ABSTRACT
At least 14 different α-carbonic anhydrase (CA, EC 4.2.1.1) isoforms have been isolated in higher vertebrates, wherein these zinc enzymes play crucial physiological roles. Some of these isozymes are cytosolic (CA I, CA II, CA III and CA VII), others are membrane bound (CA IV, CA IX, CA XII and CA XIV), one is mitochondrial (CA V) and one is secreted in the saliva (CA VI). Three acatalytic forms are also known, designated CA-related proteins (CARPs): CARP VIII, CARP X and CARP XI. Representatives of the β-and γ-CA family are highly abundant in plants, bacteria and archaea. These enzymes are very efficient catalysts for the reversible hydration of carbon dioxide to bicarbonate, and at least α-CAs possess a high versatility, being able to catalyze other different hydrolytic processes, such as the hydration of cyanate to carbamic acid or of cyanamide to urea; aldehyde hydration to gem-diols; hydrolysis of carboxylic or sulfonic acids esters; as well as other less investigated hydrolytic processes, such as hydrolysis of halogeno derivatives and
3systems in which these enzymes are present. The catalytic mechanism of α-CAs is understood in great detail. The active site consists of a Zn(II) ion coordinated by three histidine residues and a water molecule/hydroxide ion. The latter is the active species, acting as a potent nucleophile. For β-and γ-CAs, the zinc hydroxide mechanism is valid too, although at least some β-class enzymes do not have water directly coordinated to the metal ion. CAs are inhibited primarily by two main classes of inhibitors: the metal-complexing inorganic anions (such as cyanide, cyanate, thiocyanate, azide and hydrogensulfide) and the unsubstituted sulfonamides possessing the general formula RSO2NH2 (R = aryl, hetaryl, perhaloalkyl). Several important physiological and physiopathological functions are played by the CA isozymes, which are present in organisms at all levels of the phylogenetic tree. Among these functions are respiration and transport of CO2/bicarbonate between metabolizing tissues and lungs, pH and CO2 homeostasis, electrolyte secretion in a variety of tissues and organs, biosynthetic reactions, such as the gluconeogenesis and urea synthesis (in animals) and CO2 fixation (in plants and algae). The presence of these ubiquitous enzymes in so many tissues and in so many different isoforms makes them useful to design inhibitors or activators that have biomedical applications.
