TRITRICHOMONAS-FETUS - A STRATEGY FOR STRUCTURE-BASED INHIBITOR DESIGN OF A PROTOZOAN INOSINE-5'-MONOPHOSPHATE DEHYDROGENASE

Inosine-5'-monophosphate dehydrogenase (IMPDH) is an attractive drug t arget for the control of parasitic infections. The enzyme catalyzes th e NAD-dependent oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP), the committed step in guanosine monophosphate (G MP) biosynthesis. We have determined the crystal structures of IMPDH f rom the protozoan parasite Tritrichomonas foetus in the apo form at 2. 3 Angstrom resolution and the enzyme-XMP complex at 2.6 Angstrom resol ution. The enzyme forms a cyclic (C4) homotetramer. The core domain of each monomer forms an eight-stranded parallel beta/alpha barrel with the enzyme active sire at the C-termini of the barrel beta strands whi ch lies near the center of the fourfold axis of the tetramer. While th e electron-density for XMP in the complex structure is well-defined, t he NAD cofactor and a nearby loop containing the catalytic cysteine (C ys-319) are disordered. This disorder at the active site suggests that a high degree of flexibility may be inherent to the catalytic functio n of IMPDH, making this area a difficult target for structure-based in hibitor design. Unlike IMPDHs from other species, the T. foetus enzyme coordinates the substrate phosphate with a single arginine guanidiniu m in the active site. Furthermore, a deep groove extends 8 Angstrom fr om the substrate phosphate away from the sugar. This structural unique ness forms the basis of our efforts to design compounds that specifica lly inhibit the parasite enzyme. (C) 1997 Academic Press.