Carbonic Anhydrase Inhibitors and Epilepsy: State of the Art and Future Perspectives

Carbonic anhydrases (CAs) are a group of ubiquitously expressed metalloenzymes that catalyze the reversible hydration/dehydration of CO2/HCO3. Thus, they are involved in those physiological and pathological processes in which cellular pH buffering plays a relevant role. The inhibition of CAs has pharmacologic applications for several diseases. In addition to the well-known employment of CA inhibitors (CAIs) as diuretics and antiglaucoma drugs, it has recently been demonstrated that CAIs could be considered as valid therapeutic agents against obesity, cancer, kidney dysfunction, migraine, Alzheimer’s disease and epilepsy. Epilepsy is a chronic brain disorder that dramatically affects people of all ages. It is characterized by spontaneous recurrent seizures that are related to a rapid change in ionic composition, including an increase in intracellular potassium concentration and pH shifts. It has been reported that CAs II, VII and XIV are implicated in epilepsy. In this context, selective CAIs towards the mentioned isoforms (CAs II, VII and XIV) have been proposed and actually exploited as anticonvulsants agents in the treatment of epilepsy. Here, we describe the research achievements published on CAIs, focusing on those clinically used as anticonvulsants. In particular, we examine the new CAIs currently under development that might represent novel therapeutic options for the treatment of epilepsy.

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Effect of Sulfonamides and Their Structurally Related Derivatives on the Activity of ι-Carbonic Anhydrase from Burkholderia territorii

International Journal of Molecular Sciences ◽

10.3390/ijms22020571 ◽

2021 ◽

Vol 22 (2) ◽

pp. 571

Author(s):

Viviana De Luca ◽

Andrea Petreni ◽

Alessio Nocentini ◽

Andrea Scaloni ◽

Claudiu T. Supuran ◽

...

Keyword(s):

Carbon Dioxide ◽

Antibiotic Resistance ◽

Pathogenic Bacteria ◽

Selective Inhibition ◽

Extensive Study ◽

Protein Isoforms ◽

Carbonic Anhydrases ◽

Physiological Processes ◽

Microbial Survival ◽

Reversible Hydration

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.

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Drug treatment of epilepsy: From serendipitous discovery to evolutionary mechanisms

Current Medicinal Chemistry ◽

10.2174/0929867328666210910124727 ◽

2021 ◽

Vol 28 ◽

Author(s):

Shengying Lou ◽

Sunliang Cui

Keyword(s):

Drug Treatment ◽

Antiepileptic Drugs ◽

Brain Disorder ◽

Evolutionary Mechanisms ◽

Main Method ◽

New Era ◽

Treatment Of Epilepsy ◽

New Antiepileptic Drugs ◽

Novel Drugs ◽

Voltage Gated Ion Channels

: Epilepsy is a chronic brain disorder caused by abnormal firing of neurons. Up to now, using antiepileptic drugs is the main method of epilepsy treatment. The development of antiepileptic drugs lasted for centuries. In general, most agents entering clinical practice act on the balance mechanisms of brain “excitability-inhibition”. More specifically, they target voltage-gated ion channels, GABAergic transmission and glutamatergic transmission. In recent years, some novel drugs representing new mechanisms of action have been discovered. Although there are about 30 available drugs in the market, it is still in urgent need of discovering more effective and safer drugs. The development of new antiepileptic drugs is into a new era: from serendipitous discovery to evolutionary mechanism-based design. This article presents an overview of drug treatment of epilepsy, including a series of traditional and novel drugs.

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

International Journal of Molecular Sciences ◽

10.3390/ijms222212601 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12601

Author(s):

Viviana De Luca ◽

Andrea Angeli ◽

Valeria Mazzone ◽

Claudia Adelfio ◽

Fabrizio Carta ◽

...

Keyword(s):

Pathogenic Fungus ◽

Seborrheic Dermatitis ◽

Co2 Concentration ◽

Carbonic Anhydrases ◽

Medical Sciences ◽

Inhibitory Effects ◽

Malassezia Pachydermatis ◽

Sensing Systems ◽

Promising Target ◽

Reversible Hydration

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.

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Structural elucidation of the hormonal inhibition mechanism of the bile acid cholate on human carbonic anhydrase II

Acta Crystallographica Section D Biological Crystallography ◽

10.1107/s1399004714007457 ◽

2014 ◽

Vol 70 (6) ◽

pp. 1758-1763 ◽

Cited By ~ 12

Author(s):

Christopher D. Boone ◽

Chingkuang Tu ◽

Robert McKenna

Keyword(s):

Bile Acid ◽

Mucosal Injury ◽

Inhibition Mechanism ◽

Crystallographic Structure ◽

Carbonic Anhydrases ◽

Hydrogen Bond Interactions ◽

Zinc Metalloenzymes ◽

Ordered Water ◽

Biophysical Interactions ◽

Reversible Hydration

The carbonic anhydrases (CAs) are a family of mostly zinc metalloenzymes that catalyze the reversible hydration/dehydration of CO2into bicarbonate and a proton. Human isoform CA II (HCA II) is abundant in the surface epithelial cells of the gastric mucosa, where it serves an important role in cytoprotection through bicarbonate secretion. Physiological inhibition of HCA IIviathe bile acids contributes to mucosal injury in ulcerogenic conditions. This study details the weak biophysical interactions associated with the binding of a primary bile acid, cholate, to HCA II. The X-ray crystallographic structure determined to 1.54 Å resolution revealed that cholate does not make any direct hydrogen-bond interactions with HCA II, but instead reconfigures the well ordered water network within the active site to promote indirect binding to the enzyme. Structural knowledge of the binding interactions of this nonsulfur-containing inhibitor with HCA II could provide the template design for high-affinity, isoform-specific therapeutic agents for a variety of diseases/pathological states, including cancer, glaucoma, epilepsy and osteoporosis.

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Amino Acids as Building Blocks for Carbonic Anhydrase Inhibitors

10.20944/preprints201805.0145.v1 ◽

2018 ◽

Author(s):

Niccolò Chiaramonte ◽

Maria Novella Romanelli ◽

Elisabetta Teodori ◽

Claudiu Supuran

Keyword(s):

Organic Chemistry ◽

Amino Acids ◽

Carbonic Anhydrase ◽

Chemical Properties ◽

Building Blocks ◽

Carbonic Anhydrases ◽

Carbonic Anhydrase Inhibitors ◽

Physiological Processes ◽

Long Time ◽

Reversible Hydration

Carbonic Anhydrases (CAs) are a superfamily of metalloenzymes widespread in all life kingdoms, classified into seven genetically different families (α-θ). These enzymes catalyse the reversible hydration of carbonic anhydride (CO2), generating bicarbonate (HCO3-) and protons (H+). Fifteen isoforms of human CA (hCA I-XV) have been isolated, their presence being fundamental for the regulation of many physiological processes. In addition, overexpression of some isoforms has been associated with the outbreak or the progression of several diseases. For this reason, for a long time CA inhibitors (CAIs) are used in the control of glaucoma and as diuretics. Furthermore, the search for new potential CAIs for other pharmacological applications is a very active field. Amino acids constitute the smallest fundamental monomers of protein and, due to their useful bivalent chemical properties, are widely used in organic chemistry. Both proteinogenic and non-proteinogenic amino acids have been extensively used to synthesize CAIs. This article provides an overview of the different strategies that have been used to design new CAIs containing amino acids, and how these bivalent molecules influence the properties of the inhibitors.

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THE INCREASED OF CARBONIC ANHYDRASE IN LIVER TISSUE OF RAT INDUCED BY CHRONIC SYSTEMIC HYPOXIA

Acta Biochimica Indonesiana ◽

10.32889/actabioina.v1i1.1 ◽

2018 ◽

Vol 1 (1) ◽

pp. 1-6

Author(s):

Rahmawati Ridwan ◽

Febriana Catur Iswanti ◽

Mohamad Sadikin

Keyword(s):

Oxidative Stress ◽

Liver Tissue ◽

Specific Activity ◽

Hypoxic Condition ◽

Carbonic Anhydrases ◽

Acid Base Balance ◽

Physiological Processes ◽

Systemic Hypoxia ◽

Base Balance ◽

Reversible Hydration

Background: Carbonic anhydrases (CAs) are metalloenzymes which catalyze the reversible hydration/dehydration reaction of CO2, in order to maintain the cell homeostasis. These enzymes are found in various tissues and involve in a number of different physiological processes, including ion transport, acid-base balance, bone formation, gluconeogenesis and so on.Objective: To examine the specific activity of CA and to observe the liver tissue respond to oxidative stress by measured the malondialdehyde (MDA) concentration, in rat liver tissue induced by chronic systemic hypoxia for 1, 3, 5, 7 and 14 days of hypoxia.Results: The study showed that the activity of CA which induced by chronic systemic hypoxia significantly increasing at early exposure to the hypoxic condition, at day 1 and days 3 of hypoxia (0.281 and 0.262 nmol/mg protein/minute compared to control 0.155 nmol/mg protein/minute) (p<0.05). No statistically difference at treatments of hypoxia 5, 7 and 14 days. The concentration of MDA also increased significantly in day 3 of liver tissue hypoxia (0.013 nmol/mg compared to control 0.009 nmol/mg liver tissue) (p<0.05), and no statistically differences at day 1, 5, 7, and 14 days of hypoxia.Conclusion : There was damage of membrane cells affected by oxidative stress in liver tissue of rat induced by chronic systemic hypoxia.

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An Update on the Metabolic Roles of Carbonic Anhydrases in a Model Alga Chlamydomonas reinhardtii

10.20944/preprints201801.0110.v1 ◽

2018 ◽

Cited By ~ 1

Author(s):

Ashok Aspatwar ◽

Susanna Haapanen ◽

Seppo Parkkila

Keyword(s):

Gene Family ◽

Chlamydomonas Reinhardtii ◽

Gene Families ◽

Carbonic Anhydrases ◽

Unicellular Alga ◽

Photosynthetic Organisms ◽

Basic Reaction ◽

Multiple Copies ◽

Living Organisms ◽

Reversible Hydration

Carbonic anhydrases (CAs) are metalloenzymes that are omnipresent in nature. The CAs catalyze the basic reaction of reversible hydration of CO2 to HCO3− and H+ in all living organisms. Photosynthetic organisms contain six evolutionarily different classes of CAs, namely, α-CAs, β-CAs, γ-CAs, δ-CAs, ζ-CAs, and θ-CAs. Many of the photosynthetic organisms contain multiple isoforms of each CA family. Model alga, Chlamydomonas reinhardtii contains fifteen CAs belonging to three different CA gene families. Out of the fifteen CAs, three belong to α-CA gene family, nine to β-CA gene family, and three are γ-CAs. The multiple copies of the CAs in each gene family may be due to gene duplications within the particular CA gene family. The CAs of Chlamydomonas reinhardtii are localized in different subcellular compartments of this unicellular alga. The presence of a large number of CAs and their diverse subcellular localization within a single cell suggests the importance of these enzymes in metabolic and biochemical roles they perform in this unicellular alga. In the present review, we update the information on molecular biology of all the fifteen CAs and their metabolic and biochemical roles in Chlamydomonas reinhardtii. We also present a hypothetical model showing the known functions of CAs and predicting the functions of CAs for which precise metabolic roles are yet to be discovered.

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Transient responses during hyperosmotic shock in the filamentous fungus Neurospora crassa

Microbiology ◽

10.1099/mic.0.023507-0 ◽

2009 ◽

Vol 155 (3) ◽

pp. 903-911 ◽

Cited By ~ 14

Author(s):

Roger R. Lew ◽

Shanar Nasserifar

Keyword(s):

Neurospora Crassa ◽

Filamentous Fungus ◽

Unit Length ◽

Ionic Composition ◽

Rapid Change ◽

Ion Uptake ◽

Transient Responses ◽

Serine Kinase ◽

Extracellular Medium ◽

Hyperosmotic Shock

Fungal cells maintain an internal hydrostatic pressure (turgor) of about 400–500 kPa. In the filamentous fungus Neurospora crassa, the initial cellular responses to hyperosmotic treatment are loss of turgor, a decrease in relative hyphal volume per unit length (within 1 min) and cell growth arrest; all recover over a period of 10–60 min due to increased net ion uptake and glycerol production. The electrical responses to hyperosmotic treatment are a transient depolarization of the potential (within 1 min), followed by a sustained hyperpolarization (after 4 min) to a potential more negative than the initial potential (a driving force for ion uptake). The nature of the transient depolarization was explored in the context of other transient responses to hyperosmotic shock, to determine whether activation of a specific ion permeability or some other rapid change in electrogenic transport was responsible. Changing the ionic composition of the extracellular medium revealed that K+ permeability increases and H+ permeability declines during the transient depolarization. We suggest that these changes are due to concerted inhibition of the electrogenic H+-ATPase, and an increase in a K+ conductance. Knockout mutants of known K+ (tok, trk, trm-8, hak-1) and Cl− (a clc-3 homologue) channels and transporters had no effect on the transient depolarization, but trk and hak-1 do play a role in osmoadaptation, as does a homologue of a serine kinase regulator of H+-ATPase in yeast, Ptk2.

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Tracking solvent and protein movement during CO2 release in carbonic anhydrase II crystals

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1520786113 ◽

2016 ◽

Vol 113 (19) ◽

pp. 5257-5262 ◽

Cited By ~ 20

Author(s):

Chae Un Kim ◽

HyoJin Song ◽

Balendu Sankara Avvaru ◽

Sol M. Gruner ◽

SangYoun Park ◽

...

Keyword(s):

Carbonic Anhydrase ◽

Active Site ◽

Zinc Ion ◽

Intermediate Water ◽

Carbonic Anhydrases ◽

Zinc Metalloenzymes ◽

Close Proximity ◽

First Time ◽

Reversible Hydration ◽

Co2 Release

Carbonic anhydrases are mostly zinc metalloenzymes that catalyze the reversible hydration/dehydration of CO2/HCO3−. Previously, the X-ray crystal structures of CO2-bound holo (zinc-bound) and apo (zinc-free) human carbonic anhydrase IIs (hCA IIs) were captured at high resolution. Here, we present sequential timeframe structures of holo- [T = 0 s (CO2-bound), 50 s, 3 min, 10 min, 25 min, and 1 h] and apo-hCA IIs [T = 0 s, 50 s, 3 min, and 10 min] during the “slow” release of CO2. Two active site waters, WDW (deep water) and WDW′ (this study), replace the vacated space created on CO2 release, and another water, WI (intermediate water), is seen to translocate to the proton wire position W1. In addition, on the rim of the active site pocket, a water W2′ (this study), in close proximity to residue His64 and W2, gradually exits the active site, whereas His64 concurrently rotates from pointing away (“out”) to pointing toward (“in”) active site rotameric conformation. This study provides for the first time, to our knowledge, structural “snapshots” of hCA II intermediate states during the formation of the His64-mediated proton wire that is induced as CO2 is released. Comparison of the holo- and apo-hCA II structures shows that the solvent network rearrangements require the presence of the zinc ion.

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The structure of a tetrameric α-carbonic anhydrase fromThermovibrio ammonificansreveals a core formed around intermolecular disulfides that contribute to its thermostability

Acta Crystallographica Section D Biological Crystallography ◽

10.1107/s1399004714016526 ◽

2014 ◽

Vol 70 (10) ◽

pp. 2607-2618 ◽

Cited By ~ 22

Author(s):

Paul James ◽

Michail N. Isupov ◽

Christopher Sayer ◽

Vahid Saneei ◽

Svein Berg ◽

...

Keyword(s):

Carbon Dioxide ◽

Carbonic Anhydrase ◽

Carbon Dioxide Capture ◽

Carbonic Anhydrases ◽

Native Form ◽

Industrial Carbon ◽

E Coli ◽

Reducing Environment ◽

Reversible Hydration ◽

Unique Core

Carbonic anhydrase enzymes catalyse the reversible hydration of carbon dioxide to bicarbonate. A thermophilicThermovibrio ammonificansα-carbonic anhydrase (TaCA) has been expressed inEscherichia coliand structurally and biochemically characterized. The crystal structure of TaCA has been determined in its native form and in two complexes with bound inhibitors. The tetrameric enzyme is stabilized by a unique core in the centre of the molecule formed by two intersubunit disulfides and a single lysine residue from each monomer that is involved in intersubunit ionic interactions. The structure of this core protects the intersubunit disulfides from reduction, whereas the conserved intrasubunit disulfides are not formed in the reducing environment of theE. colihost cytosol. When oxidized to mimic the environment of the periplasmic space, TaCA has increased thermostability, retaining 90% activity after incubation at 70°C for 1 h, making it a good candidate for industrial carbon-dioxide capture. The reduction of all TaCA cysteines resulted in dissociation of the tetrameric molecule into monomers with lower activity and reduced thermostability. Unlike other characterized α-carbonic anhydrases, TaCA does not display esterase activity towardsp-nitrophenyl acetate, which appears to result from the increased rigidity of its protein scaffold.

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