aconitase

Aconitase (aconitate hydratase) contains a [4Fe-4S] iron-sulfur cluster essential for its catalytic activity. In the TCA cycle, it catalyzes the stereospecific isomerization of citrate to isocitrate through a two-step dehydration-rehydration mechanism, forming the intermediate cis-aconitate. This step is important because citrate itself is a poor substrate for subsequent oxidative decarboxylation, whereas isocitrate can be efficiently oxidized by isocitrate dehydrogenase.

There are two isoforms: mitochondrial aconitase (ACO2), involved directly in the TCA cycle, and cytosolic aconitase (ACO1), which under low iron conditions loses its Fe-S cluster and converts to iron regulatory protein 1 (IRP1). IRP1 then binds iron-responsive elements (IREs) on mRNAs encoding proteins like ferritin and transferrin receptor, regulating their translation/stability to maintain iron homeostasis—a key concept linking metabolism and iron regulation.

Clinically, aconitase is inhibited by fluoroacetate (found in some plants and used as rodenticide), which is converted to fluorocitrate, a toxic metabolite that blocks aconitase and halts the TCA cycle, causing energy failure particularly in cardiac and neural tissue. Aconitase is also sensitive to oxidative damage because reactive oxygen species can disrupt its Fe-S cluster, contributing to mitochondrial dysfunction in oxidative stress conditions and neurodegenerative diseases like Friedreich ataxia (due to frataxin deficiency impairing Fe-S cluster biogenesis).

High-yield associations: TCA cycle step 2, Fe-S cluster enzyme, fluoroacetate/fluorocitrate toxicity, IRP1/iron homeostasis, Friedreich ataxia link via frataxin.