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Special Issue "Carbonic Anhydrases: A Superfamily of Ubiquitous Enzymes 2.0"

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

Deadline for manuscript submissions: 31 May 2021.

Special Issue Editor

Prof. Dr. Clemente Capasso
E-Mail Website
Guest Editor
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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Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous special issue "Carbonic Anhydrases: A Superfamily of Ubiquitous Enzymes".

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+. Their crucial role is to equilibrate the reaction between three essential chemical species: CO2, bicarbonate (HCO3), and protons (H+). These chemical species are metabolites distributed throughout the fluids of all living organisms and are involved in a large number of physiologic and biosynthetic processes, such as respiration, photosynthesis, gluconeogenesis, lipogenesis, ureagenesis, carboxylation, and biochemical pathways involving pH homeostasis. Furthermore, processes such as secretion of electrolytes, calcification, bone resorption, transport of CO2 and bicarbonate are assisted by these enzymes. Up to date, the CA superfamily contains seven genetically distinct families (or classes), named α-, β-, γ-, δ-, ζ-, η-, and ɵ-CAs. The α-CAs were discovered in vertebrates, eubacteria, algae, and in the cytoplasm of green plants; the β-CAs were identified in eubacteria, algae, and in the chloroplasts of both mono- and dicotyledons; the γ-CAs were found mainly in Archaea and some eubacteria; the δ- and ζ-CAs are typical of the marine diatoms. The η- and q-CAs were recently discovered. The η-CA was recognized in the genome of the protozoa Plasmodia falciparum, while the q-CA was identified in the lumen of the pyrenoid-penetrating thylakoid of the unicellular alga Phaeodactylum tricornutum. From a phylogenetic viewpoint, the seven classes are an example of convergent evolution, since all classes show low sequence similarity and different folds and structures, while having a common CO2 hydratase activity, with the catalytically active species represented by a metal hydroxide derivative. These enzymes are also characterized by the presence of a large number of isoforms in most organisms investigated so far.

Drugs interfering with CAs activity have been clinically used for more than 70 years, most of them belonging to the sulfonamide class. 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); 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 in the therapy and diagnosis of cancer.  An emerging area is studying CAI as anti-infectives, i.e., as antifungal, antibacterial, and antiprotozoan agents with a novel mechanism of action, since it has been seen that the inhibition of pathogens’ CAs leads to growth impairment or growth defects in the host microorganisms.

The CA superfamily can bind molecules known as “activators” (CAA) through the middle-exit part of the active site. CAA are biogenic amines (histamine, serotonin, and catecholamines), amino acids, oligopeptides, or small proteins. CAAs enhance the catalytic constant (kcat) of the enzyme, with no effect on the KM. CAAs may have pharmacologic applications in the therapy of memory-related disorders, neurodegenerative diseases (Alzheimer’s disease), and genetic CA-deficiency syndromes.

Moreover, since most bacteria are incredibly abundant in environments that are hostile to all other forms of life, CAs from extremophiles are exciting candidates for industrial and medical applications, such as the post-combustion carbon-capture process and the realization of artificial lungs and biosensors. The ancient CAs can be considered as a biotechnological multitasking superfamily because the various CA classes are potentially able to both fight the increase of CO2 in the atmosphere produced by anthropogenic activities and ameliorate human health because of their biomedical applications.

This Special Issue is dedicated to all the important advances in the field of carbonic anhydrases, their inhibitors and activators, and their potential use in medical and biotechnological applications, since the CA superfamily represents a very promising target for the scientific community for its ubiquity 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

Manuscript Submission Information

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Keywords

  • Metalloenzymes
  • bacteria
  • pathogens
  • sulfonamides
  • inhibitors
  • activators
  • antiinfective agents
  • medicine
  • anticancer
  • neurodegenerative diseases
  • biomedical applications
  • biotechnology
  • carbon capture

Published Papers (3 papers)

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Research

Open AccessArticle
Synthesis and Enantioselective Pharmacokinetic/Pharmacodynamic Analysis of New CNS-Active Sulfamoylphenyl Carbamate Derivatives
Int. J. Mol. Sci. 2021, 22(7), 3361; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073361 - 25 Mar 2021
Viewed by 242
Abstract
We recently reported a new class of carbamate derivatives as anticonvulsants. Among these, 3-methylpentyl(4-sulfamoylphenyl)carbamate (MSPC) stood out as the most potent compound with ED50 values of 13 mg/kg (i.p.) and 28 mg/kg (p.o.) in the rat maximal electroshock test (MES). 3-Methylpropyl(4-sulfamoylphenyl)carbamate (MBPC), [...] Read more.
We recently reported a new class of carbamate derivatives as anticonvulsants. Among these, 3-methylpentyl(4-sulfamoylphenyl)carbamate (MSPC) stood out as the most potent compound with ED50 values of 13 mg/kg (i.p.) and 28 mg/kg (p.o.) in the rat maximal electroshock test (MES). 3-Methylpropyl(4-sulfamoylphenyl)carbamate (MBPC), reported and characterized here, is an MSPC analogous compound with two less aliphatic carbon atoms in its structure. As both MSPC and MBPC are chiral compounds, here, we studied the carbonic anhydrase inhibitory and anticonvulsant action of both MBPC enantiomers in comparison to those of MSPC as well as their pharmacokinetic properties. Racemic-MBPC and its enantiomers showed anticonvulsant activity in the rat maximal electroshock (MES) test with ED50 values in the range of 19–39 mg/kg. (R)-MBPC had a 65% higher clearance than its enantiomer and, consequently, a lower plasma exposure (AUC) than (S)-MSBC and racemic-MSBC. Nevertheless, (S)-MBPC had a slightly better brain permeability than (R)-MBPC with a brain-to-plasma (AUC) ratio of 1.32 (S-enantiomer), 1.49 (racemate), and 1.27 (R-enantiomer). This may contribute to its better anticonvulsant-ED50 value. The clearance of MBPC enantiomers was more enantioselective than the brain permeability and MES-ED50 values, suggesting that their anticonvulsant activity might be due to multiple mechanisms of action. Full article
(This article belongs to the Special Issue Carbonic Anhydrases: A Superfamily of Ubiquitous Enzymes 2.0)
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Open AccessArticle
In Silico Investigation of Potential Applications of Gamma Carbonic Anhydrases as Catalysts of CO2 Biomineralization Processes: A Visit to the Thermophilic Bacteria Persephonella hydrogeniphila, Persephonella marina, Thermosulfidibacter takaii, and Thermus thermophilus
Int. J. Mol. Sci. 2021, 22(6), 2861; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062861 - 11 Mar 2021
Viewed by 472
Abstract
Carbonic anhydrases (CAs) have been identified as ideal catalysts for CO2 sequestration. Here, we report the sequence and structural analyses as well as the molecular dynamics (MD) simulations of four γ-CAs from thermophilic bacteria. Three of these, Persephonella marina, Persephonella hydrogeniphila, [...] Read more.
Carbonic anhydrases (CAs) have been identified as ideal catalysts for CO2 sequestration. Here, we report the sequence and structural analyses as well as the molecular dynamics (MD) simulations of four γ-CAs from thermophilic bacteria. Three of these, Persephonella marina, Persephonella hydrogeniphila, and Thermosulfidibacter takaii originate from hydrothermal vents and one, Thermus thermophilus HB8, from hot springs. Protein sequences were retrieved and aligned with previously characterized γ-CAs, revealing differences in the catalytic pocket residues. Further analysis of the structures following homology modeling revealed a hydrophobic patch in the catalytic pocket, presumed important for CO2 binding. Monitoring of proton shuttling residue His69 (P. marina γ-CA numbering) during MD simulations of P. hydrogeniphila and P. marina’s γ-CAs (γ-PhCA and γ-PmCA), showed a different behavior to that observed in the γ-CA of Escherichia coli, which periodically coordinates Zn2+. This work also involved the search for hotspot residues that contribute to interface stability. Some of these residues were further identified as key in protein communication via betweenness centrality metric of dynamic residue network analysis. T. takaii’s γ-CA showed marginally lower thermostability compared to the other three γ-CA proteins with an increase in conformations visited at high temperatures being observed. Hydrogen bond analysis revealed important interactions, some unique and others common in all γ-CAs, which contribute to interface formation and thermostability. The seemingly thermostable γ-CA from T. thermophilus strangely showed increased unsynchronized residue motions at 423 K. γ-PhCA and γ-PmCA were, however, preliminarily considered suitable as prospective thermostable CO2 sequestration agents. Full article
(This article belongs to the Special Issue Carbonic Anhydrases: A Superfamily of Ubiquitous Enzymes 2.0)
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Open AccessArticle
Effect of Sulfonamides and Their Structurally Related Derivatives on the Activity of ι-Carbonic Anhydrase from Burkholderia territorii
Int. J. Mol. Sci. 2021, 22(2), 571; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020571 - 08 Jan 2021
Cited by 2 | Viewed by 481
Abstract
Carbonic anhydrases (CAs) are essential metalloenzymes in nature, catalyzing the carbon dioxide reversible hydration into bicarbonate and proton. In humans, breathing and many other critical physiological processes depend on this enzymatic activity. The CA superfamily function and inhibition in pathogenic bacteria has recently [...] Read more.
Carbonic anhydrases (CAs) are essential metalloenzymes in nature, catalyzing the carbon dioxide reversible hydration into bicarbonate and proton. In humans, breathing and many other critical physiological processes depend on this enzymatic activity. The CA superfamily function and inhibition in pathogenic bacteria has recently been the object of significant advances, being demonstrated to affect microbial survival/virulence. Targeting bacterial CAs may thus be a valid alternative to expand the pharmacological arsenal against the emergence of widespread antibiotic resistance. Here, we report an extensive study on the inhibition profile of the recently discovered ι-CA class present in some bacteria, including Burkholderia territorii, namely BteCAι, using substituted benzene-sulfonamides and clinically licensed sulfonamide-, sulfamate- and sulfamide-type drugs. The BteCAι inhibition profile showed: (i) several benzene-sulfonamides with an inhibition constant lower than 100 nM; (ii) a different behavior with respect to other α, β and γ-CAs; (iii) clinically used drugs having a micromolar affinity. This prototype study contributes to the initial recognition of compounds which efficiently and selectively inhibit a bacterial member of the ι-CA class, for which such a selective inhibition with respect to other protein isoforms present in the host is highly desired and may contribute to the development of novel antimicrobials. Full article
(This article belongs to the Special Issue Carbonic Anhydrases: A Superfamily of Ubiquitous Enzymes 2.0)
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