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Title: Analysis of Quaternary Structure of a [LDH-like] Malate Dehydrogenase of Plasmodium falciparum with Oligomeric Mutants

Author
item PRADHAN, ANUPAM - University Of South Florida
item MUKHERJEE, PRASENJIT - University Of Mississippi
item TRIPATHI, ABHAI - Johns Hopkins University
item AVERY, MITCHELL - University Of Mississippi
item WALKER, LARRY - University Of Mississippi
item TEKWANI, BABU - University Of Mississippi

Submitted to: Molecular and Cellular Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/15/2009
Publication Date: 1/29/2009
Citation: Pradhan, A., Mukherjee, P., Tripathi, A.K., Avery, M.A., Walker, L.A., Tekwani, B.L. 2009. Analysis of Quaternary Structure of a [LDH-like] Malate Dehydrogenase of Plasmodium falciparum with Oligomeric Mutants. Molecular and Cellular Biochemistry. 325:141-148.

Interpretive Summary: Plamodium falciparum malate deydrogenase (PfMDH) is a dimer of dimers (tetrameric). 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.

Technical Abstract: 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 archea 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 cytosole. 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.