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Human guanine monophosphate synthetase - glutaminase domain

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PDB Code 2VPI Target Class Nucleotide metabolism Target GMPS Alias GMPS Disease Area/Function cancer Date Deposited Feb 29 2008 Authors M.WELIN, L.TRESAUGUES, C.H.ARROWSMITH, H.BERGLUND, R.D.BUSAM, R.COLLINS, L.G.DAHLGREN, A.M.EDWARDS, S.FLODIN, A.FLORES, S.GRASLUND, M.HAMMARSTROM, M.D.HERMAN, I.JOHANSSON, A.KALLAS, T.KARLBERG, T.KOTENYOVA, L.LEHTIO, M.MOCHE, M.E.NILSSON, T.NYMAN, C.PERSSON, J.SAGEMARK, L.SVENSSON, A.G.THORSELL, S.VAN DEN BERG, J.WEIGELT, P.NORDLUND. Related Structure 2VXO

About this structure

GMP synthetase (GMPS, E.C. 6.3.5.2) is a glutamine amidotransferase involved in the de novo synthesis of purines. It catalyzes the conversion xanthosine 5'-phosphate to guanosine 5'-phosphate in the presence of glutamine and ATP. GMPS is a bifunctional enzyme with two domains, an N-terminal glutaminase domain that generates ammonia from glutamine, and a C-terminal synthetase domain that in turn aminates XMP to form GMP [1].

XMP + ATP + GLN + H2O -> GMP + AMP + GLU + PPi

The active site of GMPS has been observed to have increased activity in rapidly proliferating cells and is thus a potential target for anticancer therapies and glutamine analogs, like acivicin has been shown to inhibit GMPS [2,3,4]. The structure of the E. coli GMPS revealed that the active sites of the two domains are separated by 30 Å, but no obvious route for the ammonia transfer could be obtained. Instead large movements between the domains during reaction have been suggested [1,5].

Here we have solved the structure of the glutaminase domain of human GMPS to a resolution of 2.4 Å. The structure was solved with molecular replacement using the glutaminase domain of E. coli GMP synthetase (pdb-code: 1GPM). GMPS belongs to the class 1 glutamine dependent amidotranferases which has a conserved catalytic triad consisting of a Cys-His-Glu [5]. The corresponding residues of the catalytic triad in GMPS are Cys104, His190 and Glu192. So far no structural information regarding glutamine binding of GMP synthetases has been obtained. In the structure of the glutaminase domain of GMPS, the C-terminal of a symmetry related molecule is bound in proximity to the catalytic triad.

References

  1. Huang X, Holden HM, Raushel FM. Channeling of substrates and intermediates in enzyme-catalyzed reactions. Annu Rev Biochem. 2001;70:149-80.
  2. Hirst M, Haliday E, Nakamura J, Lou L. Human GMP synthetase. Protein purification, cloning, and functional expression of cDNA.. J Biol Chem. 1994 Sep 23;269(38):23830-7.
  3. Nakamura J, Straub K, Wu J, Lou L. The glutamine hydrolysis function of human GMP synthetase. Identification of an essential active site cysteine. J Biol Chem. 1995 Oct 6;270(40):23450-5.
  4. Chittur SV, Klem TJ, Shafer CM, Davisson VJ. Mechanism for acivicin inactivation of triad glutamine amidotransferases. Biochemistry. 2001 Jan 30;40(4):876-87.
  5. Tesmer JJ, Klem TJ, Deras ML, Davisson VJ, Smith JL. The crystal structure of GMP synthetase reveals a novel catalytic triad and is a structural paradigm for two enzyme families. Nat Struct Biol. 1996 Jan;3(1):74-86.