Carbonic Anhydrase as CO2 capturing agent: its Classes and Catalytic Mechanisms

Carbonic anhydrase (CA; EC 4.2.4.1), metalloenzyme, can catalyze reversible hydration of CO2 (CO2 + H2O ↔ H+ + HCO3 -) with high efficiency (kcat ~106 s-1) and plays fundamental roles in many biological processes like photosynthesis, respiration, pH homeostasis and ion transport. Recently, CA has been considered as an important biocatalyst for CO2 sequestration technology because the accumulation of CO2 is the main cause for global climate change and it is critical to develop technologies that can reduce atmospheric CO2 level. This review deals with the classes and mechanisms of several CAs as CO2 capture agents

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

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.

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.

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

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.

Desolvation induced crystal jumping: reversible hydration and dehydration of a spironolactone–saccharin cocrystal with water as the jumping-mate

We present a spironolactone–saccharin cocrystal hydrate as the first example of a crystal that jumps without changes in either the lattice parameter or the molecular conformation to highlight the unique advantages of the jumping-mate strategy.

Aspirin: A Suicide Inhibitor of Carbonic Anhydrase II

Carbonic anhydrase II (CAII) is a metalloenzyme that catalyzes the reversible hydration/dehydration of CO2/HCO3−. In addition, CAII is attributed to other catalytic reactions, including esterase activity. Aspirin (acetyl-salicylic acid), an everyday over-the-counter drug, has both ester and carboxylic acid moieties. Recently, compounds with a carboxylic acid group have been shown to inhibit CAII. Hence, we hypothesized that Aspirin could act as a substrate for esterase activity, and the product salicylic acid (SA), an inhibitor of CAII. Here, we present the crystal structure of CAII in complex with SA, a product of CAII crystals pre-soaked with Aspirin, to 1.35Å resolution. In addition, we provide kinetic data to support the observation that CAII converts Aspirin to its deacetylated form, SA. This data may also explain the short half-life of Aspirin, with CAII so abundant in blood, and that Aspirin could act as a suicide inhibitor of CAII.

A pseudorotaxane formed from a cucurbit[7]uril wheel and a bioinspired molecular axle with pH, light and redox-responsive properties

A pH-, light- and redox-responsive flavylium-bipyridinium molecular dyad (bioinspired in natural anthocyanins) was synthesized and employed to devise a pseudorotaxane with the macrocycle cucurbit[7]uril (CB7) in aqueous solution. The inclusion complex was characterized by UV-Vis absorption, fluorescence emission, NMR and electrochemical techniques which demonstrate formation of a stable binary complex between the dyad and CB7 both under acidic and neutral conditions. It is noteworthy that the flavylium-bipyridinium tricationic dyad is only stable in highly acidic media, undergoing a reversible hydration reaction at slightly acidic or neutral pH to give a trans-chalcone-bipyridinium dication. 1H NMR experiments showed that in this last species the CB7 binds to the bipyridinium unit while in the tricationic species the macrocycle is positioned between the flavylium and the bipyridinium moieties. The different location of the CB7 wheel in the two dyad states allows control of the shuttling movement using light and pH stimuli that trigger the interconversion between these two species.

Computational Modeling Reveals the Mechanism of Fluorescent State Recovery in the Reversibly Photoswitchable Protein Dreiklang

<p>The unique properties of the photoswitchable protein Dreiklang are attributed to a reversible hydration/dehydration reaction at the imidazolinone ring of the chromophore. Recovery of the fluorescent state, which is associated with a chemical reaction of chromophore dehydration, is an important part of the photocycle of this protein. Here we characterize the fluorescent (ON) and non-fluorescent (OFF) states of Dreiklang and simulate the thermal recovery reaction OFF → ON using computational approaches. By using molecular modeling methods including the quantum mechanics/molecular mechanics (QM/MM) technique, we characterize the structures and spectra of the ON- and OFF-states. The results are consistent with relevant experimental data. The computed reaction profile explains the observed recovery reaction and clarifies the mechanism of chemical transformations in the chromophore-containing pocket in Dreiklang. </p>