Thymidylate kinase: Difference between revisions

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{{STRUCTURE_1e99|  PDB=1e99  | SIZE=350| SCENE= |right|CAPTION=Human thymidylate kinase complex with HIV prodrug AZTP, ADP (stick model) and Mg+2 ion (green) [[1e99]] }}
<StructureSection load='' size='350' side='right' scene='54/542330/Cv/1' caption='Human thymidylate kinase complex with HIV prodrug AZTP, ADP and Mg+2 ion (green)'>
__TOC__
== Function ==
'''Thymidylate kinase''' (TMK) catalyzes the conversion of thymidine-5’-phosphate (dTMP) and ATP to thymidine-5’-diphosphate and ADP.  TMK is important for DNA synthesis<ref>PMID:23394555</ref>.  Inhibitors of TMK include bisubstrate compounds of the type TP(n)X where P(n) are the number of phosphoryl groups and X is the nucleoside moiety of the acceptor.  For more details see [[Student Project 8 for UMass Chemistry 423 Spring 2015]].


'''Thymidylate kinase''' (TMK) catalyzes the conversion of thymidine-5’-phosphate (dTMP) and ATP to thymidine-5’-diphosphate and ADP.  TMK is important for DNA synthesis.  Inhibitors of TMK include bisubstrate compounds of the type TP(n)X where P(n) are the number of phosphoryl groups and X is the nucleoside moiety of the acceptor.  The TMK inhibitor azido-dTMP (AZTP) is an HIV AZT prodrug metabolite.  For more details see [[Student Project 8 for UMass Chemistry 423 Spring 2015]].
== Relevance ==
The TMK inhibitor azido-dTMP (AZTP) is an HIV AZT prodrug metabolite<ref>PMID:15722537</ref>.  Inhibitors of TMK are used as antibacterial agents<ref>PMID:23043329</ref>.


== Structural highlights ==
The active site of TMK contains HIV prodrug azido-thymidine, ADP and Mg+2 ion<ref>PMID:11071809</ref>.
*<scene name='54/542330/Cv/6'>Azido-thymidine binding site</scene>. Water molecules are shown as red spheres.
*<scene name='54/542330/Cv/7'>Mg coordination site</scene>.
*<scene name='54/542330/Cv/8'>ATM binding site</scene>.
*<scene name='54/542330/Cv/9'>Whole binding site</scene>.
== 3D Structures of thymidylate kinase ==
== 3D Structures of thymidylate kinase ==
[[Thymidylate kinase 3D structures]]


Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
</StructureSection>
{{#tree:id=OrganizedByTopic|openlevels=0|


*Thymidylate kinase
== References ==
 
<references/>
**[[2cck]], [[4f4i]] – SaTMK  – ''Staphylococcus aureus'' <br />
**[[2pbr]] – TMK  – ''Aquifex aeolicus'' <br />
**[[2plr]] – TMK  – ''Sulfolobus tokodaii'' <br />
**[[3ld9]] – TMK – ''Ehrlichia chafeensis''<br />
**[[3v9p]] – TMK – ''Burkholderia thailandensis''<br />
**[[3uwk]], [[3uwo]] – PaTMK – ''Pseudomonas aeruginosa''<br />
 
*Thymidylate kinase complex with HIV prodrug AZT derivative
 
**[[2tmk]] – yTMK + AZTP <br />
**[[4eaq]] – SaTMK + AZTP <br />
**[[4gmd]] – PaTMK + AZTP <br />
**[[4tmk]], [[5tmp]] – TMK + AZTP – ''Escherichia coli''<br />
**[[1w2h]] – MtTMK + AZTP - ''Mycobacterium tuberculosis'' <br />
**[[1e98]], [[1e99]], [[1e9d]] – hTMK (mutant) + AZTP + ADP<br />
 
*Thymidylate kinase complex with nucleotides
 
**[[2v54]] – VvTMK  + TDP – Vaccinia virus<br />
**[[2w0s]] – VvTMK + brivudin-MP <br />
**[[1tmk]] – yTMK + dTMP - yeast<br />
**[[4e5u]] – PaTMK + dTMP <br />
**[[2ccg]], [[2ccj]], [[4dwj]] – SaTMK + dTMP <br />
**[[1g3u]], [[1gsi]], [[1n5i]], [[1n5k]] – MtTMK + dTMP <br />
**[[1w2g]] – MtTMK + thymidine  <br />
**[[1gtv]] – MtTMK + TDP  <br />
**[[1n5j]] – MtTMK + TDP  + TTP<br />
**[[1n5l]] – MtTMK + TDP + dTMP <br />
**[[1mrs]] – MtTMK + UMP derivative  <br />
**[[3uxm]], [[4esh]] – PaTMK + deoxy thymidine derivative <br />
**[[3hjn]] – TMK + ADP + TDP – ''Thermotoga maritima''<br />
**[[1e2d]], [[1e2e]], [[1e2f]], [[1e9e]], [[1e9f]] – hTMK (mutant) + ADP + dTMP - human<br />
**[[1e9f]] – hTMK (mutant) + ADP + dTMP - human<br />
**[[4edh]] – PaTMK + ADP + dTMP <br />
**[[3lv8]] – VcTMK + ADP + dTMP  + TDP – ''Vibrio cholerae''<br />
**[[3n2i]] – VcTMK + thymidine  + thymidine deoxy-thymidine<br />
**[[1e9b]] – hTMK (mutant) + azido-TMP + APPNP<br />
**[[1e9c]] – hTMK (mutant) + dTMP + APPNP<br />
**[[1nmx]] – hTMK (mutant) + F-TMP + ADP<br />
**[[1nmy]], [[1nn0]], [[1nnz]], [[1nn1]], [[1nn3]], [[1nn5]], [[1nmz]] – hTMK (mutant) + dTMP derivative + APPNP<br />
**[[2xx3]] – hTMK + dTMP derivative + ADP<br />
**[[2yof]], [[2yog]], [[2yoh]] - TMK + thymidine analog – ''Plasmodium falciparum''<br />
 
*Other thymidylate kinase binary complexes
 
**[[4gfd]], [[4hlc]], [[4hld]], [[4hej]], [[4hdc]] – SaTMK + antibacterial drug <br />
**[[4gsy]], [[4qg7]], [[4xwa]] – SaTMK + inhibitor<br />
**[[4qg7]], [[4qgf]], [[4qgg]], [[4qgh]] – SaTMK (mutant) + inhibitor<br />
**[[4mqb]] – SaTMK + MES<br />
**[[4unp]] – MtTMK + inhibitor<br />
 
*Thymidylate kinase complex with bisubstrate inhibitor
 
**[[1mrn]] – MtTMK + TP5A  <br />
**[[3tmk]] – yTMK + TP5A <br />
**[[1e9a]] – hTMK (mutant) + azido-TP5A + ADP<br />
}}
[[Category:Topic Page]]
[[Category:Topic Page]]

Latest revision as of 14:13, 23 February 2020

Function

Thymidylate kinase (TMK) catalyzes the conversion of thymidine-5’-phosphate (dTMP) and ATP to thymidine-5’-diphosphate and ADP. TMK is important for DNA synthesis[1]. Inhibitors of TMK include bisubstrate compounds of the type TP(n)X where P(n) are the number of phosphoryl groups and X is the nucleoside moiety of the acceptor. For more details see Student Project 8 for UMass Chemistry 423 Spring 2015.

Relevance

The TMK inhibitor azido-dTMP (AZTP) is an HIV AZT prodrug metabolite[2]. Inhibitors of TMK are used as antibacterial agents[3].

Structural highlights

The active site of TMK contains HIV prodrug azido-thymidine, ADP and Mg+2 ion[4].

  • . Water molecules are shown as red spheres.
  • .
  • .
  • .

3D Structures of thymidylate kinase

Thymidylate kinase 3D structures


Human thymidylate kinase complex with HIV prodrug AZTP, ADP and Mg+2 ion (green)

Drag the structure with the mouse to rotate

ReferencesReferences

  1. ↑ Cui Q, Shin WS, Luo Y, Tian J, Cui H, Yin D. Thymidylate kinase: an old topic brings new perspectives. Curr Med Chem. 2013;20(10):1286-305. PMID:23394555
  2. ↑ Wohrl BM, Loubiere L, Brundiers R, Goody RS, Klatzmann D, Konrad M. Expressing engineered thymidylate kinase variants in human cells to improve AZT phosphorylation and human immunodeficiency virus inhibition. J Gen Virol. 2005 Mar;86(Pt 3):757-64. PMID:15722537 doi:http://dx.doi.org/10.1099/vir.0.80529-0
  3. ↑ Martinez-Botella G, Breen JN, Duffy JE, Dumas J, Geng B, Gowers IK, Green OM, Guler S, Hentemann MF, Hernandez-Juan FA, Joseph-McCarthy D, Kawatkar SP, Larsen NA, Lazari O, Loch JT, Macritchie JA, McKenzie AR, Newman JV, Olivier NB, Otterson LG, Owens AP, Read J, Sheppard DW, Keating TA. Discovery of Selective and Potent Inhibitors of Gram-positive Bacterial Thymidylate Kinase (TMK). J Med Chem. 2012 Oct 8. PMID:23043329 doi:http://dx.doi.org/10.1021/jm3011806
  4. ↑ Ostermann N, Lavie A, Padiyar S, Brundiers R, Veit T, Reinstein J, Goody RS, Konrad M, Schlichting I. Potentiating AZT activation: structures of wild-type and mutant human thymidylate kinase suggest reasons for the mutants' improved kinetics with the HIV prodrug metabolite AZTMP. J Mol Biol. 2000 Nov 17;304(1):43-53. PMID:11071809 doi:10.1006/jmbi.2000.4175

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Michal Harel, Alexander Berchansky, Joel L. Sussman
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