Thymidylate kinase

From Proteopedia

Contents 1 Function 2 Relevance 3 Structural highlights 4 3D Structures of thymidylate kinase 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]. Azido-thymidine binding site. Water molecules are shown as red spheres. Mg coordination site. ATM binding site. Whole binding site. 3D Structures of thymidylate kinase Thymidylate kinase 3D structures

spinqualitylabelsall models Human thymidylate kinase complex with HIV prodrug AZTP, ADP and Mg+2 ion (green) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

References

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