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

Abstract

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.

Kinetic and CD/MCD Spectroscopic Studies of the Atypical, Three-His-Ligated, Non-Heme Fe2+ Center in Diketone Dioxygenase: The Role of Hydrophilic Outer Shell Residues in Catalysis

“…The Glu98 variants of Dke1 actually lead to a 4-fold decrease in Fe 2+ detachment rates from 0.002 s -1 to 0.0005 s -1 . Second sphere carboxylate residues H-bonded to the non-coordinated nitrogen of a metal-ligated histidine have been reported to increase metal-cofactor stability when the carboxylate acts as a strong H-acceptor (31,32). In Dke1, the H-bonding interaction of Glu98 with Arg80 (Figure 1) lowers the p K a of Glu98 and likely prevents a similar role for Glu98 here.…”

Formation of the Iron–Oxo Hydroxylating Species in the Catalytic Cycle of Aromatic Amino Acid Hydroxylases

“…Although several factors contribute to the proton abstraction, it should be noted that one of these, the basicity of Glu286, may be overestimated due to the present cluster model. [53][54][55][56] The first of the two alternative pathways (…”

Nucleophilicity of zinc-bound thiolates

“…Due to the d 10 electronic structure of zinc(II), we observe a "push-pull" effect between the ligand set around the metal. [31] Indeed, the lengthening of the Zn-S(aryl) bond induces a shortening of all other Zn-ligand bonds. Thus, the alkylthiolate of 13' is slightly more tightly coordinated to zinc than the same alkylthiolate of 13.…”

“…In this study, we have determine the S N 2 activation barrier for a variety of zinc complexes. In order to conserve as much as possible along the reaction path the tetrahedral arrangement around zinc observed in biomimetic complexes and enzymatic active sites and to avoid unexpected structural deformation, [31] these complexes include a relatively rigid tripodal core. This will allow us to compare the donating capability of tripodal ligands and to determine a good correlation between the zinc-bound thiolate nucleophilicity and the thiolate gas phase basicity.…”