High-resolution crystal structure of Trypanosoma brucei UDP-galactose 4′-epimerase: A potential target for structure-based development of novel trypanocides

The crystal structure of UDP-galactose 4′-epimerase from the protozoan parasite Trypanosoma brucei in complex with the cofactor NAD⁺ and a fragment of the substrates, UDP, has been determined at 2.0Å resolution (1Å=0.1nm). This enzyme, recently proven to be essential for this pathogenic parasite, shares 33% sequence identity with the corresponding enzyme in the human host. Structural comparisons indicate that many of the protein-ligand interactions are conserved between the two enzymes. However, in the UDP-binding pocket there is a non-conservative substitution from Gly237 in the human enzyme to Cys266 in the T. brucei enzyme. Such a significant difference could be exploited by the structure-based design of selective inhibitors using the structure of the trypanosomatid enzyme as a template.