Aconitate hydratase, mitochondrial (Plasmodium) (ACO)

Mitochondrial aconitase, also known as aconitate hydratase, is a critical enzyme within the tricarboxylic acid (TCA) cycle of Plasmodium species and other respiration-dependent apicomplexan parasites (UniProt: Q8I0S1). It facilitates the stereospecific isomerization of citrate to isocitrate through a cis-aconitate intermediate, a process dependent on a 4Fe-4S iron-sulfur cluster. In Plasmodium falciparum, the enzyme is vital for maintaining metabolic flux, particularly during the mosquito and gametocyte stages where mitochondrial respiration is more pronounced than in the primarily glycolytic asexual blood stages (MacRae et al., 2013, PMID: 23934124). Beyond energy production, the TCA cycle in these parasites provides essential precursors for heme biosynthesis and maintains redox homeostasis (Ke et al., 2015, PMID: 25561495). As a potential therapeutic target, inhibition of mitochondrial aconitase aims to starve the parasite of these critical metabolites, leading to growth arrest. However, the high degree of structural conservation between the parasite enzyme and human mitochondrial aconitase poses a significant challenge for achieving the necessary drug selectivity. Consequently, while it is a validated metabolic node, safety concerns regarding host toxicity remain a primary hurdle in the development of aconitase-targeted antimalarials.

Other names

AconitaseMitochondrial aconitaseCitrate hydro-lyasePfACOAconitate hydratase 2ACO2

Inhibition of the enzymatic conversion of citrate to isocitrate, leading to TCA cycle arrest and depletion of downstream metabolic intermediates.