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Abstract #21191 Published in IGR 10-2
Carbonic anhydrases - An overview
Supuran CTCurrent Pharmaceutical Design 2008; 14: 603-614
Carbonic anhydrases (CAs, EC 4.2.1.1) are widespread metalloenzymes all over the phylogenetic tree, with at least 4 distinct gene families encoding for them. At least 16 different (alpha)- CA isoforms were isolated in mammals, where these enzymes play crucial physiological roles. Representatives of the β - (delta)-CA family are highly abundant in plants, diatoms, cubacteria and arhaca. These enzymes are 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 α-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 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 by two classes of compounds: the metal complexing anions and the sulfonamides and their isosteres (sulfamates, sulfamides etc.) possessing the formula RXSO(2)NH(2) (R = aryl: hetaryl; perhaloalkyl; X = nothing, O or NH). At least 25 clinically used drugs/agents in clinical development show applications as diuretics and antiglaucoma drug, anticonvulsants, with some compounds beings developed as anticancer agents/diagnostic tools tumors, antiobesity agents, and antimicrobials/antifungals (inhibitors targeting Cas from pathogenic organisms such as Helicobacter pylori, Mycobacterium tuberculosis, Plasmodium falciparum, Candida albicans, etc.). Several important physiological and physio-pathological functions are played by 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), CO2 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 or activators with biomedical applications.
Dr. C.T. Supuran, Universita degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Via della Lastruccia 3, I-50019 Sesto Fiorentino Firenze, Italy. Claudiu.supuran@unifi.it
Classification:
11.5 Carbonic anhydrase inhibitors (Part of: 11 Medical treatment)