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Physiological and Pathophysiological Functions of a Wide-Spread Superfamily of Metalloenzymes Known as Carbonic Anhydrases (CA)

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 March 2023) | Viewed by 17601

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Dr. Clemente Capasso

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Institute of Bioscience and Bioresources (IBBR), National Research Council, Via Pietro Castellino 111, 80131 Napoli, Italy
Interests: protein biochemistry; recombinant protein; heterologous expression; carbonic anhydrase; enzyme and protein purification; enzyme characterization; enzyme thermostability; cold-adapted enzymes
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Dear Colleagues,

The superfamily of carbonic anhydrases (CAs, EC 4.2.1.1) represents a group of ubiquitous proteins, which catalyze the physiologically important hydration–dehydration reaction of carbon dioxide to bicarbonate and protons: CO₂ + H₂O ⇄ HCO₃⁻ + H⁺.

Since CO₂, HCO₃⁻, and H⁺ are metabolites distributed throughout the fluids of all living organisms, CAs are involved in a large number of physiologic and biosynthetic processes, such as respiration, photosynthesis, gluconeogenesis, lipogenesis, ureagenesis, carboxylation, secretion of electrolytes, pH homeostasis, calcification, bone resorption, and transport of CO₂ and HCO₃⁻. To date, the CA superfamily contains eight genetically distinct families (or classes), named α-, β-, γ-, δ-, ζ-, η-, θ-, and ι-CAs. The distribution of the CA classes is somewhat assorted in most investigated organisms, and except for mammals which encode only for α-CAs, most of them possess multiple representatives of two or even more genetic families. In plants, α- and β-CAs have been recognized.

In Bacteria, Archaea, and cyanobacteria, α-, β-, γ-, and ι-CA classes are present. Marine diatoms encode for α-, δ-, ζ-, θ- and ι-CAs. In protozoa, α-, β-, and η-CAs have been detected. In the fungal kingdom, the typical class is represented by β-CAs, and most fungi encode at least one β-CA. In filamentous ascomycetes, it is also possible to find genes encoding for α-CAs. From a phylogenetic viewpoint, the eight CA classes are an example of convergent evolution: all CA classes show low sequence similarity and different folds and structures, having a common CO₂ hydratase activity.

Many CA inhibitors (CAI) exist, which could be classified as inhibitors binding the metal ion (anion, sulfonamides and their bioisosteres, dithiocarbamates, xanthates), inhibitors anchoring to the water molecule/hydroxide ion coordinated to the metal (phenols, polyamines, thioxocoumarins, sulfocumarins), and inhibitors occluding the active site entrance (coumarins and their isosteres); inhibitors binding outside of the active site.

Inhibition of CAs has many pharmacologic applications, such as against glaucoma, convulsions, obesity, and cancer. Today, an emerging area is studying CAI as anti-infectives, i.e., antifungal, antibacterial, and antiprotozoan agents.

This Special Issue is dedicated to all the fundamental advances in the field of carbonic anhydrases since the CA superfamily represents a very promising target for the scientific community for its ubiquitous and crucial role in many physiologic and pathologic processes.

Original papers, reviews articles, and perspectives from experts in the field are welcome.

Prof. Dr. Clemente Capasso
Guest Editor

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Keywords

metalloenzymes
bacteria
pathogens
sulfonamides
inhibitors
activators
anti-infective agents
medicine
anticancer
neurodegenerative diseases
biomedical applications
biotechnology

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Published Papers (7 papers)

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25 pages, 7131 KiB

Open AccessArticle

Conformationally Restricted Glycoconjugates Derived from Arylsulfonamides and Coumarins: New Families of Tumour-Associated Carbonic Anhydrase Inhibitors

by Mónica Martínez-Montiel, Laura L. Romero-Hernández, Simone Giovannuzzi, Paloma Begines, Adrián Puerta, Ana I. Ahuja-Casarín, Miguel X. Fernandes, Penélope Merino-Montiel, Sara Montiel-Smith, Alessio Nocentini, José M. Padrón, Claudiu T. Supuran, José G. Fernández-Bolaños and Óscar López

Int. J. Mol. Sci. 2023, 24(11), 9401; https://doi.org/10.3390/ijms24119401 - 28 May 2023

Cited by 3 | Viewed by 2034

Abstract

The involvement of carbonic anhydrases (CAs) in a myriad of biological events makes the development of new inhibitors of these metalloenzymes a hot topic in current Medicinal Chemistry. In particular, CA IX and XII are membrane-bound enzymes, responsible for tumour survival and chemoresistance. Herein, a bicyclic carbohydrate-based hydrophilic tail (imidazolidine-2-thione) has been appended to a CA-targeting pharmacophore (arylsulfonamide, coumarin) with the aim of studying the influence of the conformational restriction of the tail on the CA inhibition. For this purpose, the coupling of sulfonamido- or coumarin-based isothiocyanates with reducing 2-aminosugars, followed by the sequential acid-promoted intramolecular cyclization of the corresponding thiourea and dehydration reactions, afforded the corresponding bicyclic imidazoline-2-thiones in good overall yield. The effects of the carbohydrate configuration, the position of the sulfonamido motif on the aryl fragment, and the tether length and substitution pattern on the coumarin were analysed in the in vitro inhibition of human CAs. Regarding sulfonamido-based inhibitors, the best template turned out to be a d-galacto-configured carbohydrate residue, meta-substitution on the aryl moiety (9b), with K_i against CA XII within the low nM range (5.1 nM), and remarkable selectivity indexes (1531 for CA I and 181.9 for CA II); this provided an enhanced profile in terms of potency and selectivity compared to more flexible linear thioureas 1–4 and the drug acetazolamide (AAZ), used herein as a reference compound. For coumarins, the strongest activities were found for substituents devoid of steric hindrance (Me, Cl), and short linkages; derivatives 24h and 24a were found to be the most potent inhibitors against CA IX and XII, respectively (K_i = 6.8, 10.1 nM), and also endowed with outstanding selectivity (K_i > 100 µM against CA I, II, as off-target enzymes). Docking simulations were conducted on 9b and 24h to gain more insight into the key inhibitor–enzyme interactions. Full article

(This article belongs to the Special Issue Physiological and Pathophysiological Functions of a Wide-Spread Superfamily of Metalloenzymes Known as Carbonic Anhydrases (CA))

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15 pages, 2062 KiB

Open AccessArticle

Effects of Phosphorylation on the Activity, Inhibition and Stability of Carbonic Anhydrases

by Xiaojing Huang, Daniel Winter, Dominic J. Glover, Claudiu T. Supuran and William A. Donald

Int. J. Mol. Sci. 2023, 24(11), 9275; https://doi.org/10.3390/ijms24119275 - 25 May 2023

Viewed by 2123

Abstract

Carbonic anhydrases (CAs) are a metalloenzyme family that have important roles in cellular processes including pH homeostasis and have been implicated in multiple pathological conditions. Small molecule inhibitors have been developed to target carbonic anhydrases, but the effects of post-translational modifications (PTMs) on the activity and inhibition profiles of these enzymes remain unclear. Here, we investigate the effects of phosphorylation, the most prevalent carbonic anhydrase PTM, on the activities and drug-binding affinities of human CAI and CAII, two heavily modified active isozymes. Using serine to glutamic acid (S > E) mutations to mimic the effect of phosphorylation, we demonstrate that phosphomimics at a single site can significantly increase or decrease the catalytic efficiencies of CAs, depending on both the position of the modification and the CA isoform. We also show that the S > E mutation at Ser50 of hCAII decreases the binding affinities of hCAII with well-characterized sulphonamide inhibitors including by over 800-fold for acetazolamide. Our findings suggest that CA phosphorylation may serve as a regulatory mechanism for enzymatic activity, and affect the binding affinity and specificity of small, drug and drug-like molecules. This work should motivate future studies examining the PTM-modification forms of CAs and their distributions, which should provide insights into CA physiopathological functions and facilitate the development of ‘modform-specific’ carbonic anhydrase inhibitors. Full article

(This article belongs to the Special Issue Physiological and Pathophysiological Functions of a Wide-Spread Superfamily of Metalloenzymes Known as Carbonic Anhydrases (CA))

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9 pages, 660 KiB

Open AccessCommunication

Membrane Permeability Is Required for the Vasodilatory Effect of Carbonic Anhydrase Inhibitors in Porcine Retinal Arteries

by Thor Eysteinsson, Andrea García-Llorca, Arnar Oessur Hardarson, Daniela Vullo, Fabrizio Carta and Claudiu T. Supuran

Int. J. Mol. Sci. 2023, 24(9), 8140; https://doi.org/10.3390/ijms24098140 - 2 May 2023

Cited by 1 | Viewed by 1674

Abstract

It has been demonstrated previously that a variety of carbonic anhydrase inhibitors (CAIs) can induce vasodilation in pre-contracted retinal arteriolar segments although with different efficacy and potency. Since the CAIs tested so far are able to permeate cell membranes and inhibit both intracellular and extracellular isoforms of the enzyme, it is not clear whether extra- or intracellular isoforms or mechanisms are mediating their vasodilatory effects. By means of small wire myography, we have tested the effects of four new CAIs on wall tension in pre-contracted retinal arteriolar segments that demonstrably do not enter cell membranes but have high affinity to both cytosolic and membrane-bound isoforms of CA. At concentrations between 10⁻⁶ M to 10⁻³ M, none of the four membrane impermeant CAIs had any significant effect on arteriolar wall tension, while the membrane permeant CAI benzolamide (10⁻³ M) fully dilated all arteriolar segments tested. This suggests that CAI act as vasodilators through cellular mechanisms located in the cytoplasm of vascular cells. Full article

(This article belongs to the Special Issue Physiological and Pathophysiological Functions of a Wide-Spread Superfamily of Metalloenzymes Known as Carbonic Anhydrases (CA))

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17 pages, 3376 KiB

Open AccessArticle

Antimicrobial and Antibiofilm Activities of Carvacrol, Amoxicillin and Salicylhydroxamic Acid Alone and in Combination vs. Helicobacter pylori: Towards a New Multi-Targeted Therapy

by Valentina Puca, Gabriele Turacchio, Beatrice Marinacci, Claudiu T. Supuran, Clemente Capasso, Pamela Di Giovanni, Ilaria D’Agostino, Simone Carradori and Rossella Grande

Int. J. Mol. Sci. 2023, 24(5), 4455; https://doi.org/10.3390/ijms24054455 - 24 Feb 2023

Cited by 16 | Viewed by 2730

Abstract

The World Health Organization has indicated Helicobacter pylori as a high-priority pathogen whose infections urgently require an update of the antibacterial treatments pipeline. Recently, bacterial ureases and carbonic anhydrases (CAs) were found to represent valuable pharmacological targets to inhibit bacterial growth. Hence, we explored the underexploited possibility of developing a multiple-targeted anti-H. pylori therapy by assessing the antimicrobial and antibiofilm activities of a CA inhibitor, carvacrol (CAR), amoxicillin (AMX) and a urease inhibitor (SHA), alone and in combination. Minimal Inhibitory (MIC) and Minimal Bactericidal (MBC) Concentrations of their different combinations were evaluated by checkerboard assay and three different methods were employed to assess their capability to eradicate H. pylori biofilm. Through Transmission Electron Microscopy (TEM) analysis, the mechanism of action of the three compounds alone and together was determined. Interestingly, most combinations were found to strongly inhibit H. pylori growth, resulting in an additive FIC index for both CAR-AMX and CAR-SHA associations, while an indifferent value was recorded for the AMX-SHA association. Greater antimicrobial and antibiofilm efficacy of the combinations CAR-AMX, SHA-AMX and CAR-SHA against H. pylori were found with respect to the same compounds used alone, thereby representing an innovative and promising strategy to counteract H. pylori infections. Full article

(This article belongs to the Special Issue Physiological and Pathophysiological Functions of a Wide-Spread Superfamily of Metalloenzymes Known as Carbonic Anhydrases (CA))

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16 pages, 4962 KiB

Open AccessArticle

Inhibitors of Mitochondrial Human Carbonic Anhydrases VA and VB as a Therapeutic Strategy against Paclitaxel-Induced Neuropathic Pain in Mice

by Laura Micheli, Lara Testai, Andrea Angeli, Donatello Carrino, Alessandra Pacini, Francesco Margiotta, Lorenzo Flori, Claudiu T. Supuran, Vincenzo Calderone, Carla Ghelardini and Lorenzo Di Cesare Mannelli

Int. J. Mol. Sci. 2022, 23(11), 6229; https://doi.org/10.3390/ijms23116229 - 2 Jun 2022

Cited by 11 | Viewed by 2411

Abstract

Neuropathy development is a major dose-limiting side effect of anticancer treatments that significantly reduces patient’s quality of life. The inadequate pharmacological approaches for neuropathic pain management warrant the identification of novel therapeutic targets. Mitochondrial dysfunctions that lead to reactive oxygen species (ROS) increase, cytosolic Ca²⁺ imbalance, and lactate acidosis are implicated in neuropathic pain pathogenesis. It has been observed that in these deregulations, a pivotal role is played by the mitochondrial carbonic anhydrases (CA) VA and VB isoforms. Hence, preclinical studies should be conducted to assess the efficacy of two novel selenides bearing benzenesulfonamide moieties, named 5b and 5d, and able to inhibit CA VA and VB against paclitaxel-induced neurotoxicity in mice. Acute treatment with 5b and 5d (30–100 mg/kg, per os – p.o.) determined a dose-dependent and long-lasting anti-hyperalgesic effect in the Cold plate test. Further, repeated daily treatment for 15 days with 100 mg/kg of both compounds (starting the first day of paclitaxel injection) significantly prevented neuropathic pain development without the onset of tolerance to the anti-hyperalgesic effect. In both experiments, acetazolamide (AAZ, 100 mg/kg, p.o.) used as the reference drug was partially active. Moreover, ex vivo analysis demonstrated the efficacy of 5b and 5d repeated treatments in reducing the maladaptive plasticity that occurs to glia cells in the lumbar portion of the spinal cord and in improving mitochondrial functions in the brain and spinal cord that were strongly impaired by paclitaxel-repeated treatment. In this regard, 5b and 5d ameliorated the metabolic activity, as observed by the increase in citrate synthase activity, and preserved an optimal mitochondrial membrane potential (ΔΨ) value, which appeared depolarized in brains from paclitaxel-treated animals. In conclusion, 5b and 5d have therapeutic and protective effects against paclitaxel-induced neuropathy without tolerance development. Moreover, 5b and 5d reduced glial cell activation and mitochondrial dysfunction in the central nervous system, being a promising candidate for the management of neuropathic pain and neurotoxicity evoked by chemotherapeutic drugs. Full article

(This article belongs to the Special Issue Physiological and Pathophysiological Functions of a Wide-Spread Superfamily of Metalloenzymes Known as Carbonic Anhydrases (CA))

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12 pages, 2396 KiB

Open AccessArticle

Inhibitory Effects of Sulfonamide Derivatives on the β-Carbonic Anhydrase (MpaCA) from Malassezia pachydermatis, a Commensal, Pathogenic Fungus Present in Domestic Animals

by Viviana De Luca, Andrea Angeli, Valeria Mazzone, Claudia Adelfio, Fabrizio Carta, Silvia Selleri, Vincenzo Carginale, Andrea Scaloni, Claudiu T. Supuran and Clemente Capasso

Int. J. Mol. Sci. 2021, 22(22), 12601; https://doi.org/10.3390/ijms222212601 - 22 Nov 2021

Cited by 3 | Viewed by 2408

Abstract

Fungi are exposed to various environmental variables during their life cycle, including changes in CO₂ concentration. CO₂ has the potential to act as an activator of several cell signaling pathways. In fungi, the sensing of CO₂ triggers cell differentiation and the biosynthesis of proteins involved in the metabolism and pathogenicity of these microorganisms. The molecular machineries involved in CO₂ sensing constitute a promising target for the development of antifungals. Carbonic anhydrases (CAs, EC 4.2.1.1) are crucial enzymes in the CO₂ sensing systems of fungi, because they catalyze the reversible hydration of CO₂ to proton and HCO₃^-. Bicarbonate in turn boots a cascade of reactions triggering fungal pathogenicity and metabolism. Accordingly, CAs affect microorganism proliferation and may represent a potential therapeutic target against fungal infection. Here, the inhibition of the unique β-CA (MpaCA) encoded in the genome of Malassezia pachydermatis, a fungus with substantial relevance in veterinary and medical sciences, was investigated using a series of conventional CA inhibitors (CAIs), namely aromatic and heterocyclic sulfonamides. This study aimed to describe novel candidates that can kill this harmful fungus by inhibiting their CA, and thus lead to effective anti-dandruff and anti-seborrheic dermatitis agents. In this context, current antifungal compounds, such as the azoles and their derivatives, have been demonstrated to induce the selection of resistant fungal strains and lose therapeutic efficacy, which might be restored by the concomitant use of alternative compounds, such as the fungal CA inhibitors. Full article

(This article belongs to the Special Issue Physiological and Pathophysiological Functions of a Wide-Spread Superfamily of Metalloenzymes Known as Carbonic Anhydrases (CA))

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Review

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19 pages, 1083 KiB

Open AccessReview

Roles of Carbonic Anhydrases and Carbonic Anhydrase Related Proteins in Zebrafish

by Ashok Aspatwar, Leo Syrjänen and Seppo Parkkila

Int. J. Mol. Sci. 2022, 23(8), 4342; https://doi.org/10.3390/ijms23084342 - 14 Apr 2022

Cited by 7 | Viewed by 3101

Abstract

During recent decades, zebrafish (Danio rerio) have become one of the most important model organisms in which to study different physiological and biological phenomena. The research field of carbonic anhydrases (CAs) and carbonic anhydrase related proteins (CARPs) is not an exception to this. The best-known function of CAs is the regulation of acid–base balance. However, studies performed with zebrafish, among others, have revealed important roles for these proteins in many other physiological processes, some of which had not yet been predicted in the light of previous studies and suggestions. Examples include roles in zebrafish pigmentation as well as motor coordination. Disruption of the function of these proteins may generate lethal outcomes. In this review, we summarize the current knowledge of CA-related studies performed in zebrafish from 1993–2021 that was obtained from PubMed search. Full article

(This article belongs to the Special Issue Physiological and Pathophysiological Functions of a Wide-Spread Superfamily of Metalloenzymes Known as Carbonic Anhydrases (CA))

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