Leishmania pyruvate kinase: the crystal structure reveals the structural basis of its unique regulatory properties

Glycolysis occupies a central role in cellular metabolism, and is of partic ular importance for the catabolic production of ATP in protozoan parasites such as Leishmania and Trypanosoma. In these organisms pyruvate kinase play s a key regulatory role, and is unique in responding to fructose 2,6-bispho sphate as allosteric activator. The determination of the crystal structure of the first eukaryotic pyruvate kinase in the T-state (the inactive or 'te nse' conformation of allosteric enzymes) is described. A comparison of the effector sites of the Leishmania and yeast enzymes reveals the structural b asis for the different effector specificity. Two loops, comprising residues 443-453 and 480-489, adopt very different conformations in the two enzymes , and Lys-453 and His-480 that are a feature of trypanosomatid enzymes prov ide probable ligands for the 2-phospho group of the effecter molecule. Thes e and other differences offer an opportunity for the design of drugs that w ould exploit regulatory differences between parasite and host.