L-Malate dehydrogenase (PfMDH) from Plasmodium falciparum, the causative agent 
for the most severe form of malaria, has shown remarkable similarities to L: 
-lactate dehydrogenase (PfLDH). PfMDH is more closely related to [LDH-like] MDHs 
characterized in archae and other prokaryotes. Initial sequence analysis and 
identification of critical amino acid residues involved in inter-subunit 
salt-bridge interactions predict tetrameric structure for PfMDH. The 
catalytically active recombinant PfMDH was characterized as a tetramer. The 
enzyme is localized primarily in the parasites cytosol. To gain molecular 
insights into PfMDH/PfLDH relationships and to understand the quaternary 
structure of PfMDH, dimers were generated by mutation to the potential 
salt-bridge interacting sites. The R183A and R214G mutations, which snapped the 
salt bridges between the dimers and resulted in lower dimeric state, did not 
affect catalytic properties of the enzyme. The mutant dimers of PfMDH were 
active equally as the wild-type PfMDH. The studies reveal structure of PfMDH as 
a dimer of dimers. The tetrameric state of PfMDH was not essential for catalytic 
functions of the enzyme but may be an evolutionary adaptation for cytosolic 
localization to support its role in NAD/NADH coupling, an important metabolic 
function for survival of the malaria parasite.