ABSTRACT
Activation of carbonic anhydrases (CAs) has been a controversial phenomenon for a long time. Recently, kinetic, spectroscopic and x-ray crystallographic data have offered a clear-cut explanation for this phenomenon, based on the catalytic mechanism of these enzymes. It has been demonstrated that molecules acting as carbonic anhydrase activators (CAAs) bind at the entrance of the enzyme active-site cavity and participate in assisted proton transfer processes between the active site and the reaction medium, thereby facilitating the rate-determining step of the CA catalytic cycle. In addition to CA II-activator adducts, x-ray crystallographic studies have been reported for ternary complexes of this isozyme with activators and anion inhibitors. Drug design studies have been successfully performed to obtain strong CAAs belonging to several chemical classes: amines and their derivatives, azoles, amino acids and oligopeptides, etc. Structure-activity correlations for diverse classes of activators are discussed for the isozymes for which the phenomenon has been
About half of the 14 different isoforms of carbonic anhydrase (CA) isolated until the present time in higher vertebrates (Hewett-Emmett 2000) act in reversible CO2 hydration under physiological conditions as some of the most efficient enzymatic catalysts. Detailed studies based on kinetics, spectroscopy, x-ray crystallography and site-specific mutagenesis have clearly revealed that CA II, CA VII and CA IX are among the fastest E-CAs, possessing turnover numbers kcat = 106 s-1 and secondorder steady-state rate constants close to the diffusion-controlled processes (e.g., for hCA II, kcat /KM 108 M-1s-1; Lindskog and Silverman 2000; Stams and Christianson 2000; Mauksch et al. 2001).
