THE 1.8 Å RESOLUTION CRYSTAL STRUCTURE OF HGPRTASE FROM THE HUMAN PARASITE SCHISTOSOMA MANSONI WITH BOUND INHIBITOR Pamela J. Focia, Douglas M. Freymann, John R. Somoza, Ching C. Wang, Robert J. Fletterick, Departments of Pharmaceutical Chemistry and Biochemistry and Biophysics, U.C.S.F.

The crystal structure of an enzyme crucial for nucleotide metabolism in the human parasite Schistosoma mansoni has been solved and compared to the human homolog. The differences between the two structures will guide structure based drug design efforts against the parasite.

Schistosomiasis affects over 300 million people in tropical countries who become infected with the parasite through fresh water contact. The parasite, S. mansoni, has been found to lack de novo nucleotide biosynthesis, and relies on recycling the host's nucleotide precursors for cellular metabolism. The purines guanine and hypoxanthine are recycled via the salvage pathway by hypoxanthine-guanine phosphoribosyltransferase, HGPRTase, to form the ribonucleotides, GMP and IMP. S. mansoni also lacks adenine-guanine interconversion enzymes, thus HGPRTase is the parasite's sole source of guanine nucleotides and a critical metabolic enzyme.

The structure of S. mansoni HGPRTase was solved by molecular replacement using a modified human HGPRTase as the search model. The structure has been refined to 1.8 Å resolution against X-ray data collected from a single cryofrozen crystal.