Aconitase

Illustration of pig aconitase in complex with the [Fe₄S₄] cluster, PDB ID 7ACN. The protein is colored by secondary structure, and iron atoms are blue and the sulfur red.

Aconitase (aconitate hydratase; EC 4.2.1.3) is an enzyme that catalyses the stereo-specific isomerization of citrate to isocitrate via cis-aconitate in the tricarboxylic acid cycle, a non-redox-active process.

Citric acid

Aconitic acid

Isocitric acid

Function

In contrast with the majority of iron-sulfur proteins that function as electron carriers, the iron-sulfur cluster of aconitase reacts directly with an enzyme substrate. Aconitase has an active [Fe₄S₄]²⁺ cluster, which may convert to an inactive [Fe₃S₄]⁺ form. Three cysteine (Cys) residues have been shown to be ligands of the [Fe₄S₄] centre. In the active state, the labile iron ion of the [Fe₄S₄] cluster is not coordinated by Cys but by water molecules.

The iron-responsive element binding protein (IRE-BP) and 3-isopropylmalate dehydratase (α-isopropylmalate isomerase; EC 4.2.1.33), an enzyme catalysing the second step in the biosynthesis of leucine, are known aconitase homologues. Iron regulatory elements (IREs) constitute a family of 28-nucleotide, non-coding, stem-loop structures that regulate iron storage, heme synthesis and iron uptake. They also participate in ribosome binding and control the mRNA turnover (degradation). The specific regulator protein, the IRE-BP, binds to IREs in both 5' and 3' regions, but only to RNA in the apo form, without the Fe-S cluster. Expression of IRE-BP in cultured cells has revealed that the protein functions either as an active aconitase, when cells are iron-replete, or as an active RNA-binding protein, when cells are iron-depleted. Mutant IRE-BPs, in which any or all of the three Cys residues involved in Fe-S formation are replaced by serine, have no aconitase activity, but retain RNA-binding properties.

Aconitase is inhibited by fluoroacetate, therefore fluoroacetate is poisonous. The iron sulfur cluster is highly sensitive to oxidation by superoxide^[1].

References

• Beinert, H., Kennedy, M.C. and Stout, C.D. (1996). "Aconitase as iron-sulfur protein, enzyme, and iron-regulatory protein". Chem. Rev. 96: 2335–2373. doi:10.1021/cr950040z. 
• Flint, D.H. and Allen, R.M. (1996). "Iron-sulfur proteins with nonredox functions". Chem. Rev. 96: 2315–2334. doi:10.1021/cr950041r. 
• Frishman, D. and Hentze, M.W. (1996). "Conservation of aconitase residues revealed by multiple sequence analysis". Eur. J. Biochem. 239: 197–200. doi:10.1111/j.1432-1033.1996.0197u.x. 

External links

• 7ACN - PDB structure of pig aconitase in complex with [Fe₄S₄] cluster and isocitrate
• 1L5J - PDB structure of Escherichia coli aconitase complexed with [Fe₃S₄] cluster and aconitate
• IPR000573 - InterPro entry for aconitase
• MeSH Aconitase