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Leishmania parasites are reliant on salvage mechanisms to acquire purines from the extracellular environment. GMP reductase (GMPR) catalyzes the conversion of GMP to IMP, an integral reaction for maintaining purine nucleotide balance. Enzymatically active L. major GMPR (LmGMPR) has been cloned, expressed and purified. The LmGMPR gene complements GMPR deficiency in E. coli strains. Quaternary structure analysis indicates that LmGMPR forms tetramers and higher order complexes under reducing conditions. Kinetic assays reveal that the enzyme deviates from hyperbolic behaviour with regard to GMP but conforms to typical Michaelis-Menten kinetics for NADPH. Sequence analysis indicates that LmGMPR contains CBS domains and an MPA binding site. MPA competes for the NADPH binding site with a K i of 20 muM. ATP and GTP regulate enzymatic activity through inhibition and activation, respectively. This data indicates that LmGMPR is a novel enzyme that performs a highly regulated step in Leishmania purine metabolism.