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Human glycinamide ribonucleotide synthetase

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PDB Code 2QK4 Target Class Nucleotide metabolism Target GART Alias AIRS, GARS, GART, GARTF, MGC47764, PAIS, PGFT, PRGS Disease Area/Function cancer Date Deposited Jul 10 2007 Authors LEHTIO, L., WELIN, M., ARROWSMITH, C., BERGLUND, H., BUSAM, R., COLLINS, R., DAHLGREN, L.G., HERMAN, M.D., EDWARDS, A., FLODIN, S., FLORES, A., GRASLUND, S., HAMMARSTROM, M., HALLBERG, B.M., HOLMBERG-SCHIAVONE, L., JOHANSSON, I., KALLAS, A., KARLBERG, T., KOTENYOVA, T., MOCHE, M., NYMAN, T., PERSSON, C., SAGEMARK, J., STENMARK, P., SUNDSTROM, M., THORSELL, A.G., TRESAUGUES, L., VAN DEN BERG, S., WEIGELT, J., NORDLUND, P. Related Structure 2V9Y

About this structure

Glycinamide ribonucleotide synthetase (GARS) forms an N-terminal domain of a trifunctional human enzyme encoded by GART-gene catalyzing three enzymatic reactions in the purine de novo synthesis pathway: glycinamide ribonucleotide synthetase, glycinamide ribonucleotide transformylase and aminoimidazole ribonucleotide synthetase [1]. The three domains catalyze the steps 2, 5 and 3 of the purine synthesis pathway, respectively. The structure reported here is of the N-terminal domain catalyzing the ATP-dependent synthesis of glycinamide ribonucleotide from an unstable phosphoribosylamine amine intermediate and glycine. The instability of the substrate requires substrate channeling to GARS from the previous enzyme in the pathway, phosphoribosyl pyrophosphate amidotransferase, by a mechanism, which is not yet understood [2].

Structure of an E. coli glycinamide ribonucleotide synthetase, which is in contrast to the eukaryotic enzyme, encoded as a polypeptide with single function, has been reported before [3; PDB id: 1GSO] and here we report the structure of a human enzyme in complex with a cofactor, ATP.

Inhibitors of purine synthesis are effective against cancer and inflammation and thus the enzymes of the pathway are potential targets for drug design [1].

References

  1. Adam, T. (2005) Purine de novo synthesis – mechanism and clinical implications Klin. Biochem. Metab. 13:177-181.
  2. Rudolph, J. & Stubbe, J. (1995) Investigation of the mechanism of phosphoribosylamine transfer from glutamine phosphoribosylpyrophosphate amidotransferase to glycinamide ribonucleotide synthetase. Biochemistry 34:2241-2250.
  3. Wang, W., Kappock, T.J., Stubbe, J. & Ealick, S.E. (1998) X-ray crystal structure of glycinamide ribonucleotide synthetase from Escherichia coli. Biochemistry 37:15647-15662.