ABSTRACT
Activators of the zinc enzymes carbonic anhydrases (CAs) accelerate the hydration of carbon dioxide (CO2) to bicarbonate and a proton by favoring the rate-determining step in the catalytic cycle. CA activators (CAAs) bind within the enzyme active site cavity, at a site different to the inhibitor-or substrate-binding sites, facilitating the proton-transfer processes between the active site and the reaction medium. Adducts of isoforms CA I and II with various activators have been characterized by means of X-ray crystallography, allowing thus for a rationale in the design of such agents. Solution studies were performed on the activation of isoforms CA I, II, IV, VA, VII, and XIV with a variety of activators. Such studies led to the discovery of strong CAAs belonging to several chemical classes. Structure-activity correlations for such activators are discussed for the various isozymes for which the phenomenon has been studied. In the human brain, at least seven CA isoforms are present (CA I, II, IV, VII, VIII, XII, and XIV), most of which are activated by these types of modulators of activity. The physiologic relevance of brain CA activation and the possible application
of activators in the management of Alzheimer’s disease and other memory therapies are also reviewed, although research in this field is in its early phase.
