Current Pharmaceutical Design - Volume 14, Issue 7, 2008

Carbonic anhydrases (CAs), the metalloenzymes that catalyze the conversion between carbon dioxide and bicarbonate, continue to be surprising targets, as many exciting new discoveries related to them emerge constantly. This is indeed unprecedented as these are quite “old” enzymes, which were discovered in 1933, and thoroughly investigated since then as drug targets. Furthermore, their inhibitors are in clinical use si Read More

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 α- CA isoforms were isolated in mammals, where these enzymes play crucial physiological roles. Representatives of the β - δ-CA family are highly abundant in plants, diatoms, eubacteria and archaea. These enzymes are efficient cata Read More

Zinc ion plays a crucial role in the protein's functions and is linked to a variety of physiological processes. It constitutes an essential component of numerous enzymes especially carbonic anhydrase (CAs, EC 4.2.1.1), a pharmaceutically-important metalloprotein which catalyses efficiently the reversible hydration of carbon dioxide to bicarbonate with discharge of a proton. The potential therapeutic applications of selective carb Read More

Helicobacter pylori (H. pylori) successfully resides in the human stomach in highly acidic conditions, causing a variety of gastroduodenal lesions, including gastric ulcer, gastric cancer and MALT lymphoma. For acid acclimation of H. pylori, two types of enzymes, urease and carbonic anhydrase (CA), play a central role. They cooperatively function to maintain neutral pH in the bacterial cytoplasm and periplasm. The genome proj Read More

Plasmodium falciparum is the protozoan parasite responsible for the majority of life-threatening cases of human malaria, causing more than one million deaths a year. The global emergence of drug-resistant malarial parasites necessitates identification and characterization of novel drug targets. At present, α-carbonic anhydrase (CA) genes are identified in limited numbers of parasites in both protozoa and helminthes, ho Read More

The widely clinically used benzothiadiazines and high ceiling diuretics, such as hydrochlorothiazide, hydroflumethiazide, quinethazone, metolazone, chlorthalidone, indapamide, furosemide and bumetanide, contain SO2NH2 moieties acting as an effective zincbinding function in carbonic anhydrases (CAs, EC 4.2.1.1) inhibitors. These drugs were launched in a period when only isoform CA II was known and considered physi Read More

Inhibition of carbonic anhydrase (CA, EC 4.2.1.1) isoforms present in the eyes (CA I, II, IV and XII), with sulfonamides such as acetazolamide, methazolamide, ethoxzolamide and dichlorophenamide, is still widely used for the systemic treatment of glaucoma. The mechanism of action of these drugs consists in inhibition of CA isozymes present in ciliary processes of the eye, with the consequent reduction of bicarbonate an Read More

Obesity is widespread disease both in the developed and developing world, which currently affects over 300 million individuals worldwide and is associated with premature mortality and chronic morbidity. Although diet, physical activity and behavioral modifications should theoretically help in controlling this condition, very often these strategies are insufficient to normalize the multiple risks associated with this condition. Thus, Read More

The marketed antiepileptic drugs can not solve entirely the problem of seizure in patients suffering from refractory epilepsies. Therefore, new anticonvulsant compounds structurally and pharmacologically different of the currently prescribed drugs are needed. Carbonic anhydrase (CA) inhibitors are known to act as anticonvulsant since several decades while the link between CA and seizure is not straightforward. Howev Read More

The carbonic anhydrase (CA) enzyme family consists of thirteen active isozymes in mammals. The most recently characterized members of this family are cytosolic CA XIII and membrane-bound CA XV. This article describes recent advances in the CA family, especially CA XIII and XV. We have also included catalytic activity data on human CA XIII and mouse CA XV. Additionally, the inhibition constants of acetazolamide toward th Read More

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent the most commonly used medications for the treatment of pain and inflammation, but numerous well-described adverse drug reactions (ADRs) limit their use. These drugs act via the inhibition of cyclooxygenase (COX) enzyme of which at least two isoforms were described: COX-1 which plays important roles in homeostatic processes such as thrombogenesis and homeos Read More

Cells of the growing tumor tissue are exposed to physiological stresses connected with insufficient delivery of oxygen (hypoxia) and accumulation of acidic products of the glycolytic metabolism (acidosis). Adaptation to these microenvironmental stresses involves remodeling of the cellular expression program mediated by hypoxia-inducible factor (HIF), which activates broad array of genes functionally involved in angiogene Read More

Carbonic anhydrase IX (hCA IX) is a membrane-associated glycoprotein that is observed in many tumor tissues and is strongly overexpressed by hypoxia conditions. Hypoxia is a clinically important tumor parameter and this enzyme can play an important role as a potential marker of hypoxic tumor and as a therapeutic target too. In the last years, Carbonic Anhydrase IX Inhibitors which possess fluorescent probe were largely Read More

The activation mechanism of Carbonic Anhydrase was recently explained using kinetic, spectroscopic and X-ray techniques. It has been demonstrated that the activators molecules (CAAs) bind at the entrance of the enzyme active-site facilitating the ratedetermining step of CA catalitic cycle. Drug design studies have been performed in order to obtain strong CAAs belonging to several chemical classes: amino ac Read More

There are currently five (α,β,γ,δ,Ezgr;) classes of carbonic anhydrases (CA's) of which the α-class from mammalian sources has been studied to a much greater extent compared to the other four classes. Yet, CA's other than the α-class are widely distributed in Nature and play important roles in human health, the global carbon cycle, and industrial applications. In aerobic prokaryotes, β-class CA's are implicated in maintaining i Read More