Promiscuous Ability of Human Carbonic Anhydrase: QM and QM/MM Investigation of Carbon Dioxide and Carbodiimide Hydration

Abstract

The hydration of carbodiimide, isoelectronic with carbon dioxide, mediated by human carbonic anhydrase (EC 4.2.1.1) was studied at theoretical level in comparison with the native substrate. Quantum-mechanical (QM) and combined quantum-mechanics/molecular-mechanics (QM/MM) approaches indicate that human carbonic anhydrase is able to catalyze also the hydration of carbodiimide to urea with an energy barrier higher than that required by the native CO2. The rate-determining step for both substrates is represented by the nucleophilic addition to the double bond, showing the final product ureate more strongly anchored to the enzyme active site than the hydrogen carbonate. The reduced catalytic activity for the carbodiimide substrate can be ascribed not only to the highest barrier but also to the difficulty in releasing the product in favor of the water molecule, delaying the catalytic turnover as indicated by QM and QM/MM analyses.

Direct Hydrogenation of Carbon Dioxide by an Artificial Reductase Obtained by Substituting Rhodium for Zinc in the Carbonic Anhydrase Catalytic Center. A Mechanistic Study

“…This cluster model was found to be adequate in the elucidation of the catalytic mechanism followed by hCAII towards native CO 2 63-65 and other isoelectronic promiscuous substrates studied in previous works. 44,45 In particular, we mention that the computed barrier for the CO 2 substrate is about 2 kcal mol -1 different from that extracted from an experimental kinetics study. 44 …”

“…44,45 In particular, we mention that the computed barrier for the CO 2 substrate is about 2 kcal mol -1 different from that extracted from an experimental kinetics study. 44 …”

“…In fact, the authors observe the stereoselective direct hydrogenation of olefins with high catalytic efficiency. 40,41 Inspired by these recent and important discoveries, considering that some rhodium organometallic complexes have been previously proposed as promising catalysts for CO 2 hydrogenation 27,28,42,43 and continuing our previous work on the promiscuous ability of hCA, 44,45 we have undertaken a detailed theoretical work with the aim of verifying if the "artificial" Rh(I)-CA is able to efficiently catalyze the direct hydrogenation of carbon dioxide.…”

Some examples on the performance of density functional theory in the description of bioinorganic systems and processes

“…Due to its unique ability to reduce the thermodynamically stable carbon dioxide, human carbonic anhydrase II (hCAII) is of continuous interest and a huge number of experimental and theoretical studies have been devoted to its chemistry and biology [7][8][9][10][11] In spite of this impressive amount of data, hCAII continues to attract the researchers' attention since it is able to show substrate and catalytic promiscuity maintaining its catalytic power [12][13][14][15][16][17]. Our quantum mechanical study, performed by using quantum mechanical on the promiscuous ability of hCAII have been performed by Some examples on the performance of density functional theory in the description of bioinorganic systems and processes Tiziana Marino, Nino Russo, Emilia Sicilia, and Marirosa Toscano M using a cluster model that include, other than the amino acids directly coordinated to the zinc ion center also the second coordination shell in which are present other residues that can play a role in the catalytic reaction (see scheme 1)…”

“…This result can explain the difference in the experimentally observed kinetics for the three reactions. [10,11].…”