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Human dCMP deaminase

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PDB Code 2W4L Target Class Nucleotide metabolism Target DCTD Alias DCTD, MGC111062 Disease Area/Function cancer Date Deposited Nov 28 2008 Authors M.I.Siponen, M.Moche, C.H.Arrowsmith, H.Berglund, C.Bountra, R.Collins, L.G.Dahlgren, A.M.Edwards, S.Flodin, A.Flores, S.Graslund, M.Hammarstrom, A.Johansson, I.Johansson, T.Karlberg, T.Kotenyova, L.Lehtio, M.E.Nilsson, T.Nyman, C.Persson, J.Sagemark, H.Schuler, A.G.Thorsell, L.Tresaugues, S.VanDenBerg, J.Weigelt, M.Welin, M.Wikstrom, M.Wisniewska, P.Nordlund

About this structure

2´-Deoxycytidylate deaminase (dCMP deaminase or dCD) is a key enzyme in the pyrimidine metabolism catalysing the deamination of deoxycytidine monophosphate (dCMP) into deoxyuridine-5´-monophosphate (dUMP). In humans, dCMP deaminase is hexameric and allosterically activated by magnesium associated dCTP (Mg*dCTP) while inhibited by deoxythymidine-5'-triphosphated (dTTP)(1-3). In Humans, dCD modifies several anticancer(4) and antiviral(5) drugs by deamination thereby reducing drug efficiency giving dCD inhibitors therapeutic potential. A crystal structure of the dCD enzyme from Streptococcus mutans was recently determined with the active site zinc to 3.0Å resolution (2HVV) and in complex with zinc, Mg*dCTP and the substrate analogue DHOMP to 1.7Å resolution (2HVW) (6).

We have determined the crystal structure of human dCMP deaminase to 2.1Å resolution with a zinc ion in the active site (2W4L). The enzyme is found to be hexameric and current experiments aim to determine the structural basis for its allosteric mechanism. Comparing this human and S. mutans dCD enzymes reveal that the protein part, bridging the allosteric effector and the zinc active sites, is quite different between the two enzymes.

References

  1. G. F. Maley, F. Maley, Science 141, 1278 (Sep 27, 1963).
  2. G. F. Maley, F. Maley, Biochemistry 21, 3780 (Aug 3, 1982).
  3. W. R. Mancini, Y. C. Cheng, Mol Pharmacol 23, 159 (Jan, 1983).
  4. B. Hernandez-Santiago et al., Antimicrob Agents Chemother 46, 1728 (Jun, 2002).
  5. J. Y. Liou, P. Krishnan, C. C. Hsieh, G. E. Dutschman, Y. C. Cheng, Mol Pharmacol 63, 105 (Jan, 2003).
  6. H. F. Hou, Y. H. Liang, L. F. Li, X. D. Su, Y. H. Dong, J Mol Biol 377, 220 (Mar 14, 2008).