ReviewCarbonic anhydrases as targets for medicinal chemistry
Graphical abstract
Introduction
The carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous zinc enzymes, present in prokaryotes and eukaryotes, being encoded by four distinct, evolutionarily unrelated gene families: the α-CAs (present in vertebrates, Bacteria, algae and cytoplasm of green plants), the β-CAs (predominantly found in Bacteria, algae and chloroplasts of both mono- as well as dicotyledons), the γ-CAs (mainly present in Archaea and some Bacteria) and the δ-CAs, present in some marine diatoms, respectively.1, 2, 3, 4, 5, 6, 7, 8 In mammals, 16 different α-CA isozymes or CA-related proteins (CARP) were described (Table 1), with very different subcellular localization and tissue distribution.1, 2, 3, 4, 5, 6, 7, 8 Basically, there are several cytosolic forms (CA I–III and CA VII), five membrane-bound isozymes (CA IV, CA IX, CA XII, CA XIV and CA XV), one mitochondrial form (CA V), as well as a secreted CA isozyme, CA VI.These enzymes catalyze a very simple physiological reaction, the interconversion between carbon dioxide and the bicarbonate ion, and are thus involved in crucial physiological processes connected with respiration and transport of CO2/bicarbonate between metabolizing tissues and lungs, pH and CO2 homeostasis, electrolyte secretion in a variety of tissues/organs, biosynthetic reactions (such as gluconeogenesis, lipogenesis and ureagenesis), bone resorption, calcification, tumorigenicity and many other physiologic or pathologic processes.1, 2, 3, 4, 5, 6, 7, 8 As it will be discussed shortly, many of these isozymes are important targets for the design of inhibitors with clinical applications.
In addition to the physiological reaction, the reversible hydration of CO2 to bicarbonate (reaction 1.1, Fig. 1), α-CAs catalyze a variety of other reactions, such as: the hydration of cyanate to carbamic acid, or of cyanamide to urea (reactions 1.2 and 1.3); the aldehyde hydration to gem-diols (reaction 1.4); the hydrolysis of carboxylic esters, or sulfonic acid esters (reactions 1.5 and 1.6), as well as other less investigated hydrolytic processes, such as those described by Eqs. 1.7–1.9 in Figure 1.9, 10, 11 It should be mentioned that the previously reported phosphatase activity of CA III was recently proved to be an artefact.1 It is unclear at this moment whether other α-CA catalyzed reactions than the CO2 hydration have physiological significance. The X-ray crystal structure has been determined for six α-CAs at this moment (isozymes CA I–VA, CA XII and CA XIV)1, 2, 3, 4, 5, 6, 12, 13 as well as for representatives of the β- and γ-CA families.14, 15, 16, 17, 18
Section snippets
α-CAs
The metal ion (which is Zn(II) in all α-CAs investigated up to now) is essential for catalysis.1, 2, 3, 4, 5, 6, 7, 8 X-ray crystallographic data showed that the metal ion is situated at the bottom of a 15 Å deep active site cleft (Fig. 2), being coordinated by three histidine residues (His94, His96 and His119) and a water molecule/ hydroxide ion.1, 2, 3, 4, 5, 6, 7, 8 The zinc-bound water is also engaged in hydrogen bond interactions with the hydroxyl moiety of Thr199, which in turn is bridged
Distribution of CAs
CAs were shown to be present in a multitude of prokaryotes, where these enzymes play important functions such as respiration, transport of carbon dioxide and photosynthesis.1, 2, 3, 4, 5, 6, 7, 8 The possibility to develop CA inhibitor-based antibiotics/antifungals, by inhibiting bacterial/fungal CAs present in pathogenic species, raised much interest recently.34, 35, 36 Thus, Muhlschlegel’s group34 investigated the ascomycete Candida albicans (the most common fungal pathogen in
Physiological functions of CAs, their inhibition and medicinal chemistry applications
It is not clear whether other reactions catalyzed by CAs (Fig. 1) except for CO2 hydration/bicarbonate dehydration have physiological relevance.2, 3 Thus, presently, only reaction 1.1 is considered to be the physiological one in which these enzymes are involved.
In prokaryotes, as shown also in the preceding sections, CAs possess two general functions: (i) transport of CO2/bicarbonate between different tissues of the organism; (ii) provision of CO2/bicarbonate for enzymatic reactions.4 In
Selectivity issues in the design of CAIs
Although many sulfonamide/sulfamate CAIs possess high affinity for the major mammalian isozymes considered to play important physiological functions (such as CA II, CA VA, CA VB, CA VII, CA IX or CA XII—see Table 2 for derivatives 1–8),1, 2, 3, 27 the critical challenge for the design of novel pharmacological agents from this class is constituted by the lack of specificity of such compounds towards the different targeted isozymes.1, 2, 3 Among the 16 mammalian isozymes described up to now, the
Acknowledgments
Research from the authors’ laboratory was supported in part by two EU grants of the 6th framework program (EUROXY and DeZnIt projects).
References and notes (60)
- et al.
FEMS Microbiol. Rev.
(2000) - et al.
J. Biol. Chem.
(2000) - et al.
Bioorg. Med. Chem. Lett.
(2003) - et al.
Bioorg. Med. Chem. Lett.
(2004) - et al.
J. Biol. Chem.
(2001) - et al.
Bioorg. Med. Chem. Lett.
(2004) - et al.
Bioorg. Med. Chem. Lett.
(2004) - et al.
Curr. Biol.
(2005) - et al.
Bioorg. Med. Chem. Lett.
(2006) - et al.
Bioorg. Med. Chem.
(2005)
FEBS Lett.
Trends Pharmacol. Sci.
Eur. J. Med. Chem.
Eur. J. Med. Chem.
Eur. J. Med. Chem.
Eur. J. Med. Chem.
Eur. J. Med. Chem.
J. Pharm. Sci.
Eur. J. Med. Chem.
Eur. J. Med. Chem.
FEBS Lett.
Expert Opin. Ther. Pat.
Med. Res. Rev.
Nat. New Biol.
Eur. J. Biochem.
Proc. Natl. Acad. Sci. U.S.A.
Biochem. J.
J. Biol. Inorg. Chem.
Biochemistry
Cited by (532)
Combining BNCT with carbonic anhydrase inhibition for mesothelioma treatment: Synthesis, in vitro, in vivo studies of ureidosulfamido carboranes
2024, European Journal of Medicinal ChemistryRecent drug design strategies and identification of key heterocyclic scaffolds for promising anticancer targets
2024, Pharmacology and TherapeuticsSynthesis and in vitro carbonic anhydrase and acetylcholinesterase inhibitory activities of novel hydrazide–hydrazone compounds containing 1,2,4-triazole ring
2024, Phosphorus, Sulfur and Silicon and the Related ElementsMolecular docking and inhibition profiles of some antidepressants on human carbonic anhydrase enzymes
2023, Results in Chemistry