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1
Prosser, Kathleen E., Alysia J. Kohlbrand, Hyeonglim Seo, Mark Kalaj y Seth M. Cohen. "19F-Tagged metal binding pharmacophores for NMR screening of metalloenzymes". Chemical Communications 57, n.º 40 (2021): 4934–37. http://dx.doi.org/10.1039/d1cc01231b.
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This study demonstrates the screening of a collection of twelve 19F-tagged metal-binding pharmacophores (MBPs) against the Zn(ii)-dependent metalloenzyme human carbonic anhydrase II (hCAII) by 19F NMR.
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So, Anthony K.-C. y George S. Espie. "Cyanobacterial carbonic anhydrases". Canadian Journal of Botany 83, n.º 7 (1 de julio de 2005): 721–34. http://dx.doi.org/10.1139/b05-057.
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Carbonic anhydrases (CAs) are ubiquitous zinc metalloenzymes that catalyze the reversible dehydration of HCO3. These enzymes are encoded by at least five distinct, evolutionarily unrelated gene families, four of which have been found among the cyanobacteria examined to date. However, the distribution and expression of these cyanobacterial α-, β-, γ-, and ∈-CAs and their homologues among species have not yet been investigated in great detail. In this study, the number, distribution, and catalytic function of known and putative CAs and CA-like proteins from a variety of freshwater and marine cyanobacteria are examined.Key words: carbonic anhydrase, carboxysome, CO2-concentrating mechanism, cyanobacteria, Prochlorococcus, Synechococcus, Synechocystis.
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Supuran, Claudiu T. "Carbonic Anhydrase Inhibitors from Marine Natural Products". Marine Drugs 20, n.º 11 (17 de noviembre de 2022): 721. http://dx.doi.org/10.3390/md20110721.
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Carbonic anhydrases (CAs, EC 4.2.1.1) are widespread metalloenzymes in organisms in all life kingdoms, being involved in pH regulation, metabolic processes and many other physiological and pathological conditions. CA inhibitors and activators thus possess applications as pharmacological agents in the management of a range of diseases. Marine natural products have allowed the identification of some highly interesting CA inhibitors, among which are sulfonamides, phenols, polyamines, coumarins and several other miscellaneous inhibitors, which are reviewed here. Psammaplin C and some bromophenols were the most investigated classes of such marine-based inhibitors and have been used as lead molecules for developing interesting types of potent and, in some cases, isoform-selective inhibitors, with applications as antitumor agents by inhibiting human CA XII and P-glycoprotein activities. Some phenols have shown interesting bacterial and fungal β-CA inhibitory effects. Marine natural products thus constitute a gold mine for identifying novel CA inhibitors, some of which may lead to the development of novel types of pharmacological agents.
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Wani, Tanvi V. y Mrunmayee P. Toraskar. "QSAR STUDIES ON HUMAN CARBONIC ANHYDRASE II INHIBITORS". INDIAN DRUGS 58, n.º 11 (28 de diciembre de 2021): 18–28. http://dx.doi.org/10.53879/id.58.11.12350.
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Carbonic anhydrase II is one of the forms of human α carbonic anhydrases which are ubiquitous metalloenzymes that catalyze inter-conversion of carbon dioxide and water to bicarbonate and proton, overexpression of which leads to disorders such as glaucoma. 2D and 3D Quantitative Structure Activity Relationship studies were carried out on previously synthesized series of sulfanilamide derivatives by VLife MDS software using stepwise variable, multi-linear regression and k-nearest neighbor molecular field analysis methods. 2D-QSAR model depicts contribution of halogens (such as chlorine and fluorine), methylene and oxygen atoms to inhibition of human carbonic anhydrases II activity. Using k-nearest neighbor molecular field analysis method two 3D-QSAR models (model A and B) were generated from which model A was found to be the best validated model with q2 (0.9494), pred_r2 (0.7367) and q2 _ se (0.2037). It displayed the fact that the inhibitory action of sulfanilamide derivatives against human carbonic anhydrases II is influenced by hydrophobicity and electro positivity.
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Lomelino, Carrie L., Jacob T. Andring y Robert McKenna. "Crystallography and Its Impact on Carbonic Anhydrase Research". International Journal of Medicinal Chemistry 2018 (13 de septiembre de 2018): 1–21. http://dx.doi.org/10.1155/2018/9419521.
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X-ray and neutron crystallography are powerful techniques utilized to study the structures of biomolecules. Visualization of enzymes in complex with substrate/product and the capture of intermediate states can be related to activity to facilitate understanding of the catalytic mechanism. Subsequent analysis of small molecule binding within the enzyme active site provides insight into mechanisms of inhibition, supporting the design of novel inhibitors using a structure-guided approach. The first X-ray crystal structures were determined for small, ubiquitous enzymes such as carbonic anhydrase (CA). CAs are a family of zinc metalloenzymes that catalyze the hydration of CO2, producing HCO3- and a proton. The CA structure and ping-pong mechanism have been extensively studied and are well understood. Though the function of CA plays an important role in a variety of physiological functions, CA has also been associated with diseases such as glaucoma, edema, epilepsy, obesity, and cancer and is therefore recognized as a drug target. In this review, a brief history of crystallography and its impact on CA research is discussed.
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Carta, Fabrizio, Pascal Dumy, Claudiu T. Supuran y Jean-Yves Winum. "Multivalent Carbonic Anhydrases Inhibitors". International Journal of Molecular Sciences 20, n.º 21 (28 de octubre de 2019): 5352. http://dx.doi.org/10.3390/ijms20215352.
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Biomolecular recognition using a multivalent strategy has been successfully applied, this last decade on several biological targets, especially carbohydrate-processing enzymes, proteases, and phosphorylases. This strategy is based on the fact that multivalent interactions of several inhibitory binding units grafted on a presentation platform may enhance the binding affinity and selectivity. The zinc metalloenzymes carbonic anhydrases (CAs, EC 4.2.1.1) are considered as drug targets for several pathologies, and different inhibitors found clinical applications as diuretics, antiglaucoma agents, anticonvulsants, and anticancer agents/diagnostic tools. Their main drawback is related to the lack of isoform selectivity leading to serious side effects for all pathologies in which they are employed. Thus, the multivalent approach may open new opportunities in the drug design of innovative isoform-selective carbonic anhydrase inhibitors with biomedical applications.
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Bozdag, Murat, Abdulmalik Saleh Alfawaz Altamimi, Daniela Vullo, Claudiu T. Supuran y Fabrizio Carta. "State of the Art on Carbonic Anhydrase Modulators for Biomedical Purposes". Current Medicinal Chemistry 26, n.º 15 (25 de julio de 2019): 2558–73. http://dx.doi.org/10.2174/0929867325666180622120625.
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The current review is intended to highlight recent advances in the search of new and effective modulators of the metalloenzymes Carbonic Anhydrases (CAs, EC 4.2.1.1) expressed in humans (h). CAs reversibly catalyze the CO2 hydration reaction, which is of crucial importance in the regulation of a plethora of fundamental processes at cellular level as well as in complex organisms. The first section of this review will be dedicated to compounds acting as activators of the hCAs (CAAs) and their promising effects on central nervous system affecting pathologies mainly characterized from memory and learning impairments. The second part will focus on the emerging chemical classes acting as hCA inhibitors (CAIs) and their potential use for the treatment of diseases.
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Mikolajczak, Dorian J. y Beate Koksch. "Peptide–Gold Nanoparticle Conjugates as Artificial Carbonic Anhydrase Mimics". Catalysts 9, n.º 11 (29 de octubre de 2019): 903. http://dx.doi.org/10.3390/catal9110903.
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We herein describe the design and synthesis of a catalytically active peptide–gold nanoparticle conjugate (Pep-Au-NP) that binds Zn(II) within its peptide monolayer and develops carbonic anhydrase activity. Specifically, a modified variant of the β-sheet forming IHIHIQI-peptide (IHQ), which forms an interstrand 3-His Zn(II)-binding site, was used as a ligand for spherical gold nanoparticles (Au-NPs). The resulting immobilized peptide maintains its ability to form β-sheets, as determined by circular dichroism (CD)-spectroscopy and, thus, maintains its ability to form Zn(II)-binding sites. The addition of Zn(II)-ions to the peptide–gold nanoparticle conjugates (Au@IHQ-NP) resulted in significant improvements in rates of ester hydrolysis of 4-nitrophenyl acetate (4-NPA) and the hydration of CO2 compared to the unconjugated peptide variants. Recycling of the catalyst revealed that Au@IHQ-NP remains intact with at least 94% of its initial activity after five rounds of CO2 hydration. The herein reported results reveal that Pep-Au-NPs are able to perform reactions catalyzed by natural metalloenzymes and open up new possibilities for the implementation of these conjugates.
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Angeli, Andrea, Victor Kartsev, Anthi Petrou, Mariana Pinteala, Roman M. Vydzhak, Svitlana Y. Panchishin, Volodymyr Brovarets et al. "New Sulfanilamide Derivatives Incorporating Heterocyclic Carboxamide Moieties as Carbonic Anhydrase Inhibitors". Pharmaceuticals 14, n.º 8 (23 de agosto de 2021): 828. http://dx.doi.org/10.3390/ph14080828.
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Carbonic Anhydrases (CAs) are ubiquitous metalloenzymes involved in several disease conditions. There are 15 human CA (hCA) isoforms and their high homology represents a challenge for the discovery of potential drugs devoid of off-target side effects. For this reason, many synthetic and pharmacologic research efforts are underway to achieve the full pharmacological potential of CA modulators of activity. We report here a novel series of sulfanilamide derivatives containing heterocyclic carboxamide moieties which were evaluated as CA inhibitors against the physiological relevant isoforms hCA I, II, IX, and XII. Some of them showed selectivity toward isoform hCA II and hCA XII. Molecular docking was performed for some of these compounds on isoforms hCA II and XII to understand the possible interaction with the active site amino acid residues, which rationalized the reported inhibitory activity.
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Mitra, Mautusi, Catherine B. Mason, Ying Xiao, Ruby A. Ynalvez, Scott M. Lato y James V. Moroney. "The carbonic anhydrase gene families of Chlamydomonas reinhardtii". Canadian Journal of Botany 83, n.º 7 (1 de julio de 2005): 780–95. http://dx.doi.org/10.1139/b05-065.
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Carbonic anhydrases (CAs) are zinc-containing metalloenzymes that catalyze the reversible interconversion of CO2 and HCO3. Aquatic photosynthetic organisms have evolved different forms of CO2-concentrating mechanisms to aid Rubisco in capturing CO2 from the surrounding environment. One aspect of all CO2-concentrating mechanisms is the critical roles played by various specially localized extracellular and intracellular CAs. There are three evolutionarily unrelated CA families designated α-, β-, and γ-CA. In the green alga, Chlamydomonas reinhardtii Dangeard, eight CAs have now been identified, including three α-CAs and five β-CAs. In addition, C. reinhardtii has another CA-like gene, Glp1 that is similar to known γ-CAs. To characterize these different CA isoforms, some of the CA genes have been overexpressed to determine whether the proteins have CA activity and to generate antibodies for in vivo immunolocalization. The CA proteins Cah3, Cah6, and Cah8, and the γ-CA-like protein, Glp1, have been overexpressed. Cah3, Cah6, and Cah8 have CA activity, but Glp1 does not. At least two of these proteins, Cah3 and Cah6, are localized to the chloroplast. Using immunolocalization and sequence analyses, we have determined that Cah6 is located to the chloroplast stroma and confirmed that Cah3 is localized to the chloroplast thylakoid lumen. Activity assays show that Cah3 is 100 times more sensitive to sulfonamides than Cah6. We present a model on how these two chloroplast CAs might participate in the CO2-concentrating mechanism of C. reinhardtii. Key words: carbonic anhydrase, CO2-concentrating mechanism, Chlamydomonas, immunolocalization.
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Deodhar, Meenakshi N., Priyanka L. Khopade y Mahesh G. Varat. "Sulfonamide Based β-Carbonic Anhydrase Inhibitors: 2D QSAR Study". ISRN Medicinal Chemistry 2013 (19 de diciembre de 2013): 1–8. http://dx.doi.org/10.1155/2013/107840.
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The carbonic anhydrases (CAs) (or carbonate dehydratases) form a family of metalloenzymes that catalyze the rapid interconversion of carbon dioxide and water to bicarbonate and protons (or vice versa), a reversible reaction that occurs rather slowly in the absence of a catalyst. The β-CAs have been characterized in a high number of human pathogens, such as the fungi/yeasts Candida albicans, Candida glabrata, Cryptococcus neoformans, and Saccharomyces cerevisiae and the bacteria Helicobacter pylori, Mycobacterium tuberculosis, Haemophilus influenzae, Brucella suis, and Streptococcus pneumonia. The β-CAs in microorganisms provide physiological concentration of carbon dioxide and bicarbonate (CO2/HCO3-) for their growth. Inhibition of β-CAs from the pathogenic microorganism is recently being explored as a novel pharmacological target to treat infections caused by the these organisms. The present study aimed to establish a relationship between the β-CAs inhibitory activity for structurally related sulphonamide derivatives and the physicochemical descriptors in quantitative terms. The statistically validated two-dimensional quantitative structure activity relationship (2D QSAR) model was obtained through multiple linear regression (MLR) analysis method using Vlife molecular design suits (MDS). Five descriptors showing positive and negative correlation with the β-CAs inhibitory activity have been included in the model. This validated 2D QSAR model may be used to design sulfonamide derivatives with better inhibitory properties.
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Culver, Billy W. y Philip K. Morton. "The Evolutionary History of Daphniid α-Carbonic Anhydrase within Animalia". International Journal of Evolutionary Biology 2015 (29 de marzo de 2015): 1–11. http://dx.doi.org/10.1155/2015/538918.
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Understanding the mechanisms that drive acid-base regulation in organisms is important, especially for organisms in aquatic habitats that experience rapidly fluctuating pH conditions. Previous studies have shown that carbonic anhydrases (CAs), a family of zinc metalloenzymes, are responsible for acid-base regulation in many organisms. Through the use of phylogenetic tools, this present study attempts to elucidate the evolutionary history of the α-CA superfamily, with particular interest in the emerging model aquatic organism Daphnia pulex. We provide one of the most extensive phylogenies of the evolution of α-CAs, with the inclusion of 261 amino acid sequences across taxa ranging from Cnidarians to Homo sapiens. While the phylogeny supports most of our previous understanding on the relationship of how α-CAs have evolved, we find that, contrary to expectations, amino acid conservation with bacterial α-CAs supports the supposition that extracellular α-CAs are the ancestral state of animal α-CAs. Furthermore, we show that two cytosolic and one GPI-anchored α-CA in Daphnia genus have homologs in sister taxa that are possible candidate genes to study for acid-base regulation. In addition, we provide further support for previous findings of a high rate of gene duplication within Daphnia genus, as compared with other organisms.
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Del Prete, Sonia, Viviana De Luca, Alessio Nocentini, Andrea Scaloni, Margaret D. Mastrolorenzo, Claudiu T. Supuran y Clemente Capasso. "Anion Inhibition Studies of the Beta-Carbonic Anhydrase from Escherichia coli". Molecules 25, n.º 11 (31 de mayo de 2020): 2564. http://dx.doi.org/10.3390/molecules25112564.
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The interconversion of CO2 and HCO3− is catalyzed by a superfamily of metalloenzymes, known as carbonic anhydrases (CAs, EC 4.2.1.1), which maintain the equilibrium between dissolved inorganic CO2 and HCO3−. In the genome of Escherichia coli, a Gram-negative bacterium typically colonizing the lower intestine of warm-blooded organisms, the cyn operon gene includes the CynT gene, encoding for a β-CA, and CynS gene, encoding for the cyanase. CynT (β-CA) prevents the depletion of the cellular bicarbonate, which is further used in the reaction catalyzed by cyanase. A second β-CA (CynT2 or Can or yadF), as well as a γ and ι-CAs were also identified in the E. coli genome. CynT2 is essential for bacterial growth at atmospheric CO2 concentration. Here, we characterized the kinetic properties and the anion inhibition profiles of recombinant CynT2. The enzyme showed a good activity for the physiological CO2 hydratase reaction with the following parameters: kcat = 5.3 × 105 s−1 and kcat/KM = of 4.1 × 107 M−1 s−1. Sulfamide, sulfamate, phenylboronic acid, phenylarsonic acid, and diethyldithiocarbamate were the most effective CynT2 inhibitors (KI = 2.5 to 84 µM). The anions allowed for a detailed understanding of the interaction of inhibitors with the amino acid residues surrounding the catalytic pocket of the enzyme and may be used as leads for the design of more efficient and specific inhibitors.
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Sauze, Joana, Sam P. Jones, Lisa Wingate, Steven Wohl y Jérôme Ogée. "The role of soil pH on soil carbonic anhydrase activity". Biogeosciences 15, n.º 2 (30 de enero de 2018): 597–612. http://dx.doi.org/10.5194/bg-15-597-2018.
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Abstract. Carbonic anhydrases (CAs) are metalloenzymes present in plants and microorganisms that catalyse the interconversion of CO2 and water to bicarbonate and protons. Because oxygen isotopes are also exchanged during this reaction, the presence of CA also modifies the contribution of soil and plant CO18O fluxes to the global budget of atmospheric CO18O. The oxygen isotope signatures (δ18O) of these fluxes differ as leaf water pools are usually more enriched than soil water pools, and this difference is used to partition the net CO2 flux over land into soil respiration and plant photosynthesis. Nonetheless, the use of atmospheric CO18O as a tracer of land surface CO2 fluxes requires a good knowledge of soil CA activity. Previous studies have shown that significant differences in soil CA activity are found in different biomes and seasons, but our understanding of the environmental and ecological drivers responsible for the spatial and temporal patterns observed in soil CA activity is still limited. One factor that has been overlooked so far is pH. Soil pH is known to strongly influence microbial community composition, richness and diversity in addition to governing the speciation of CO2 between the different carbonate forms. In this study we investigated the CO2–H2O isotopic exchange rate (kiso) in six soils with pH varying from 4.5 to 8.5. We also artificially increased the soil CA concentration to test how pH and other soil properties (texture and phosphate content) affected the relationship between kiso and CA concentration. We found that soil pH was the primary driver of kiso after CA addition and that the chemical composition (i.e. phosphate content) played only a secondary role. We also found an offset between the δ18O of the water pool with which CO2 equilibrates and total soil water (i.e. water extracted by vacuum distillation) that varied with soil texture. The reasons for this offset are still unknown.
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Aggarwal, Mayank, Chingkuang Tu, David Silverman y Robert McKenna. "Insights into Activity Enhancement of H64A Carbonic Anhydrase by Imidazoles". Acta Crystallographica Section A Foundations and Advances 70, a1 (5 de agosto de 2014): C803. http://dx.doi.org/10.1107/s2053273314091967.
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Human carbonic anhydrases (CAs) are zinc metalloenzymes that catalyze the hydration and dehydration of CO2 and HCO3-, respectively. The reaction follows a ping-pong mechanism, where the rate limiting step is the transfer of a proton from the zinc-bound solvent out of the active site, via His64 which is widely believed to be the proton shuttling residue. Being involved in a number of physiological processes such as respiration, pH regulation, ureagenesis etc., CAs are therapeutic targets for inhibition to treat various diseases. However, the physiologically dominant isoform is CA II, which is catalytically highly efficient and is easily crystallizable. Thus, most of our knowledge in the design of CA inhibitors with pharmacological applications is based on detailed CA II crystallographic studies. The catalytic activity of a variant of CA II in which His64 is replaced with Ala (H64A CA II) can be enhanced by exogenous proton donors/acceptors, usually derivatives of imidazoles and pyridines. This article examines the mechanism through which this activity enhancement might occur. X-ray crystal structures of H64A CA II in complex with four imidazole derivatives have been determined and reveal multiple binding sites. We have identified two molecules of imidazoles that bind in region that is otherwise occupied by the "in" and "out" dual conformation of the side chain of His64 in wild-type CA II. The data presented here not only corroborates the importance of imidazole side chain of His64 in proton transfer during CA catalysis, but also provides a complete structural understanding of the mechanism by which imidazoles enhance (and inhibit when used in higher concentrations) the activity of H64A CA II. In addition to inhibition of CA by these imidazoles, the presence of a large number of binding sites also gives insights and preliminary data required to fragment addition approach of drug design against CA.
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Cabaleiro-Lago, Celia y Martin Lundqvist. "The Effect of Nanoparticles on the Structure and Enzymatic Activity of Human Carbonic Anhydrase I and II". Molecules 25, n.º 19 (25 de septiembre de 2020): 4405. http://dx.doi.org/10.3390/molecules25194405.
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Human carbonic anhydrases (hCAs) belong to a well characterized group of metalloenzymes that catalyze the conversion of carbonic dioxide into bicarbonate. There are currently 15 known human isoforms of carbonic anhydrase with different functions and distribution in the body. This links to the relevance of hCA variants to several diseases such as glaucoma, epilepsy, mountain sickness, ulcers, osteoporosis, obesity and cancer. This review will focus on two of the human isoforms, hCA I and hCA II. Both are cytosolic enzymes with similar topology and 60% sequence homology but different catalytic efficiency and stability. Proteins in general adsorb on surfaces and this is also the case for hCA I and hCA II. The adsorption process can lead to alteration of the original function of the protein. However, if the function is preserved interesting biotechnological applications can be developed. This review will cover the knowledge about the interaction between hCAs and nanomaterials. We will highlight how the interaction may lead to conformational changes that render the enzyme inactive. Moreover, the importance of different factors on the final effect on hCAs, such as protein stability, protein hydrophobic or charged patches and chemistry of the nanoparticle surface will be discussed.
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Ciccone, Lidia, Chiara Cerri, Susanna Nencetti y Elisabetta Orlandini. "Carbonic Anhydrase Inhibitors and Epilepsy: State of the Art and Future Perspectives". Molecules 26, n.º 21 (22 de octubre de 2021): 6380. http://dx.doi.org/10.3390/molecules26216380.
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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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Bhakta, Abhijit, Maitreyi Bandyopadhyay, Sayantan Dasgupta, Santanu Sen, Arun Kumar y Utpal Kumar Biswas. "Effect of NaHS on carbonic anhydrase activity of human erythrocyte". Asian Journal of Medical Sciences 7, n.º 3 (6 de enero de 2016): 23–27. http://dx.doi.org/10.3126/ajms.v7i3.14047.
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Background: In contrast to its role as poison, hydrogen sulfide (H2S) is recently considered as a gaso-transmitter which mediates important physiologic functions in humans. Evidence is accumulating to demonstrate that inhibitors of H2S production or therapeutic H2S donor compounds exert significant effects in various experimental models. Carbonic anhydrases (CA) are a group of zinc-containing metalloenzymes that catalyse the reversible hydration of carbon dioxide. CAs activity in erythrocytes (CAI and CAII) has recently been observed to be associated with various pathological conditions especially in diabetes mellitus, hypertension and lipid disorders. Alteration of this enzyme activity has been reported by the effect of advanced glycation end products methylglyoxal and reduced glutathione. Aims and Objectives: As H2S, being a mediator of many physiological functions and synthesized in vivo, may affect functions of many intracellular proteins like carbonic anhydrase, the objective of this study is to find out if there is any change in the carbonic anhydrase activity under the effect of H2S- donor NaHS in dose dependant manner using RBC model in vitro.Materials and Methods: Blood sample was collected from forty (40) numbers of healthy volunteers of 18-40 years of in heparin containing vials and packed cells were prepared immediately by centrifugation The packed erythrocytes were washed three times with normal saline and diluted (1:10) with the normal saline. One ml each of diluted packed cells was taken in eight test tubes. Serial dilutions of NaHS (1to 250 µMol/L) was added to all the test tubes except for the first test tube where only normal saline was added and incubated at room temperature for one hour. Haemolysates was prepared from the erythrocytes with equal volume of distilled water in each tube and the CA activity was determined in the haemolysates using standardized method.Results: There is significant increase of CA activity in dose dependent manner under the effect of NaHS and also compared to the activity of hemolysate prepared without NaHS. Conclusions:Our study for the first time demonstrated that the Carbonic Anhydrase activity of erythrocytes is significantly increases by the effect of NaHS and this study reveals some important biological role of H2S and carbonic anhydrase.Asian Journal of Medical Sciences Vol. 7(3) 2016 23-27
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Pinard, Melissa A., Brian Mahon y Robert McKenna. "Probing the Surface of Human Carbonic Anhydrase for Clues towards the Design of Isoform Specific Inhibitors". BioMed Research International 2015 (2015): 1–15. http://dx.doi.org/10.1155/2015/453543.
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The alpha carbonic anhydrases (α-CAs) are a group of structurally related zinc metalloenzymes that catalyze the reversible hydration of CO2toHCO3-. Humans have 15 differentα-CAs with numerous physiological roles and expression patterns. Of these, 12 are catalytically active, and abnormal expression and activities are linked with various diseases, including glaucoma and cancer. Hence there is a need for CA isoform specific inhibitors to avoid off-target CA inhibition, but due to the high amino acid conservation of the active site and surrounding regions between each enzyme, this has proven difficult. However, residues towards the exit of the active site are variable and can be exploited to design isoform selective inhibitors. Here we discuss and characterize this region of “selective drug targetability” and how these observations can be utilized to develop isoform selective CA inhibitors.
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Kim, Chae Un, HyoJin Song, Balendu Sankara Avvaru, Sol M. Gruner, SangYoun Park y Robert McKenna. "Tracking solvent and protein movement during CO2 release in carbonic anhydrase II crystals". Proceedings of the National Academy of Sciences 113, n.º 19 (25 de abril de 2016): 5257–62. http://dx.doi.org/10.1073/pnas.1520786113.
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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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Tanini, Damiano, Antonella Capperucci, Claudiu T. Supuran y Andrea Angeli. "Sulfur, selenium and tellurium containing amines act as effective carbonic anhydrase activators". Bioorganic Chemistry 87 (junio de 2019): 516–22. http://dx.doi.org/10.1016/j.bioorg.2019.03.062.
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Aggarwal, Mayank, Bhargav Kondeti, Chingkuang Tu, C. Mark Maupin, David N. Silverman y Robert McKenna. "Structural insight into activity enhancement and inhibition of H64A carbonic anhydrase II by imidazoles". IUCrJ 1, n.º 2 (28 de febrero de 2014): 129–35. http://dx.doi.org/10.1107/s2052252514004096.
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Human carbonic anhydrases (CAs) are zinc metalloenzymes that catalyze the hydration and dehydration of CO2and HCO3−, respectively. The reaction follows a ping-pong mechanism, in which the rate-limiting step is the transfer of a proton from the zinc-bound solvent (OH−/H2O) in/out of the active siteviaHis64, which is widely believed to be the proton-shuttling residue. The decreased catalytic activity (∼20-fold lower with respect to the wild type) of a variant of CA II in which His64 is replaced with Ala (H64A CA II) can be enhanced by exogenous proton donors/acceptors, usually derivatives of imidazoles and pyridines, to almost the wild-type level. X-ray crystal structures of H64A CA II in complex with four imidazole derivatives (imidazole, 1-methylimidazole, 2-methylimidazole and 4-methylimidazole) have been determined and reveal multiple binding sites. Two of these imidazole binding sites have been identified that mimic the positions of the `in' and `out' rotamers of His64 in wild-type CA II, while another directly inhibits catalysis by displacing the zinc-bound solvent. The data presented here not only corroborate the importance of the imidazole side chain of His64 in proton transfer during CA catalysis, but also provide a complete structural understanding of the mechanism by which imidazoles enhance (and inhibit when used at higher concentrations) the activity of H64A CA II.
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Boone, Christopher D., Chingkuang Tu y Robert McKenna. "Structural elucidation of the hormonal inhibition mechanism of the bile acid cholate on human carbonic anhydrase II". Acta Crystallographica Section D Biological Crystallography 70, n.º 6 (30 de mayo de 2014): 1758–63. http://dx.doi.org/10.1107/s1399004714007457.
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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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Ridwan, Rahmawati, Febriana Catur Iswanti y Mohamad Sadikin. "THE INCREASED OF CARBONIC ANHYDRASE IN LIVER TISSUE OF RAT INDUCED BY CHRONIC SYSTEMIC HYPOXIA". Acta Biochimica Indonesiana 1, n.º 1 (9 de octubre de 2018): 1–6. http://dx.doi.org/10.32889/actabioina.v1i1.1.
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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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Mueller, Sarah L., Panagiotis K. Chrysanthopoulos, Maria A. Halili, Caryn Hepburn, Tom Nebl, Claudiu T. Supuran, Alessio Nocentini, Thomas S. Peat y Sally-Ann Poulsen. "The Glitazone Class of Drugs as Carbonic Anhydrase Inhibitors—A Spin-Off Discovery from Fragment Screening". Molecules 26, n.º 10 (18 de mayo de 2021): 3010. http://dx.doi.org/10.3390/molecules26103010.
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The approved drugs that target carbonic anhydrases (CA, EC 4.2.1.1), a family of zinc metalloenzymes, comprise almost exclusively of primary sulfonamides (R-SO2NH2) as the zinc binding chemotype. New clinical applications for CA inhibitors, particularly for hard-to-treat cancers, has driven a growing interest in the development of novel CA inhibitors. We recently discovered that the thiazolidinedione heterocycle, where the ring nitrogen carries no substituent, is a new zinc binding group and an alternate CA inhibitor chemotype. This heterocycle is curiously also a substructure of the glitazone class of drugs used in the treatment options for type 2 diabetes. Herein, we investigate and characterise three glitazone drugs (troglitazone 11, rosiglitazone 12 and pioglitazone 13) for binding to CA using native mass spectrometry, protein X-ray crystallography and hydrogen–deuterium exchange (HDX) mass spectrometry, followed by CA enzyme inhibition studies. The glitazone drugs all displayed appreciable binding to and inhibition of CA isozymes. Given that thiazolidinediones are not credited as a zinc binding group nor known as CA inhibitors, our findings indicate that CA may be an off-target of these compounds when used clinically. Furthermore, thiazolidinediones may represent a new opportunity for the development of novel CA inhibitors as future drugs.
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Nocentini, Alessio, Clemente Capasso y Claudiu T. Supuran. "Carbonic Anhydrase Inhibitors as Novel Antibacterials in the Era of Antibiotic Resistance: Where Are We Now?" Antibiotics 12, n.º 1 (10 de enero de 2023): 142. http://dx.doi.org/10.3390/antibiotics12010142.
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Resistance to antibiotic treatment developed by bacteria in humans and animals occurs when the microorganisms resist treatment with clinically approved antibiotics. Actions must be implemented to stop the further development of antibiotic resistance and the subsequent emergence of superbugs. Medication repurposing/repositioning is one strategy that can help find new antibiotics, as it speeds up drug development phases. Among them, the Zn2+ ion binders, such as sulfonamides and their bioisosteres, are considered the most promising compounds to obtain novel antibacterials, thus avoiding antibiotic resistance. Sulfonamides and their bioisosteres have drug-like properties well-known for decades and are suitable lead compounds for developing new pharmacological agent families for inhibiting carbonic anhydrases (CAs). CAs are a superfamily of metalloenzymes catalyzing the reversible reaction of CO2 hydration to HCO3− and H+, being present in most bacteria in multiple genetic families (α-, β-, γ- and ι-classes). These enzymes, acting as CO2 transducers, are promising drug targets because their activity influences microbe proliferation, biosynthetic pathways, and pathogen persistence in the host. In their natural or slightly modified scaffolds, sulfonamides/sulfamates/sulamides inhibit CAs in vitro and in vivo, in mouse models infected with antibiotic-resistant strains, confirming thus their role in contrasting bacterial antibiotic resistance.
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Monnard, Fabien W., Elisa S. Nogueira, Tillmann Heinisch, Tilman Schirmer y Thomas R. Ward. "Human carbonic anhydrase II as host protein for the creation of artificial metalloenzymes: the asymmetric transfer hydrogenation of imines". Chemical Science 4, n.º 8 (2013): 3269. http://dx.doi.org/10.1039/c3sc51065d.
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De Luca, Viviana, Andrea Petreni, Alessio Nocentini, Andrea Scaloni, Claudiu T. Supuran y Clemente Capasso. "Effect of Sulfonamides and Their Structurally Related Derivatives on the Activity of ι-Carbonic Anhydrase from Burkholderia territorii". International Journal of Molecular Sciences 22, n.º 2 (8 de enero de 2021): 571. http://dx.doi.org/10.3390/ijms22020571.
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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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De Luca, Viviana, Andrea Petreni, Alessio Nocentini, Andrea Scaloni, Claudiu T. Supuran y Clemente Capasso. "Effect of Sulfonamides and Their Structurally Related Derivatives on the Activity of ι-Carbonic Anhydrase from Burkholderia territorii". International Journal of Molecular Sciences 22, n.º 2 (8 de enero de 2021): 571. http://dx.doi.org/10.3390/ijms22020571.
Texto completoResumen
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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Shen, Jinyu, Zhiyong Li, Yajuan Fu y Jiansheng Liang. "Identification and molecular characterization of the alternative spliced variants of beta carbonic anhydrase 1 (βCA1) from Arabidopsis thaliana". PeerJ 9 (23 de diciembre de 2021): e12673. http://dx.doi.org/10.7717/peerj.12673.
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Carbonic anhydrases (CAs) are ubiquitous zinc metalloenzymes that catalyze the interconversion of carbon dioxide and bicarbonate. Higher plants mainly contain the three evolutionarily distinct CA families αCA, βCA, and γCA, with each represented by multiple isoforms. Alternative splicing (AS) of the CA transcripts is common. However, there is little information on the spliced variants of individual CA isoforms. In this study, we focused on the characterization of spliced variants of βCA1 from Arabidopsis. The expression patterns and subcellular localization of the individual spliced variants of βCA1 were examined. The results showed that the spliced variants of βCA1 possessed different subcellular and tissue distributions and responded differently to environmental stimuli. Additionally, we addressed the physiological role of βCA1 in heat stress response and its protein-protein interaction (PPI) network. Our results showed that βCA1 was regulated by heat stresses, and βca1 mutant was hypersensitive to heat stress, indicating a role for βCA1 in heat stress response. Furthermore, PPI network analysis revealed that βCA1 interacts with multiple proteins involved in several processes, including photosynthesis, metabolism, and the stress response, and these will provide new avenues for future investigations of βCA1.
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Geçkil, Ayşegül Altıntop, Tuğba Raika Kıran, Nurcan Kırıcı Berber, Önder Otlu, Mehmet Erdem y Erdal İn. "Carbonic Anhydrase IX as a Marker of Disease Severity in Obstructive Sleep Apnea". Medicina 58, n.º 11 (14 de noviembre de 2022): 1643. http://dx.doi.org/10.3390/medicina58111643.
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Background and Objectives: Carbonic anhydrase (CA) enzymes are a family of metalloenzymes that contain a zinc ion in their active sites. CA enzymes have been implied in important situations such as CO2 transport, pH regulation, and oncogenesis. CA-IX is a transmembrane glycoprotein and stimulates the expression of hypoxia-inducible factor-1 (HIF-1) CA-IX. This study aimed to determine serum CA-IX levels in OSA patients in whom intermittent hypoxia is important and to investigate the relationship between serum CA-IX levels and disease severity. Materials and Methods: The study included 88 people who applied to Malatya Turgut Özal University Training and Research Hospital Sleep Disorders Center without a history of respiratory disease, malignancy, and smoking. Patients were divided into three groups: control (AHI < 5, n = 31), mild–moderate OSA (AHI = 5–30, n = 27) and severe OSA (AHI > 30, n = 30). The analysis of the data included in the research was carried out with the SPSS (IBM Statistics 25, NY, USA). The Shapiro–Wilk Test was used to check whether the data included in the study had a normal distribution. Comparisons were made with ANOVA in multivariate groups and the t-test in bivariate groups. ANCOVA was applied to determine the effect of the CA-IX parameter for OSA by controlling the effect of independent variables. The differentiation in CA-IX and OSA groups was analyzed regardless of BMI, age, gender, and laboratory variables. ROC analysis was applied to determine the parameter cut-off point. Sensitivity, specificity, and cut-off were calculated, and the area under the curve (AUC) value was calculated. Results: Serum CA-IX levels were 126.3 ± 24.5 pg/mL in the control group, 184.6 ± 59.1 pg/mL in the mild–moderate OSA group, and 332.0 ± 39.7 pg/mL in the severe OSA group. Serum CA-IX levels were found to be higher in the severe OSA group compared to the mild–moderate OSA group and control group and higher in the mild–moderate OSA group compared to the control group (p < 0.001, p < 0.001, p < 0.001, respectively). In addition, a negative correlation between CA-IX and minimum SaO2 and mean SaO2 (r = –0.371, p = 0.004; r = –0.319, p = 0.017, respectively). A positive correlation between CA-IX and desaturation index (CT90) was found (r = 0.369, p = 0.005). A positive correlation was found between CA-IX and CRP (r = 0.340, p = 0.010). When evaluated by ROC curve analysis, the area under the curve (AUC) value was determined as 0.940 (95% CI 0.322–0.557; p < 0.001). When the cut-off value for CA-IX was taken as 254.5 pg/mL, it was found to have 96.7% sensitivity and 94.8% specificity in demonstrating severe OSA. Conclusions: Our study found that serum CA-IX value was higher in OSA patients than in control patients, and this elevation was associated with hypoxemia and inflammation. CA-IX value can be a fast, precise, and useful biomarker to predict OSA.
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Lii, Chong-Kuei y Suzanne Hendrich. "Selenium Deficiency Suppresses the S-Glutathiolation of Carbonic Anhydrase III in Rat Hepatocytes under Oxidative Stress". Journal of Nutrition 123, n.º 9 (1 de septiembre de 1993): 1480–86. http://dx.doi.org/10.1093/jn/123.9.1480.
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Prete, Angeli, Ghobril, Hitce, Clavaud, Marat, Supuran y Capasso. "Anion Inhibition Profile of the β-Carbonic Anhydrase from the Opportunist Pathogenic Fungus Malassezia Restricta Involved in Dandruff and Seborrheic Dermatitis". Metabolites 9, n.º 7 (18 de julio de 2019): 147. http://dx.doi.org/10.3390/metabo9070147.
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Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous metalloenzymes, which catalyze the crucial physiological CO2 hydration/dehydration reaction (CO2 + H2O ⇌ HCO3− + H+) balancing the equilibrium between CO2, H2CO3, HCO3− and CO32−. It has been demonstrated that their selective inhibition alters the equilibrium of the metabolites above affecting the biosynthesis and energy metabolism of the organism. In this context, our interest has been focalized on the fungus Malassezia restricta, which may trigger dandruff and seborrheic dermatitis altering the complex bacterial and fungal equilibrium of the human scalp. We investigated a rather large number of inorganic metal-complexing anions (a well-known class of CA inhibitors) for their interaction with the β-CA (MreCA) encoded by the M. restricta genome. The results were compared with those obtained for the two human ?-CA isoforms (hCAI and hCAII) and the β-CA from Malassezia globosa. The most effective MreCA inhibitors were diethyldithiocarbamate, sulfamide, phenyl arsenic acid, stannate, tellurate, tetraborate, selenocyanate, trithiocarbonate, and bicarbonate. The different KI values obtained for the four proteins investigated might be attributed to the architectural features of their catalytic site. The anion inhibition profile is essential for better understanding the inhibition/catalytic mechanisms of these enzymes and for designing novel types of inhibitors, which may have clinical applications for the management of dandruff and seborrheic dermatitis.
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Del Prete, Sonia, Viviana De Luca, Silvia Bua, Alessio Nocentini, Vincenzo Carginale, Claudiu T. Supuran y Clemente Capasso. "The Effect of Substituted Benzene-Sulfonamides and Clinically Licensed Drugs on the Catalytic Activity of CynT2, a Carbonic Anhydrase Crucial for Escherichia coli Life Cycle". International Journal of Molecular Sciences 21, n.º 11 (11 de junio de 2020): 4175. http://dx.doi.org/10.3390/ijms21114175.
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Proteins are relevant antimicrobial drug targets, and among them, enzymes represent a significant group, since most of them catalyze reactions essential for supporting the central metabolism, or are necessary for the pathogen vitality. Genomic exploration of pathogenic and non-pathogenic microorganisms has revealed genes encoding for a superfamily of metalloenzymes, known as carbonic anhydrases (CAs, EC 4.2.1.1). CAs catalyze the physiologically crucial reversible reaction of the carbon dioxide hydration to bicarbonate and protons. Herein, we investigated the sulfonamide inhibition profile of the recombinant β-CA (CynT2) identified in the genome of the Gram-negative bacterium Escherichia coli. This biocatalyst is indispensable for the growth of the microbe at atmospheric pCO2. Surprisingly, this enzyme has not been investigated for its inhibition with any class of CA inhibitors. Here, we show that CynT2 was strongly inhibited by some substituted benzene-sulfonamides and the clinically used inhibitor sulpiride (KIs in the range of 82–97 nM). This study may be relevant for identifying novel CA inhibitors, as well as for another essential part of the drug discovery pipeline, such as the structure–activity relationship for this class of enzyme inhibitors.
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Del Prete, Sonia, Silvia Bua, Fatmah Alasmary, Zeid AlOthman, Sylvie Tambutté, Didier Zoccola, Claudiu Supuran y Clemente Capasso. "Comparison of the Sulfonamide Inhibition Profiles of the α-Carbonic Anhydrase Isoforms (SpiCA1, SpiCA2 and SpiCA3) Encoded by the Genome of the Scleractinian Coral Stylophora pistillata". Marine Drugs 17, n.º 3 (1 de marzo de 2019): 146. http://dx.doi.org/10.3390/md17030146.
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The ubiquitous metalloenzymes carbonic anhydrases (CAs, EC 4.2.1.1) are responsible for the reversible hydration of CO2 to bicarbonate (HCO3−) and protons (H+). Bicarbonate may subsequently generate carbonate used in many functional activities by marine organisms. CAs play a crucial role in several physiological processes, e.g., respiration, inorganic carbon transport, intra and extra-cellular pH regulation, and bio-mineralization. Multiple transcript variants and protein isoforms exist in the organisms. Recently, 16 α-CA isoforms have been identified in the coral Stylophora pistillata. Here, we focalized the interest on three coral isoforms: SpiCA1 and SpiCA2, localized in the coral-calcifying cells; and SpiCA3, expressed in the cytoplasm of the coral cell layers. The three recombinant enzymes were heterologously expressed and investigated for their inhibition profiles with sulfonamides and sulfamates. The three coral CA isoforms differ significantly in their susceptibility to inhibition with sulfonamides. This study provides new insights into the coral physiology and the comprehension of molecular mechanisms involved in the bio-mineralization processes, since CAs interact with bicarbonate transporters, accelerating the trans-membrane bicarbonate movement and modulating the pH at both sides of the plasma membranes.
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Gülçin, İlhami, Boris Trofimov, Ruya Kaya, Parham Taslimi, Lyubov Sobenina, Elena Schmidt, Olga Petrova et al. "Synthesis of nitrogen, phosphorus, selenium and sulfur-containing heterocyclic compounds – Determination of their carbonic anhydrase, acetylcholinesterase, butyrylcholinesterase and α-glycosidase inhibition properties". Bioorganic Chemistry 103 (octubre de 2020): 104171. http://dx.doi.org/10.1016/j.bioorg.2020.104171.
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Peschke, Michael, Arthur T. Blades y Paul Kebarle. "Metalloion−Ligand Binding Energies and Biological Function of Metalloenzymes Such as Carbonic Anhydrase. A Study Based on ab Initio Calculations and Experimental Ion−Ligand Equilibria in the Gas Phase". Journal of the American Chemical Society 122, n.º 7 (febrero de 2000): 1492–505. http://dx.doi.org/10.1021/ja992406l.
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Yang, Hong, Eviatar Nevo y Richard E. Tashian. "Unexpected expression of carbonic anhydrase I and selenium-binding protein as the only major non-heme proteins in erythrocytes of the subterranean mole rat (Spalax ehrenbergi )". FEBS Letters 430, n.º 3 (3 de julio de 1998): 343–47. http://dx.doi.org/10.1016/s0014-5793(98)00690-5.
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Feng, Shuoqi, Su Wang, Yashuo Wang, Qingyun Yang, Dejing Wang y Hongyan Li. "Identification and expression of carbonic anhydrase 2, myosin regulatory light chain 2 and selenium-binding protein 1 in zebrafish Danio rerio: Implication for age-related biomarkers". Gene Expression Patterns 29 (septiembre de 2018): 47–58. http://dx.doi.org/10.1016/j.gep.2018.04.007.
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Smith, Alan D., Mathew Truong, Rob Bristow, Bradley Wouters, Michael F. Milosevic y Anthony M. Joshua. "The utility of serum CA9 in prognostication in prostate cancer." Journal of Clinical Oncology 34, n.º 2_suppl (10 de enero de 2016): 309. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.309.
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309 Background: Solid tumours are invariably less well-oxygenated than their normal tissue counterparts. Tumour hypoxia is important because it leads to resistance to radiotherapy and anticancer chemotherapy, and has been associated with prognosis in localized prostate cancer. Carbonic anhydrase IX (CA9), a member of a family of metalloenzymes that catalyze the reversible hydration of carbon dioxide, is considered to be one of the best biomarkers of cellular hypoxia. Although CA9 has been negatively correlated with survival in various cancers, no published data has demonstrated prognostic significance in prostate cancer. Methods: We retrospectively assessed CA9 in samples from 68 men with localized high-risk prostate cancer (LD) treated with radical prostatectomy (RP) or radiotherapy (RT), and twenty men with CRPC treated with docetaxel chemotherapy (DC). Samples were taken before treatment with RP and RT (in LD) or DC (in CRPC) from 2010 to 2012 at the Princess Margaret Cancer Center. Results: Of the 68 patients with LD, 57 patients underwent RP and 11 patients underwent RT. The proportion of patients with recurrence was 74% for RP and 55% for RT. Median CA9 for patients with LD and recurrence was 147 (range 60-1061) and 114 (range 48-1293) for those with no recurrence. Baseline CA9 was not associated with recurrence or PSA in these patients (p 0.79 and 0.09 respectively). Median follow-up for patients with CRPC was 14.1 months and 17 of 20 patients had confirmed death at the end of follow-up. The median CA9 level before DC was 155 pg/mL (range 38-1086). CA9 level before chemotherapy correlated with overall survival -0.41, however this did not reach statistical significance (p 0.10). There was no association between CA9 and PSA in CRPC (p 0.51). Conclusions: Absolute CA9 level negatively correlated with survival in men with CRPC, with a level that approached statistical significance in this small cohort. CA9 was not associated with recurrence of disease in men with LD, treated with either RP or RT. More data evaluating the relationship between hypoxia, CA9 and outcome in prostate cancer is needed before recommending its use as a biomarker in CRPC.
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Оганесян, Д. Х., В. Б. Брин y О. Т. Кабисов. "Changes in parameters of systemic hemodynamics associated with hypercalcemia in combined and isolated administration of cobalt and Z". ZHurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia», n.º 3() (16 de septiembre de 2020): 80–86. http://dx.doi.org/10.25557/0031-2991.2020.03.80-86.
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Введение. В организме кальций находится в 3 формах - связанный с белком, главным образом с альбумином, входит в комплекс с бикарбонатом, лактатом, фосфатом и цитратом, и 50% Са в крови находится в ионизированном виде Са++. Цинк является составной частью металлоэнзимов, таких как карбоангидраза, карбоксипептидаза и ДНК-полимераза. Кобальт относится к тем металлам, с которыми кальций взаимодействует в металлоактивных ферментных системах. Установлено, что кобальт может депонироваться в матриксе лизосом в результате образования комплекса с анионными группами и вступать в конкурентную борьбу с ионами Са2+ и Мg2+ за связывание с активными центрами протонной помпы. Цель исследования - изучение особенностей изменения параметров системной гемодинамики на фоне гиперкальциемии в условиях сочетанного и изолированного введения солей тяжелых металлов кобальта и цинка. Методика. Экспериментальную гиперкальциемию у крыс Вистар воспроизводили ежедневным однократным введением 3000 МЕ препарата «Аквадетрим». Хлориды кобальта (4 мг/кг) и цинка (20 мг/кг) вводили внутрижелудочно с помощью зонда ежедневно на протяжении 1 мес. По завершении эксперимента определяли основные параметры системной гемодинамики: артериальное давление инвазивно, путем введения в бедренную артерию катетера; минутный объем крови регистрировали с помощью метода термодилюции, для чего через левую общую сонную артерию в дугу аорты вводился термистор. Рассчитывали по специальным формулам среднее артериальное давление, сердечный индекс, ударный индекс и удельное периферическое сосудистое сопротивление. Результаты. Исследование показало, что при внутрижелудочном введении в течение месяца хлорида кобальта и цинка развивается артериальная гипертензия гипокинетического типа. Экспериментальная гиперкальциемия оказывает некоторое протекторное влияние на развитие кобальтовой интоксикации, а при сочетанном введении кобальта и цинка на фоне гиперкальциемии эффекты металлов усиливаются. Также установлено, что сочетанное введение солей кобальта и цинка вызывает менее выраженный эффект на параметры системной гемодинамики, чем раздельное применение металлов. Заключение. Избыточное поступление хлоридов кобальта и цинка в организм приводит к развитию артериальной гипертензии. Гиперкальциемия может изменять токсические эффекты тяжелых металлов. Сочетанное введение кобальта и цинка оказывает менее выраженный эффект на параметры системной гемодинамики. Calcium belongs to essential macronutrients. In the human body, calcium exists in three forms: bound to proteins, primarily to albumin; as a complex with bicarbonate, lactate, phosphate, or citrate; and as an ionized form of Ca2+ (which accounts for 50% of circulating Ca). Zinc is one of the most important trace elements of the body and an integral part of metalloenzymes, such as carbonic anhydrase, carboxypeptidase, and DNA polymerase. Cobalt belongs to the metals with which calcium interacts in metal-active enzyme systems. Cobalt is able to deposit in the lysosomal matrix by complexation with anionic groups and to compete with Ca2+ and Mg2+ for binding to active centers of the proton pump. The aim of this work was to study changes in parameters of the systemic hemodynamics during hypercalcemia in combined and isolated administration of heavy metal salts of cobalt and zinc. Methods. Experimental hypercalcemia was induced in Wistar rats by intragastrical administration of a water-soluble vitamin D-3 drug Aquadetrim (3,000 IU, daily for one month). Cobalt chloride (4 mg/kg) and zinc chloride (20 mg/kg) were administered intragastrically with a probe, daily for one month. Upon completion of the experiment, the following major indexes of the systemic hemodynamics were determined: blood pressure was measured invasively, with a catheter inserted into the femoral artery, and minute blood volume was recorded using the thermodilution method, with a thermistor introduced into the aortic arch through the left common carotid artery. Mean blood pressure, cardiac index, stroke index, and specific peripheral vascular resistance were calculated using special formulas. Results showed that the monthly intragastric administration of cobalt chloride and zinc chloride was associated with hypokinetic type hypertension. Experimental hypercalcemia provided some protection against cobalt intoxication but the combined administration of the metals during hypercalcemia enhanced their toxicity. The combined administration of cobalt and zinc chloride produced a less pronounced effect on indexes of the systemic hemodynamics than each metal alone. Conclusion. Excessive intake of cobalt chloride and zinc chloride results in arterial hypertension. Hypercalcemia may change the toxic effects of heavy metals. The combined administration of cobalt with zinc produced a less pronounced effect on parameters of the systemic hemodynamics.
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Gordeuk, Victor R., Xu Zhang, Wei Zhang, Shwu-Fan Ma, Galina Miasniakova, Adelina Sergueeva, Tatiana Ammosova et al. "Iron Deficiency Modifies Gene Expression Variation Induced by Augmented Hypoxia Sensing". Blood 120, n.º 21 (16 de noviembre de 2012): 1765. http://dx.doi.org/10.1182/blood.v120.21.1765.1765.
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Abstract Abstract 1765 Hypoxia may cause pulmonary and brain edema, pulmonary hypertension, aberrant metabolism and early mortality. To better understand pathological processes associated with hypoxia, we examined gene expression in Chuvash polycythemia blood mononuclear cells. Chuvash polycythemia is a congenital disorder of up-regulated hypoxic response at normoxia wherein VHLR200W homozygosity leads to elevated hypoxia inducible factor (HIF)-1 and HIF-2 levels, thromboses, pulmonary hypertension, lower systemic blood pressure (SBP) and increased mortality. VHLR200W homozygotes are often treated by phlebotomy resulting in iron deficiency, allowing us to evaluate an interaction of augmented hypoxia sensing with iron deficiency. Expression profiling of 8 VHLR200W homozygotes and 17 VHL wildtype individuals, matched for normal iron status as reflected in serum ferritin concentration, revealed altered regulation of 3069 genes at false discovery rate <0.05, with 847 up-regulated and 2222 down-regulated in VHLR200W homozygotes. Genes induced by homozygous VHLR200W were enriched in immune response pathways; those repressed in RNA transcription and protein synthesis pathways. Forty-two genes showed a >1.5-fold change in expression level, mostly (74%) an increase. Seven showed a >2-fold increase: CA1 (carbonic anhydrase), SELENBP1 (selenium binding protein 1), IL1B (interleukin 1 beta), SLC4A1 (solute carrier family 4 member 1), HBB (hemoglobin beta), and AHSP (alpha hemoglobin stabilizing protein). Additional studies including 16 VHLR200W homozygotes with low ferritin indicated that iron deficiency enhanced the induction effect of VHLR200W for 51 of the 847 upregulated genes and suppressed the induction effect for 108 of the upregulated genes. Genes further upregulated by iron deficiency included CA1, CSDA (cold shock domain protein A), BCL2L1 (BCL-2 like 1), BPGM (2,3-bisphosphoglycerate mutase), DCAF12 (DDB1 and CUL4 associated factor 12), FECH (ferrochelatase), SELENBP1 and SLC4A1. Genes for which iron deficiency suppressed the induction included inflammatory and immune pathway genes such as CASP5, CXCL16, IFI30, IFI35, IRF5, LILRB1, NOD2, RELT, TCIRG1 and TNFAIP2. A number of the genes with altered regulation in VHLR200W homozygotes might modify risk of thrombosis (upregulated: F3, SERPINE1, SERPINB2, SERPING1, PLAUR, THBD; down regulated: SERBP1), elevated systolic pulmonary artery pressure (upregulated: HTR1B, THBS1; downregulated: S1PR1, STIM2), or benign hemangioma (downregulated: CCM2). However, expression of these genes tended not to be influenced by iron status. VEGF was induced in VHLR200W homozygotes and surprisingly this induction was suppressed by iron deficiency. Expression relationships suggested a broad effect of VHLR200W in reducing systolic blood pressure through inducing VEGF. We demonstrate that many genes have commensurate changes of their expression by both iron deficiency and VHLR200W associated normoxic up-regulation of HIFs, as expected. However, there are genes that are regulated asynchronously. Further research is needed to define the molecular bases of separate regulation of genes by HIFs and iron status and to define relative risks and benefits of therapeutic phlebotomy for polycythemia. The resulting elucidation of the genomic pathways affecting predisposition to thromboses, pulmonary hypertension, lower systolic blood pressure and the interaction of augmented hypoxia sensing with iron deficiency should have broad implications leading to a better understanding of the pathophysiology of many diseases and the development of targeted therapies. Disclosures: No relevant conflicts of interest to declare.
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Gordeuk, Victor R., Xu Zhang, Wei Zhang, Shwu-Fan Ma, Galina Miasniakova, Adelina Sergueeva, Tatiana Ammosova et al. "The Hypoxic Response and Altered Gene Expression in Patients with Sickle Cell Disease". Blood 120, n.º 21 (16 de noviembre de 2012): 3245. http://dx.doi.org/10.1182/blood.v120.21.3245.3245.
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Abstract Abstract 3245 Sickle cell disease (SCD) and Chuvash polycythemia (CP) are both monogenic hematologic disorders, the first resulting in hemolytic anemia and the second in polycythemia related to an upregulated hypoxic response at normoxia. Specifically, homozygosity for the VHLR200W mutation leads to increased levels of the transcription factors hypoxia inducible factor (HIF)-1 and HIF-2 at normoxia and altered transcription of many genes. Much attention in the pathophysiology of SCD has focused on the adverse effects of chronic inflammation, enhanced cellular adhesion pathways and hemolytic rate. However, the chronic anemia of SCD is associated with an upregulation of the hypoxic response as evidenced by high erythropoietin concentrations. In this prospective study, we compared gene expression alterations in peripheral blood mononuclear cells in SCD and CP. Our pre-specified hypothesis was that we could identify hypoxia-mediated gene expression alterations in SCD through a comparison with altered gene expression in CP and reveal molecular pathways that are potentially shared by these two conditions. We prospectively compared gene expression profiles in two independent cohorts, an SCD cohort comprised of 22 SCD patients and 19 African American controls and a CP cohort comprised of 8 VHLR200W homozygotes and 17 Chuvash controls with wildtype VHL. Because iron deficiency can influence the hypoxic response, we excluded iron-deficient subjects from each cohort. We used the identical Affymetrix exon array platform for both cohorts. Differential gene expression was highly correlated between the two conditions, with Spearman correlation ρ = 0.75 between their expression profiles across 16,642 genes, suggesting that 56% of expression variation triggered by beta hemoglobin mutation in SCD may be explained by hypoxic transcriptional responses. A small portion of differential genes were highly induced in both conditions. Among 54 genes up-regulated >1.5-fold in SCD patients, 24 (44%) overlapped with the 31 genes up-regulated >1.5-fold in VHLR200W homozygotes. The genes highly induced in both conditions included FAM46C (family with sequence similarity 46 member C), SELENBP1 (selenium binding protein 1), IL1B (interleukin 1, beta), MOP-1, SNCA (synuclein, alpha), GMPR (guanosine monophosphate reductase), BPGM (2,3-bisphosphoglycerate mutase), SLC25A37 (solute carrier family 25 member 37), CA1 (carbonic anhydrase I), DCAF12 (DDB1 and CUL4 associated factor 12), EPB42 (erythrocyte membrane protein band 4.2), AHSP (alpha hemoglobin stabilizing protein), SLC4A1 (solute carrier family 4 member 1), HBB (hemoglobin, beta), HBD (hemoglobin, delta), CSDA (cold shock domain protein A), FECH (ferrochelatase), BCL2L1 (BCL2-like 1), OSBP2 (oxysterol binding protein 2), APOBEC3A (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3A), IFIT1 (interferon-induced protein with tetratricopeptide repeats 1), IFIT3 (interferon-induced protein with tetratricopeptide repeats 3), IFI44L (interferon-induced protein 44-like), and IFI27 (interferon, alpha-inducible protein 27). Three genes were down-regulated >1.5-fold in SCD patients. One of these, GIMAP7 (GTPase, IMAP family member 7), was among the 11 genes down-regulated >1.5-fold in VHLR200Whomozygotes. These results suggest that there is a broad upregulation of the hypoxic response in SCD and that the hypoxic response may underlie or interact with an important proportion of the clinical and pathophysiologic manifestations of SCD. Disclosures: No relevant conflicts of interest to declare.
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Kim, Jin Kyun, Cheol Lee, Seon Woo Lim, Aniruddha Adhikari, Jacob T. Andring, Robert McKenna, Cheol-Min Ghim y Chae Un Kim. "Elucidating the role of metal ions in carbonic anhydrase catalysis". Nature Communications 11, n.º 1 (11 de septiembre de 2020). http://dx.doi.org/10.1038/s41467-020-18425-5.
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Abstract Why metalloenzymes often show dramatic changes in their catalytic activity when subjected to chemically similar but non-native metal substitutions is a long-standing puzzle. Here, we report on the catalytic roles of metal ions in a model metalloenzyme system, human carbonic anhydrase II (CA II). Through a comparative study on the intermediate states of the zinc-bound native CA II and non-native metal-substituted CA IIs, we demonstrate that the characteristic metal ion coordination geometries (tetrahedral for Zn2+, tetrahedral to octahedral conversion for Co2+, octahedral for Ni2+, and trigonal bipyramidal for Cu2+) directly modulate the catalytic efficacy. In addition, we reveal that the metal ions have a long-range (~10 Å) electrostatic effect on restructuring water network in the active site. Our study provides evidence that the metal ions in metalloenzymes have a crucial impact on the catalytic mechanism beyond their primary chemical properties.
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Alvala, Mallika, Aaftaab Sethi, Sharon Munagalasetty, Mohammed Arifuddin, Simone Carradori, Claudiu T. Supuran y Ravi Alvala. "Coumarin and piperazine conjugates as selective inhibitors of the tumor-associated Carbonic Anhydrase IX and XII isoforms". Anti-Cancer Agents in Medicinal Chemistry 23 (2 de febrero de 2023). http://dx.doi.org/10.2174/1871520623666230202123535.
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aims: To synthesize coumarin-piperazine conjugates as potent and selective CA IX & XII inhibitors background: Carbonic Anhydrase (CA) are a family of metalloenzymes that catalyzereversible interconversion of CO2 and water to bicarbonate. CA Isoforms I, II, IX, and XII are considered physiologically and pharmacologically relevant objective: To synthesize potent and selective CA IX &XII inhibitors. method: A library of 17 coumarin derivatives clubbed with piperazine and benzyl moiety was designed, synthesized and evaluated for its inhibitory effects and selectivity profile towards physiologically and pharmacologically relevant Carbonic Anhydrase (CA) isoforms I, II, IX, and XII. result: All the derivatives were found to be active against tumour associated isoforms IX and XII. The most active compound against hCA (human Carbonic Anhydrase) IX was found to possess a Ki of 229 nM while the one against hCA XII had a Ki of 294.2 nM. Additionally, two of the compounds were found to have exquisite selectivity. They were found to be approximately 20-fold more selective towards hCA IX than XII. The selectivity of the compounds was further investigated via molecular modeling techniques conclusion: Coumarin-piperazine hybrids were identified as potent and selective CA IX & XII antagonists. Molecular modeling techniques provided interesting cues pertaining to observed selectivity. other: NA
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Weerasooriya, Hiruni N., Robert J. DiMario, Viviana C. Rosati, Ashwani K. Rai, Lillian M. LaPlace, Victoria D. Filloon, David J. Longstreth y James V. Moroney. "Arabidopsis plastid carbonic anhydrase βCA5 is important for normal plant growth". Plant Physiology, 23 de septiembre de 2022. http://dx.doi.org/10.1093/plphys/kiac451.
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Abstract Carbonic anhydrases (CAs) are zinc-metalloenzymes that catalyze the interconversion of CO2 and HCO3-. In heterotrophic organisms, CAs provide HCO3- for metabolic pathways requiring a carboxylation step. Arabidopsis (Arabidopsis thaliana) has 14 α- and β-type CAs, two of which are plastid CAs designated as βCA1 and βCA5. To study their physiological properties, we obtained knock-out (KO) lines for βCA1 (SALK_106570) and βCA5 (SALK_121932). These mutant lines were confirmed by genomic PCR, RT-PCR, and immunoblotting. While βca1 KO plants grew normally, growth of βca5 KO plants was stunted under ambient CO2 conditions of 400 µL L−1; high CO2 conditions (30,000 µL L−1) partially rescued their growth. These results were surprising, as βCA1 is more abundant than βCA5 in leaves. However, tissue expression patterns of these genes indicated that βCA1 is expressed only in shoot tissue, while βCA5 is expressed throughout the plant. We hypothesize that βCA5 compensates for loss of βCA1 but, owing to its expression being limited to leaves, βCA1 cannot compensate for loss of βCA5. We also demonstrate that βCA5 supplies HCO3- required for anaplerotic pathways that take place in plastids, such as fatty acid biosynthesis.
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Summers, Thomas J. y Nathan J. DeYonker. "QM-cluster Model Study of CO2 Hydration Mechanisms in Metal-substituted Human Carbonic Anhydrase II". Electronic Structure, 4 de enero de 2023. http://dx.doi.org/10.1088/2516-1075/acb02c.
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Abstract Human carbonic anhydrase (CA) metalloenzymes utilize a Zn2+-containing active site to catalyze the interconversion of carbon dioxide to bicarbonate. The Zn2+ may be replaced with other divalent transition metals, though the catalytic efficiency of the enzyme will be reduced. In this work, quantum mechanical cluster models of the active site are used to map the reaction profile for the hydration mechanism of carbon dioxide. The Lipscomb proton transfer and Lindskog rotation mechanisms were examined for the native Zn2+-enzyme along with variants where the metal was substituted with Cd2+, Ni2+, Fe2+, and Fe3+. The findings highlight the impact the metal coordination geometry has on the reaction profile. The results also suggest Fe2+, which is the functional metal for a prototypical CA of an anaerobic bacterium, might also be functional for human CA if cultured within an anaerobic environment.
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Sharker, Md Rajib, Soo Cheol Kim, Shaharior Hossen, Kanij Rukshana Sumi, Sang Ki Choi, Kap Seong Choi y Kang Hee Kho. "Carbonic Anhydrase in Pacific Abalone Haliotis discus hannai: Characterization, Expression, and Role in Biomineralization". Frontiers in Molecular Biosciences 8 (15 de abril de 2021). http://dx.doi.org/10.3389/fmolb.2021.655115.
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Carbonic anhydrases (CAs) are universal zinc ion containing metalloenzymes that play a pivotal role in various physiological processes. In this study, a CA I (designated as Hdh CA I) was isolated and characterized from the mantle tissue of Pacific abalone, Haliotis discus hannai. The full-length cDNA sequence of Hdh CA I was 1,417-bp in length, encoding a protein of 337 amino acids with molecular weight of 37.58 kDa. Hdh CA I sequence possessed a putative signal peptide of 22 amino acids and a CA catalytic function domain. The predicted protein shared 94 and 78% sequence identities with Haliotis gigantea and Haliotis tuberculata CA I, respectively. Results of phylogenetic analysis indicated that Hdh CA I was evolutionarily close to CA I of H. gigantea and H. tuberculata with high bootstrap values. Significantly higher levels of Hdh CA I mRNA transcript were found in mantle than other examined tissues. In situ hybridization results showed strong hybridization signals in epithelial cells of the dorsal mantle pallial, an area known to synthesize and secrete proteins responsible for the nacreous layer formation of shell. This is the first study on Hdh CA I in H. discus hannai and the results may contribute to further study its physiological functions in shell biomineralization of abalone.
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Hirakawa, Yoshihisa, Miki Senda, Kodai Fukuda, Hong Yang Yu, Masaki Ishida, Masafumi Taira, Kazushi Kinbara y Toshiya Senda. "Characterization of a novel type of carbonic anhydrase that acts without metal cofactors". BMC Biology 19, n.º 1 (18 de mayo de 2021). http://dx.doi.org/10.1186/s12915-021-01039-8.
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Abstract Background Carbonic anhydrases (CAs) are universal metalloenzymes that catalyze the reversible conversion of carbon dioxide (CO2) and bicarbonate (HCO3-). They are involved in various biological processes, including pH control, respiration, and photosynthesis. To date, eight evolutionarily unrelated classes of CA families (α, β, γ, δ, ζ, η, θ, and ι) have been identified. All are characterized by an active site accommodating the binding of a metal cofactor, which is assumed to play a central role in catalysis. This feature is thought to be the result of convergent evolution. Results Here, we report that a previously uncharacterized protein group, named “COG4337,” constitutes metal-independent CAs from the newly discovered ι-class. Genes coding for COG4337 proteins are found in various bacteria and photosynthetic eukaryotic algae. Biochemical assays demonstrated that recombinant COG4337 proteins from a cyanobacterium (Anabaena sp. PCC7120) and a chlorarachniophyte alga (Bigelowiella natans) accelerated CO2 hydration. Unexpectedly, these proteins exhibited their activity under metal-free conditions. Based on X-ray crystallography and point mutation analysis, we identified a metal-free active site within the cone-shaped α+β barrel structure. Furthermore, subcellular localization experiments revealed that COG4337 proteins are targeted into plastids and mitochondria of B. natans, implicating their involvement in CO2 metabolism in these organelles. Conclusions COG4337 proteins shared a short sequence motif and overall structure with ι-class CAs, whereas they were characterized by metal independence, unlike any known CAs. Therefore, COG4337 proteins could be treated as a variant type of ι-class CAs. Our findings suggested that this novel type of ι-CAs can function even in metal-poor environments (e.g., the open ocean) without competition with other metalloproteins for trace metals. Considering the widespread prevalence of ι-CAs across microalgae, this class of CAs may play a role in the global carbon cycle.
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Urbański, Linda J., Silvia Bua, Andrea Angeli, Reza Zolfaghari Emameh, Harlan R. Barker, Marianne Kuuslahti, Vesa P. Hytönen, Seppo Parkkila y Claudiu T. Supuran. "The production and biochemical characterization of α-carbonic anhydrase from Lactobacillus rhamnosus GG". Applied Microbiology and Biotechnology, 25 de mayo de 2022. http://dx.doi.org/10.1007/s00253-022-11990-3.
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Abstract We report the production and biochemical characterization of an α-carbonic anhydrase (LrhCA) from gram-positive probiotic bacteria Lactobacillus rhamnosus GG. CAs form a family of metalloenzymes that catalyze hydration of CO2/interconversion between CO2 and water to bicarbonate ions and protons. They are divided into eight independent gene families (α, β, γ, δ, ζ, η, θ, and ι). Interestingly, many pathogens have been identified with only β- and/or γ-CAs, which can be targeted with CA-specific inhibitors (CAIs) acting as anti-pathogen drugs. Since it is important to study the potential off-target effects of CAIs for both the human body and its commensal bacteria, we took L. rhamnosus GG as our study subject. To date, only a single α-CA has been identified in L. rhamnosus GG, which was successfully produced and biochemically characterized. LrhCA showed moderate catalytic activity with the following kinetic parameters: kcat of 9.86 × 105 s−1 and kcat/KM of 1.41 × 107 s−1 M−1. Moderate inhibition was established with 11 of the 39 studied sulfonamides. The best inhibitors were 5-((4-aminophenyl)sulfonamido)-1,3,4-thiadiazole-2-sulfonamide, 4-(2-hydroxymethyl-4-nitrophenyl-sulfonamidoethyl)-benzenesulfonamide, and benzolamide with Ki values of 319 nM, 378 nM, and 387 nM, respectively. The other compounds showed weaker inhibitory effects. The Ki of acetazolamide, a classical CAI, was 733 nM. In vitro experiments with acetazolamide showed that it had no significant effect on cell growth in L. rhamnosus GG culture. Several sulfonamides, including acetazolamide, are in use as clinical drugs, making their inhibition data highly relevant to avoid any adverse off-target effects towards the human body and its probiotic organisms. Key points • The α-carbonic anhydrase from Lactobacillus rhamnosus GG (LrhCA) is 24.3 kDa. • LrhCA has significant catalytic activity with a kcat of 9.9 × 105 s-1. • Acetazolamide resulted in a marginal inhibitory effect on cell growth.