Stable Identifier
Reaction [binding]
Homo sapiens
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Iron and citrate are essential for the metabolism of most organisms so their regulation is critical for normal physiology and survival. Depending on cellular conditions, cytoplasmic aconitate hydratase (ACO1 aka iron regulatory protein 1, IRP1) can assume two different functions. During iron scarcity or oxidative stress, ACO1 functions as IRP1, binding to iron responsive elements (IREs) to modulate the translation of iron metabolism genes. In iron-rich conditions, IRP1 binds an iron-sulfur cluster (4Fe-4S) to function as a cytosolic aconitase. This functional duality of IRP1 connects the translational control of iron metabolising proteins to cellular iron levels.

During iron scarcity, ACO1 and iron-responsive element-binding protein 2 (IREB2) bind with high affinity to RNA stem-loops known as iron-responsive elements (IREs) present in the 5' untranslated region of the mRNAs of ferritin (composed of heavy and light subunits, FTH1 and FTL) and the erythroid form of aminolevulinic acid synthase (ALAD) and in the 3' untranslated region of the mRNA of the transferrin receptor (TFRC). Binding of ACO1 or IREB2 prevents translation of FTH1:FTL and ALAD and protects the mRNA of TFRC from degradation. ACO1 and IREB2 perform an important metabolic function in response to low intracellular iron levels by interacting with iron protein mRNAs to increase net iron uptake (via TFRC) and decrease sequestration (via FT) and utilisation (via ALAD) of iron (Kaptain et al. 1991, Philpott et al. 1994, Samaniego et al. 1994).

Glutaredoxin-3 (GLRX3) is essential for both transcriptional iron regulation and intracellular iron distribution. Silencing of human Grx3 expression in HeLa cells decreases the activities of several cytosolic Fe-S proteins, for example, iron-regulatory protein 1 (ACO1), a major component of posttranscriptional iron regulation. As a consequence, Grx3-depleted cells show decreased levels of ferritin and increased levels of transferrin receptor, features characteristic of cellular iron starvation (Haunhorst et al. 2013).

Literature References
PubMed ID Title Journal Year
7983023 Molecular characterization of a second iron-responsive element binding protein, iron regulatory protein 2. Structure, function, and post-translational regulation

Samaniego, F, Chin, J, Iwai, K, Rouault, TA, Klausner, RD

J. Biol. Chem. 1994
1946430 A regulated RNA binding protein also possesses aconitase activity

Kaptain, S, Downey, WE, Tang, C, Philpott, C, Haile, D, Orloff, DG, Harford, JB, Rouault, TA, Klausner, RD

Proc. Natl. Acad. Sci. U.S.A. 1991
23615448 Crucial function of vertebrate glutaredoxin 3 (PICOT) in iron homeostasis and hemoglobin maturation

Haunhorst, P, Hanschmann, EM, Bräutigam, L, Stehling, O, Hoffmann, B, Mühlenhoff, U, Lill, R, Berndt, C, Lillig, CH

Mol. Biol. Cell 2013
8041788 The bifunctional iron-responsive element binding protein/cytosolic aconitase: the role of active-site residues in ligand binding and regulation

Philpott, CC, Klausner, RD, Rouault, TA

Proc. Natl. Acad. Sci. U.S.A. 1994
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