bioRxiv Biochemistry
bioRxiv Biochemistry
5 years ago

Biochemical characterization and essentiality of Plasmodium fumarate hydratase

P., V., Balaram, Kunala, Kalale, Jayaraman, H., A., Suryavanshi, J.
Plasmodium falciparum (Pf), the causative agent of malaria has an iron-sulfur cluster-containing class I fumarate hydratase (FH) that catalyzes the interconversion of fumarate to malate, a well-known reaction in the tricarboxylic acid cycle. In humans, the same reaction is catalyzed by class II FH that has no sequence or structural homology with the class I enzyme. Fumarate, generated in large quantities in the parasite as a byproduct of AMP synthesis is converted to malate by the action of FH, and subsequently used in the generation of the key metabolites oxaloacetate, aspartate and pyruvate. Here we report on the kinetic characterization of purified recombinant PfFH, functional complementation of fh deficiency in Escherichia. coli and mitochondrial localization in the parasite. The substrate analog, mercaptosuccinic acid was found to be a potent inhibitor of PfFH with a Ki value in the nanomolar range. Attempts at knockout of the fh gene in P. berghei yielded parasite with either wrong integration of the selectable maker cassette or right integration in the background of fh gene duplication highlighting the essentiality of FH for the parasite.

Publisher URL: http://biorxiv.org/cgi/content/short/158956v1

DOI: 10.1101/158956

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