Carbonic Anhydrases as drug targets - An overview

At least 15 different alpha-carbonic anhydrase (CA, EC 4.2.1.1) isoforms were isolated in mammals, where these zinc enzymes play crucial physiological roles. Some of these isozymes are cytosolic (CA I, CA II, CA III, CA VII, CA XIII), others are membrane-bound (CA IV, CA IX, CA XII, CA XIV and CA XV), CA VA and CA VB are mitochondrial, and CA VI is secreted in saliva and milk. Three acatalytic forms are also known, the CA related proteins (CARP), CARP VIII, CARP X and CARP XI. Representatives of the beta - delta-CA family are highly abundant in plants, diatoms, eubacteria and archaea. These enzymes are very efficient catalysts for the reversible hydration of carbon dioxide to bicarbonate, but at least the alpha-CAs possess a high versatility, being able to catalyze different other hydrolytic processes The catalytic mechanism of the alpha-CAs is understood in detail: the active site consists of a Zn(II) ion co-ordinated by three histidine residues and a water molecule/hydroxide ion. The latter is the active species, acting as a potent nucleophile. For beta- and gamma-CAs, the zinc hydroxide mechanism is valid too, although at least some P-class enzymes do not have water directly coordinated to the metal ion. CAs are inhibited primarily by two classes of compounds: the metal complexing anions (such as cyanide, cyanate, thiocyanate, azide, hydrogensulfide, etc) and the sulfonamides/sulfamates/sulfamides possessing the general formula RXSO2NH2 (R = aryl; hetaryl perhaloalkyl; X = nothing, O or NH). Several important physiological and physio-pathological functions are played by the CA isozymes present in organisms all over the phylogenetic tree, related to respiration and transport of CO2/bicarbonate between metabolizing tissues and the lungs, pH and CO2 homeostasis, electrolyte secretion in a variety of tissues/organs, biosynthetic reactions, such as the gluconeogenesis and ureagenesis among others (in animals), Co-2 fixation (in plants and algae), etc. The presence of these ubiquitous enzymes in so many tissues and in so different isoforms, represents an attractive goal for the design of inhibitors with biomedical applications. Indeed, CA inhibitors are clinically used as antiglaucoma drugs, some other compounds being developed as antitumor agents/diagnostic tools for tumors, antiobesity agents, anticonvulsants, and antimicrobials/antifungals (inhibitors targeting CAs from pathogenic organisms such as Helicobacter pylori, Mycohacterium tuberculosis, Plasmodium falciparum, Candida albicans, etc).