'''TOXOPLASMA GONDII HYPOXANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASE WITH XMP, PYROPHOSPHATE AND TWO MG2+ IONS'''
===TOXOPLASMA GONDII HYPOXANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASE WITH XMP, PYROPHOSPHATE AND TWO MG2+ IONS===
==Overview==
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The crystal structure of the Toxoplasma gondii hypoxanthine-guanine phosphoribosyltransferase (HGPRT)-xanthosine 5'-monophosphate (XMP)-pyrophosphate-Mg(2+) ternary complex has been determined at 1. 60 A resolution. This biproduct, post-transition state structure is of a T. gondii HGPRT mutant (Asp150Ala or D150A). The D150A mutant has reduced activity (k(cat) lower by 11-, 296-, and 8.6-fold for hypoxanthine, guanine, and xanthine, respectively) compared to wild-type T. gondii HGPRT. The Michaelis constants for purine bases are altered only slightly, whereas those for alpha-D-5-phosphoribosyl 1-pyrophosphate (PRPP) are lower by approximately 6.5-fold. The ternary complex crystallizes in space group C222(1) (a = 55.21 A, b = 112.25 A, and c = 144.28 A) with two subunits in the asymmetric unit; the HGPRT tetramer is completed by the application of 2-fold crystallographic symmetry. All active sites contain XMP inverted question markbound in a fashion similar to that of the guanosine 5'-monophosphate (GMP) and inosine 5'-monophosphate (IMP) complexes reported in the preceding article [Heroux, A., et al. (1999) Biochemistry 38, 14485-14494] inverted question mark, pyrophosphate, and two Mg(2+) ions. Each Mg(2+) ion is octahedrally coordinated by two terminal pyrophosphate oxygen atoms and several ordered water molecules. This structure shows how HGPRT uses two Mg(2+) ions to orient and activate the pyrophosphate moiety of PRPP for attack by a purine base, and why mutation in humans of the residue corresponding to Asp206, the only HGPRT amino acid that directly contacts the Mg(2+) ions, causes Lesch-Nyhan syndrome (HGPRT(Kinston), D193N). The Leu78-Lys79 peptide bond in the active site adopts the cis configuration, which it must to bind PRPP or pyrophosphate. The contribution of cis-trans isomerization of this peptide bond to the energetics of substrate binding and product release is discussed. A comprehensive description of the HGPRT reaction mechanism is also proposed.
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{{ABSTRACT_PUBMED_10545171}}
==About this Structure==
==About this Structure==
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[[Category: Purine salvage]]
[[Category: Purine salvage]]
[[Category: Transferase]]
[[Category: Transferase]]
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Revision as of 16:18, 29 July 2008
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TOXOPLASMA GONDII HYPOXANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASE WITH XMP, PYROPHOSPHATE AND TWO MG2+ IONSTOXOPLASMA GONDII HYPOXANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASE WITH XMP, PYROPHOSPHATE AND TWO MG2+ IONS
Crystal structure of Toxoplasma gondii hypoxanthine-guanine phosphoribosyltransferase with XMP, pyrophosphate, and two Mg(2+) ions bound: insights into the catalytic mechanism., Heroux A, White EL, Ross LJ, Davis RL, Borhani DW, Biochemistry. 1999 Nov 2;38(44):14495-506. PMID:10545171
