Effect of the hydrogen bond network in carbonic anhydrase II zinc binding site. A theoretical study

Álvarez-Santos, Silvia; González‐Lafont, Àngels; Lluch, J. M. O.

doi:10.1139/v98-098

Cited by 3 publications

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“…The influence of indirect metal ligands on the reactivity of HCA II has been already shown, both experimentally 30 and theoretically. 19,28,[35][36][37] Our study reveals that the description of the zinc binding site depends upon the choice of the metal ligands environment included in the model, and more precisely around the Zn-His119-Glu117 triad, which were not included in previous studies. It seems that an unquestionable model should include all groups bound to the first shell, especially those including charge and those surrounding charge, even if the minimum required is still unclear.…”

Section: This Journal Is C the Owner Societies 2009mentioning

confidence: 86%

Metal-histidine-glutamate as a regulator of enzymatic cycles: a case study of carbonic anhydrase

Frison¹,

Ohanessian²

2009

Phys. Chem. Chem. Phys.

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To cite this version:Gilles Frison, Gilles Ohanessian. Metal-histidine-glutamate as a regulator of enzymatic cycles: a case study of carbonic anhydrase.. Physical Chemistry Chemical Physics, Royal Society of Chemistry, 2009Chemistry, , 11 (2), pp.374-383. 10.1039 Metal-histidine-glutamate as a regulator of enzymatic cycles: a case study of carbonic anhydrasew Gilles Frison* and Gilles Ohanessian Histidine is a very common metal ligand in metalloenzymes. Besides being an efficient Lewis base, its electronic properties are essential to shape the metal ability to catalyze the reaction. Here we show that histidine's properties can be tuned, in turn, by an easy proton transfer to a nearby glutamate. We study this situation in Human Carbonic Anhydrase II (HCA II) in which one of the three histidines bound to zinc (His119) interacts also with a glutamate residue (Glu117). Proton transfer from His119 to Glu117 has been hypothesized in the past, however realistic modeling is performed here for the first time. We show that the carboxylate group of Glu117 behaves only as a hydrogen bond acceptor in the hydroxy form of HCA II. On the other hand, our results suggest that Glu117 could exist either as a hydrogen bond acceptor or as a proton acceptor in the aqua form of HCA II, the two isomers having almost the same thermodynamic stability. We propose that this proton shift may be used by the enzyme to facilitate the final displacement of bicarbonate by water.

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Section: This Journal Is C the Owner Societies 2009mentioning

confidence: 86%

Metal-histidine-glutamate as a regulator of enzymatic cycles: a case study of carbonic anhydrase

Frison¹,

Ohanessian²

2009

Phys. Chem. Chem. Phys.

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Modelling Enzyme - Ligand Interactions

Ramos

Melo

Henriques

2001

Theoretical and Computational Chemistry

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Metalloion−Ligand Binding Energies and Biological Function of Metalloenzymes Such as Carbonic Anhydrase. A Study Based on ab Initio Calculations and Experimental Ion−Ligand Equilibria in the Gas Phase

2000

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The known structure of carbonic anhydrase includes the structure of the active site, which consists of Zn 2+ , coordinated to three histidine (His) residues and a water molecule. The ligand involved in the catalysis is the water molecule. Using imidazole (Im) to model histidine, it is found that histidine is the strongest bonding residue to Zn 2+ of all neutral amino acid residues. On the basis of high-level ab initio calculations, the sequential bond energies for one to three imidazoles attached to Zn 2+ were evaluated. The bond energy Zn(Im) 3 2+ -(H 2 O) was also determined by ab initio calculations and (gas phase) ion equilibria measurements. From a comparison of the free energy of stabilization of Zn 2+ in the enzyme and that in aqueous solution, we conclude that very strongly bonding residues such as histidine are essential to make the Zn 2+ ion in the enzyme stable, relative to the aqueous environment. The strongly bonding histidine also has another more important role. Due to the very large charge transfer and polarizability energy component with such a ligand and ligandligand repulsion, the bonding to the fourth, i.e., the H 2 O ligand, is very much weakened. It is shown that weakening of the Zn(L) 3 2+ -(H 2 O) bond energy is unfaVorable, i.e., increases the energy required for the first step of the accepted mechanism, Zn(His) 3 OH 2 2+ f Zn(His) 3 OH + + H + , while the second step, Zn(HisZn(His) 3 (H 2 O) 2+ + HCO 3 -, is favorably affected, i.e., requires less energy. The choice of the ligands L therefore must be such so as to lead to a compromise between the two opposing effects. By making a semiquantitative inclusion of the solvent effect of the protein and aqueous environment on the reaction free energies for the above two ionic reactions, it was possible to show that the "choice" of the three histidine ligands is "just right" to provide this compromise. These ligands lead to reaction free energies that are close to zero for both reactions.

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Effect of the hydrogen bond network in carbonic anhydrase II zinc binding site. A theoretical study

Cited by 3 publications

References 0 publications

Metal-histidine-glutamate as a regulator of enzymatic cycles: a case study of carbonic anhydrase

Metal-histidine-glutamate as a regulator of enzymatic cycles: a case study of carbonic anhydrase

Modelling Enzyme - Ligand Interactions

Metalloion−Ligand Binding Energies and Biological Function of Metalloenzymes Such as Carbonic Anhydrase. A Study Based on ab Initio Calculations and Experimental Ion−Ligand Equilibria in the Gas Phase

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