Plasmodium falciparum, the causative agent of the fatal form of malaria, 
synthesizes GMP primarily from IMP and, hence, needs active GMPS (GMP 
synthetase) for its survival. GMPS, a G-type amidotransferase, catalyses the 
amination of XMP to GMP with the reaction occurring in two domains, the GAT 
(glutamine amidotransferase) and ATPPase (ATP pyrophosphatase). The GAT domain 
hydrolyses glutamine to glutamate and ammonia, while the ATPPase domain 
catalyses the formation of the intermediate AMP-XMP from ATP and XMP. 
Co-ordination of activity across the two domains, achieved through channelling 
of ammonia from GAT to the effector domain, is the hallmark of 
amidotransferases. Our studies aimed at understanding the kinetic mechanism of 
PfGMPS (Plasmodium falciparum GMPS) indicated steady-state ordered binding of 
ATP followed by XMP to the ATPPase domain with glutamine binding in a random 
manner to the GAT domain. We attribute the irreversible, Ping Pong step seen in 
initial velocity kinetics to the release of glutamate before the attack of the 
adenyl-XMP intermediate by ammonia. Specific aspects of the overall kinetic 
mechanism of PfGMPS are different from that reported for the human and 
Escherichia coli enzymes. Unlike human GMPS, absence of tight co-ordination of 
activity across the two domains was evident in the parasite enzyme. Variations 
seen in the inhibition by nucleosides and nucleotide analogues between human 
GMPS and PfGMPS highlighted differences in ligand specificity that could serve 
as a basis for the design of specific inhibitors. The present study represents 
the first report on recombinant His-tagged GMPS from parasitic protozoa.