Abstract
Specific isoforms from the carbonic anhydrase (CA) family of zinc metalloenzymes have been associated with a variety of diseases. Isoform-specific carbonic anhydrase inhibitors (CAIs) are therefore a major focus of attention for specific disease treatments. Classical CAIs, primarily sulfonamide-based compounds and their bioisosteres, are examined as antiglaucoma, antiepileptic, antiobesity, antineuropathic pain and anticancer compounds. However, many sulfonamide compounds inhibit all CA isoforms nonspecifically, diluting drug effectiveness and causing undesired side effects due to off-target inhibition. In addition, a small but significant percentage of the general population cannot be treated with sulfonamide-based compounds due to a sulfa allergy. Therefore, CAIs must be developed that are not only isoform specific, but also non-classical, i.e. not based on sulfonamides, sulfamates, or sulfamides. This review covers the classes of non-classical CAIs and the recent advances in the development of isoform-specific inhibitors based on phenols, polyamines, coumarins and their derivatives.
Highlights
Carbonic anhydrase (CA, EC 4.2.1.1) is a family of zinc metalloenzymes that catalyze the reversible interconversion of carbon dioxide and water to a bicarbonate and a proton
There are 16 isoforms of αCA expressed that vary by localization and catalytic activity: carbonic anhydrase (CA) I, CA II, CA III, CA VII, CA XIII are cytosolic; CA IV, CA IX, CA XII, CA XIV, CA XV membrane-bound; CA Va and CA Vb mitochondrial; and CAVI secreted in saliva and colostrum [3,4,5]
Pofolyrapmoinlyeabminindiensg; sisimalislaorutnoiqtuheatboecfapuhseenthoeliccocmompopuonudnbdins,daingterrmeliiensaolnama mneotwniourkmogf roup anchohrysdtroogthene zbionncd-ibnogu, nwditwh akteeyr/inhtyedrarcotxioidnse oiocncutrhrrinogugbhetawheeyndrthoegeinnhbibointodr. aPnodlyTahmr1in9e9,bainrdesinidguies unique because the compound binding relies on a network of hydrogen bonding, with key interactions occurring between the inhibitor and Thr199, a residue conserved between all isoforms, and the other conserved between all isoforms, and the other terminal amine with active site residues
Summary
Carbonic anhydrase (CA, EC 4.2.1.1) is a family of zinc metalloenzymes that catalyze the reversible interconversion of carbon dioxide and water to a bicarbonate and a proton. The CA family is subdivided into six classes based upon their structural fold, which often correlate to their predominant organisms of expression. These classes include αCA expressed in vertebrates and algae; βCA in plants and prokaryotes; γCA in archaea; δCA and ζCA expressed in marine diatoms; and η in protozoa. The αCA active site structure is conserved and is conically shaped with a zinc atom located at the base, which is coordinated by three histidine residues (His, His, His119) and a water/hydroxide ion. First there is a nucleophilic attack of carbon dioxide by the zinc-bound hydroxide ion, resulting in a zinc-bound bicarbonate that is subsequently displaced by a water molecule [4,6,7]. The enzyme active site is regenerated to a zinc-bound hydroxide ion by a proton transfer mechanism from the zinc-bound water molecule to bulk solvent, facilitated by an ordered water wire within the active site and His acting as a proton donor/acceptor shuttle residue [8,9,10,11]
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