136. ^ Machovich R, Greengard O (December 1972). "Thymidine kinase in rat tissues during growth and differentiation". Biochim. Biophys. Acta 286 (2): 375–81. doi:10.1016/0304-4165(72)90273-5. PMID 4660462. 
  137. ^ Herzfeld A, Raper SM, Gore I (December 1980). "The ontogeny of thymidine kinase in tissues of man and rat". Pediatr. Res. 14 (12): 1304–10. doi:10.1203/00006450-198012000-00006. PMID 7208144. 
  138. ^ Schollenberger S, Taureck D, Wilmanns W (November 1972). "[Enzymes of thymidine and thymidylate metabolism in normal and pathological blood and bone marrow cells]" [Enzymes of thymidine and thymidylate metabolism in normal and pathological blood and bone marrow cells]. Blut (in German) 25 (5): 318–34. doi:10.1007/BF01631814. PMID 4508724. 
  139. ^ Nakao K, Fujioka S (April 1968). "Thymidine kinase activity in the human bone marrow from various blood diseases". Life Sci. 7 (8): 395–9. doi:10.1016/0024-3205(68)90039-8. PMID 5649653. 
  140. ^ Wickramasinghe SN, Olsen I, Saunders JE (September 1975). "Thymidine kinase activity in human bone marrow cells". Scand J Haematol 15 (2): 139–44. doi:10.1111/j.1600-0609.1975.tb01065.x. PMID 1059244. 
  141. ^ Gordon HL, Bardos TJ, Chmielewicz ZF, Ambrus JL (October 1968). "Comparative study of the thymidine kinase and thymidylate kinase activities and of the feedbach inhibition of thymidine kinase in normal and neoplastic human tissue". Cancer Res. 28 (10): 2068–77. PMID 5696936. 
  142. ^ Stafford MA, Jones OW (August 1972). "The presence of "fetal" thymidine kinase in human tumors". Biochim. Biophys. Acta 277 (2): 439–42. doi:10.1016/0005-2787(72)90423-6. PMID 4672678. 
  143. ^ Maehara Y, Nakamura H, Nakane Y, et al. (April 1982). "Activities of various enzymes of pyrimidine nucleotide and DNA syntheses in normal and neoplastic human tissues". Gann 73 (2): 289–98. PMID 6288502. 
  144. ^ Persson L, Gronowitz SJ, Källander CF (1986). "Thymidine kinase in extracts of human brain tumours". Acta Neurochir (Wien) 80 (3–4): 123–7. doi:10.1007/BF01812286. PMID 3012969. 
  145. ^ Filanovskaia LI, Togo AV, Shcherbakova EG, Blinov MN (1994). "[Thymidine kinase activity in leukocytes from patients with chronic myeloid leukemia at various periods in the disease]" [Thymidine kinase activity in leukocytes from patients with chronic myeloid leukemia at various periods in the disease]. Vopr. Med. Khim. (in Russian) 40 (1): 29–32. PMID 8122406. 
  146. ^ Lipkin M (July 1971). "Proliferation and differentiation of normal and neoplastic cells in the colon of man". Cancer 28 (1): 38–40. doi:10.1002/1097-0142(197107)28:1<38::AID-CNCR2820280108>3.0.CO;2-W. PMID 5110642. 
  147. ^ Lipkin M, Deschner E, Troncale F (1970). "Cell differentiation and the development of colonic neoplasms". CA Cancer J Clin 20 (6): 386–90. doi:10.3322/canjclin.20.6.386. PMID 4992499. 
  148. ^ Weber G, Lui MS, Takeda E, Denton JE (September 1980). "Enzymology of human colon tumors". Life Sci. 27 (9): 793–9. doi:10.1016/0024-3205(80)90333-1. PMID 7412505. 
  149. ^ Sagara T, Tsukada K, Iwama T, Mishima Y, Sakamoto S, Okamoto R (August 1985). "[Thymidine kinase isozymes in human colon polyps]" [Thymidine kinase isozymes in human colon polyps]. Nippon Gan Chiryo Gakkai Shi (in Japanese) 20 (7): 1312–6. PMID 4078430. 
  150. ^ Sakamoto S, Sagara T, Iwama T, Kawasaki T, Okamoto R (June 1985). "Increased activities of thymidine kinase isozymes in human colon polyp and carcinoma". Carcinogenesis 6 (6): 917–9. doi:10.1093/carcin/6.6.917. PMID 4006080. 
  151. ^ Sakamoto S, Okamoto R (October 1992). "Thymidine kinase activity in familial adenomatous polyposis". Tohoku J. Exp. Med. 168 (2): 291–301. doi:10.1620/tjem.168.291. PMID 1339104. [dead link]
  152. ^ Galloux H, Javre JL, Guerin D, Sampérez S, Jouan P (1988). "[Prognostic value of fetal thymidine kinase measurements in breast cancer]" [Prognostic value of fetal thymidine kinase measurements in breast cancer]. C. R. Acad. Sci. III, Sci. Vie (in French) 306 (3): 89–92. PMID 3126994. 
  153. ^ O'Neill KL, Hoper M, Odling-Smee GW (December 1992). "Can thymidine kinase levels in breast tumors predict disease recurrence?". J. Natl. Cancer Inst. 84 (23): 1825–8. doi:10.1093/jnci/84.23.1825. PMID 1433372. 
  154. ^ O'Neill KL, McKelvey VJ, Hoper M, et al. (December 1992). "Breast tumour thymidine kinase levels and disease recurrence". Med Lab Sci 49 (4): 244–7. PMID 1339926. 
  155. ^ Romain S, Javre JL, Samperez S, et al. (1990). "[Prognostic value of thymidine kinase in cancer of the breast]" [Prognostic value of thymidine kinase in cancer of the breast]. Bull Cancer (in French) 77 (10): 973–83. PMID 2249017. 
  156. ^ Romain S, Chinot O, Guirou O, Soullière M, Martin PM (October 1994). "Biological heterogeneity of ER-positive breast cancers in the post-menopausal population". Int. J. Cancer 59 (1): 17–9. doi:10.1002/ijc.2910590105. PMID 7927897. 
  157. ^ Sakamoto S, Iwama T, Ebuchi M, et al. (April 1986). "Increased activities of thymidine kinase isozymes in human mammary tumours". Br J Surg 73 (4): 272–3. doi:10.1002/bjs.1800730409. PMID 3697655. 
  158. ^ Greengard O, Head JF, Goldberg SL, Kirschner PA (February 1982). "Enzyme pathology and the histologic categorization of human lung tumors: the continuum of quantitative biochemical indices of neoplasticity". Cancer 49 (3): 460–7. doi:10.1002/1097-0142(19820201)49:3<460::AID-CNCR2820490312>3.0.CO;2-Y. PMID 6277448. 
  159. ^ Greengard O, Head JF, Goldberg SL, Kirschner PA (April 1985). "Biochemical measure of the volume doubling time of human pulmonary neoplasms". Cancer 55 (7): 1530–5. doi:10.1002/1097-0142(19850401)55:7<1530::AID-CNCR2820550720>3.0.CO;2-V. PMID 2983858. 
  160. ^ Yusa T, Tamiya N, Yamaguchi Y, et al. (March 1994). "[A study of thymidine kinase activity in lung cancer tissue]" [A study of thymidine kinase activity in lung cancer tissue]. Nihon Kyobu Shikkan Gakkai Zasshi (in Japanese) 32 (3): 211–5. PMID 8189640. 
  161. ^ Konishi T, Miyama T, Sakamoto S, et al. (June 1992). "Activities of thymidylate synthetase and thymidine kinase in gastric cancer". Surg Oncol 1 (3): 215–21. doi:10.1016/0960-7404(92)90067-U. PMID 1341254. 
  162. ^ Look KY, Moore DH, Sutton GP, Prajda N, Abonyi M, Weber G (1997). "Increased thymidine kinase and thymidylate synthase activities in human epithelial ovarian carcinoma". Anticancer Res. 17 (4A): 2353–6. PMID 9252646. 
  163. ^ Greengard O, Head JF, Chahinian AP, Goldberg SL (April 1987). "Enzyme pathology of human mesotheliomas". J. Natl. Cancer Inst. 78 (4): 617–22. PMID 2882044. 
  164. ^ Borovanský J, Stríbrná J, Elleder M, Netíková I (October 1994). "Thymidine kinase in malignant melanoma". Melanoma Res. 4 (5): 275–9. doi:10.1097/00008390-199410000-00001. PMID 7858409. 
  165. ^ Sakamoto S, Murakami S, Sugawara M, Mishima Y, Okamoto R (1991). "Increased activities of thymidylate synthetase and thymidine kinase in human thyroid tumors". Thyroid 1 (4): 347–51. doi:10.1089/thy.1991.1.347. PMID 1841732. 
  166. ^ Pikner R, Ludvíkova M, Ryska A, et al. (2005). "TPS, thymidine kinase, VEGF and endostatin in cytosol of thyroid tissue samples". Anticancer Res. 25 (3A): 1517–21. PMID 16033053. 
  167. ^ Wilms K, Wilmanns W (September 1972). "[Effects of dauno-rubidomycin and adriamycin on enzymes of DNA synthesis in leukocytes in vivo and in culture]" [Effects of dauno-rubidomycin and adriamycin on enzymes of DNA synthesis in leukocytes in vivo and in culture]. Klin. Wochenschr. (in German) 50 (18): 866–70. doi:10.1007/BF01488943. PMID 4507472. 
  168. ^ Wilmanns W, Wilms K (1972). "DNA synthesis in normal and leucemic cells as related to therapy with cytotoxic drugs". Enzyme 13 (1): 90–109. PMID 4507104. 
  169. ^ Zhang HJ, Kennedy BJ, Kiang DT (1984). "Thymidine kinase as a predictor of response to chemotherapy in advanced breast cancer". Breast Cancer Res. Treat. 4 (3): 221–5. doi:10.1007/BF01806488. PMID 6487823. 
  170. ^ Kuroiwa N, Nakayama M, Fukuda T, et al. (July 2001). "Specific recognition of cytosolic thymidine kinase in the human lung tumor by monoclonal antibodies raised against recombinant human thymidine kinase". Journal of Immunology Methods 253 (1–2): 1–11. doi:10.1016/S0022-1759(01)00368-4. PMID 11384664. 
  171. ^ a b He Q, Mao Y, Wu J, et al. (October 2004). "Cytosolic thymidine kinase is a specific histopathologic tumour marker for breast carcinomas". Int. J. Oncol. 25 (4): 945–53. PMID 15375544. 
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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Thymidine kinase Provide feedback

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Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001267

Thymidine kinase (TK) (EC) is an ubiquitous enzyme that catalyzes the ATP-dependent phosphorylation of thymidine.

Two different families of Thymidine kinase have been identified [PUBMED:3027984, PUBMED:2389555] and are represented in this entry; one groups together Thymidine kinase from herpesviruses, as well as cytosolic thymidylate kinases and the second family groups Thymidine kinase from various sources that include, vertebrates, bacteria, the Bacteriophage T4, poxviruses, African swine fever virus (ASFV) and Fish lymphocystis disease virus (FLDV). The major capsid protein of insect iridescent viruses also belongs to this family.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan P-loop_NTPase (CL0023), which has the following description:

AAA family proteins often perform chaperone-like functions that assist in the assembly, operation, or disassembly of protein complexes [2].

The clan contains the following 198 members:

6PF2K AAA AAA-ATPase_like AAA_10 AAA_11 AAA_12 AAA_13 AAA_14 AAA_15 AAA_16 AAA_17 AAA_18 AAA_19 AAA_2 AAA_21 AAA_22 AAA_23 AAA_24 AAA_25 AAA_26 AAA_27 AAA_28 AAA_29 AAA_3 AAA_30 AAA_31 AAA_32 AAA_33 AAA_34 AAA_35 AAA_4 AAA_5 AAA_6 AAA_7 AAA_8 AAA_9 AAA_PrkA ABC_ATPase ABC_tran ABC_tran_2 Adeno_IVa2 Adenylsucc_synt ADK AFG1_ATPase AIG1 APS_kinase Arch_ATPase Arf ArgK ArsA_ATPase ATP-synt_ab ATP_bind_1 ATP_bind_2 Bac_DnaA CbiA CMS1 CoaE CobA_CobO_BtuR CobU cobW CPT CTP_synth_N Cytidylate_kin Cytidylate_kin2 DAP3 DEAD DEAD_2 DLIC DNA_pack_C DNA_pack_N DNA_pol3_delta DNA_pol3_delta2 DnaB_C dNK DUF1253 DUF1611 DUF2075 DUF2478 DUF258 DUF2791 DUF2813 DUF3584 DUF463 DUF815 DUF853 DUF87 DUF927 Dynamin_N Exonuc_V_gamma FeoB_N Fer4_NifH Flavi_DEAD FTHFS FtsK_SpoIIIE G-alpha Gal-3-0_sulfotr GBP GTP_EFTU GTP_EFTU_D2 GTP_EFTU_D4 Gtr1_RagA Guanylate_kin GvpD HDA2-3 Helicase_C Helicase_C_2 Helicase_C_4 Helicase_RecD Herpes_Helicase Herpes_ori_bp Herpes_TK IIGP IPPT IPT IstB_IS21 KaiC KAP_NTPase Kinesin Kinesin-relat_1 Kinesin-related KTI12 LpxK MCM MEDS Mg_chelatase Mg_chelatase_2 MipZ Miro MMR_HSR1 MobB MukB MutS_V Myosin_head NACHT NB-ARC NOG1 NTPase_1 ParA Parvo_NS1 PAXNEB PduV-EutP PhoH PIF1 Podovirus_Gp16 Polyoma_lg_T_C Pox_A32 PPK2 PPV_E1_C PRK Rad17 Rad51 Ras RecA ResIII RHD3 RHSP RNA12 RNA_helicase RuvB_N SbcCD_C SecA_DEAD Septin Sigma54_activ_2 Sigma54_activat SKI SMC_N SNF2_N Spore_IV_A SRP54 SRPRB Sulfotransfer_1 Sulfotransfer_2 Sulfotransfer_3 Sulphotransf T2SE T4SS-DNA_transf Terminase_1 Terminase_3 Terminase_6 Terminase_GpA Thymidylate_kin TIP49 TK TniB Torsin TraG-D_C tRNA_lig_kinase TrwB_AAD_bind UPF0079 UvrD-helicase UvrD_C UvrD_C_2 Viral_helicase1 VirC1 VirE YhjQ Zeta_toxin Zot


We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...


This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: none
Type: Family
Author: Finn RD
Number in seed: 13
Number in full: 3293
Average length of the domain: 177.10 aa
Average identity of full alignment: 38 %
Average coverage of the sequence by the domain: 89.01 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.6 20.6
Trusted cut-off 20.6 20.6
Noise cut-off 20.5 20.5
Model length: 176
Family (HMM) version: 13
Download: download the raw HMM for this family

Species distribution

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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There is 1 interaction for this family. More...



For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the TK domain has been found. There are 53 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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