TRYPANOSOMA-CRUZI GLYCOSOMAL GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE- STRUCTURE, CATALYTIC MECHANISM AND TARGETED INHIBITOR DESIGN

The structure of the enzyme glyceraldehyde-3-phosphate dehydrogenase ( GAPDH) from glycosomes of the parasite Trypanosoma cruzi, causative ag ent of Chagas' disease, is reported. The final model at 2.8 Angstrom i ncludes the bound cofactor NAD(+) and 90 water molecules per monomer a nd resulted in an R-factor of 20.1%, R-free = 22.3%, with good geometr y indicators. The structure has no ions bound at the active site resul ting in a large change in the side chain conformation of Arg(249) whic h as a consequence forms a salt bridge to Asp(210) in the present stru cture. We propose that this conformational change could be important f or the reaction mechanism and possibly a common feature of many GAPDH structures. Comparison with the human enzyme indicates that interferin g with this salt bridge could be a nem approach to specific inhibitor design, as the equivalent to Asp(210) is a leucine in the mammalian en zymes. (C) 1998 Federation of European Biochemical Societies.