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1-Aminocyclopropane-1-carboxylic acid oxidase: insight into cofactor binding from experimental and theoretical studies

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Abstract

1-Aminocyclopropane-1-carboxylic acid oxidase (ACCO) is a nonheme Fe(II)-containing enzyme that is related to the 2-oxoglutarate-dependent dioxygenase family. The binding of substrates/cofactors to tomato ACCO was investigated through kinetics, tryptophan fluorescence quenching, and modeling studies. α-Aminophosphonate analogs of the substrate (1-aminocyclopropane-1-carboxylic acid, ACC), 1-aminocyclopropane-1-phosphonic acid (ACP) and (1-amino-1-methyl)ethylphosphonic acid (AMEP), were found to be competitive inhibitors versus both ACC and bicarbonate (HCO3 −) ions. The measured dissociation constants for Fe(II) and ACC clearly indicate that bicarbonate ions improve both Fe(II) and ACC binding, strongly suggesting a stabilization role for this cofactor. A structural model of tomato ACCO was constructed and used for docking experiments, providing a model of possible interactions of ACC, HCO3 −, and ascorbate at the active site. In this model, the ACC and bicarbonate binding sites are located close together in the active pocket. HCO3 − is found at hydrogen-bond distance from ACC and interacts (hydrogen bonds or electrostatic interactions) with residues K158, R244, Y162, S246, and R300 of the enzyme. The position of ascorbate is also predicted away from ACC. Individually docked at the active site, the inhibitors ACP and AMEP were found coordinating the metal ion in place of ACC with the phosphonate groups interacting with K158 and R300, thus interlocking with both ACC and bicarbonate binding sites. In conclusion, HCO3 − and ACC together occupy positions similar to the position of 2-oxoglutarate in related enzymes, and through a hydrogen bond HCO3 − likely plays a major role in the stabilization of the substrate in the active pocket.

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Notes

  1. For square-pyramidal geometry τ = 0 and for trigonal bipyramidal geometry τ = 1.

  2. Docking experiments were also performed on the crystal structure (using a monomer from the tetramer and removing the phosphate molecule bound on the metal ion). The position of ACC is similar to that obtained on the modeled structure, although this is twisted. The amine group of ACC is found trans to H177 and the oxygen is coordinated approximately trans to D179. When HCO3 − is docked on the ACCO/Fe/ACC complex from the above-mentioned calculations, the most favorable position is located far from ACC (more than 10 Å).

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Acknowledgments

This work was supported by a grant from the Agence Nationale de la Recherche (ANR-09-JCJC-0080). The authors acknowledge C. Schofield and Z. Zhang from Oxford University for providing the plasmid containing the gene encoding tomato ACCO as well as for useful advice.

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Authors and Affiliations

  1. Aix-Marseille Université and CNRS, Institut des Sciences Moléculaires de Marseille, UMR 7313, Service 342, Campus de Saint-Jérôme, 13397, Marseille Cedex 20, France

    Lydie Brisson, Nadia El Bakkali-Taheri, Marius Réglier, Thierry Tron, El Hassan Ajandouz & A. Jalila Simaan

  2. Spectropole, Aix-Marseille Université, Campus de Saint-Jérôme, Av. Escadrille Normandie-Niémen, 13397, Marseille Cedex 20, France

    Michel Giorgi

  3. Laboratoire de Synthèse Organique et Méthodologie, ICMMO, UMR 8182, Bât. 420, Université Paris-Sud, 91405, Orsay Cedex, France

    Antoine Fadel

  4. Department of Chemistry, University of Pannonia, 8201, Veszprém, Hungary

    József Kaizer

Authors
  1. Lydie Brisson
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  2. Nadia El Bakkali-Taheri
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  9. A. Jalila Simaan
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Corresponding author

Correspondence to A. Jalila Simaan.

Additional information

L. Brisson and N. E. Bakkali-Taheri contributed equally to the work.

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Brisson, L., El Bakkali-Taheri, N., Giorgi, M. et al. 1-Aminocyclopropane-1-carboxylic acid oxidase: insight into cofactor binding from experimental and theoretical studies. J Biol Inorg Chem 17, 939–949 (2012). https://doi.org/10.1007/s00775-012-0910-3

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  • DOI: https://doi.org/10.1007/s00775-012-0910-3

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