Carbonic anhydrase inhibitors and their therapeutic potential

Carbonic anhydrases (CAs, EC 4.2.1.1) are wide-spread zinc enzymes, present in archaeo- and eubacteria, algae, green plants and animals. Within these organisms CAs are encoded by three distinct, evolutionarily unrelated gene families: the alpha-CA, the beta-CA and the gamma-CA families, respectively. These enzymes are very efficient catalysts for the reversible hydration of CO2 to bicarbonate; the alpha-CAs possess high versatility, being able to catalyse other hydrolytic processes. It is not known whether other reactions catalysed by CAs (than the hydration of CO2/dehydration of HCO3-) may have physiological relevance in systems where these enzymes are present. CAs are inhibited primarily by two main classes of compounds: the metal complexing inorganic anions (e.g., cyanide, cyanate, thiocyanate, azide, hydrogensulphide etc.) and the unsubstituted sulphonamides possessing the general formula RSO2NH2 (R = aryl; hetaryl; perhaloalkyl). The first type of inhibitor was important for understanding in detail the catalytic and inhibitory mechanisms, whereas the second led to the development of several classes of pharmacological agents. Inhibitors of both types directly bind to the metal ion within the enzyme active site, either by substituting the zinc-bound H2O/OH-, or adding to the co-ordination sphere, leading thus to pentaco-ordinated Zn(II). Sulphonamide CA inhibitors (CAIs) are useful as diuretics, or in the treatment and prevention of a variety of diseases such as glaucoma, epilepsy, congestive heart failure, mountain sickness, gastric and duodenal ulcers, neurological disorders and osteoporosis among others, as well as diagnostic tools. Their applications are due to the wide distribution of the different alpha-CA isozymes (14 are presently known) in higher vertebrates, where they play important physiological functions related to respiration and transport of CO2/HCO3 between metabolising tissues and the lungs, pH and CO2 homeostasis, electrolyte secretion in a variety of tissues/organs, and biosynthetic reactions, such as gluconeogenesis and ureagenesis, among others. CA activators have recently been described and their mechanism of action at molecular level elucidated. Such agents might be useful for developing therapies for the CA deficiency syndrome.