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A special issue of Metabolites (ISSN 2218-1989).

Deadline for manuscript submissions: closed (21 December 2018) | Viewed by 85401

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Prof. Dr. Claudiu T. Supuran

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Neurofarba Department, Section of Farmaceutical and Neutraceutical Sciences, University of Florence, Sesto Fiorentino, 50019 Florence, Italy
Interests: drug design; metalloenzymes; carbonic anhydrases; anticancer agents; antiinfectives; sulfonamides; coumarins
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Dear Colleagues,

Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes present in all life kingdoms, as they equilibrate the reaction between three simple but essential chemical species: CO₂, bicarbonate, and protons. Discovered more than 80 year ago, in 1933, these enzymes were extensively investigated due to the biomedical application of their inhibitors, but also because they are an extraordinary example of convergent evolution, with seven genetically-distinct CA families that evolved independently in Bacteria, Archaea, and Eukarya. CAs are also among the most efficient enzymes known in nature, due to the fact that the uncatalyzed CO₂ hydration is a very slow process, and the physiologic demands for its conversion to ionic, soluble species is very high. Inhibition of the CAs has pharmacologic applications in many fields, such as antiglaucoma, anticonvulsant, antiobesity, and anticancer agents/diagnostic tools, but is also emerging for designing anti-infectives, i.e., antifungal, antibacterial and antiprotozoan agents with a novel mechanism of action. Mitochondrial CAs are implicated in de novo lipogenesis allowing the ability to consider selective inhibitors of such enzymes as useful for the development of new antiobesity drugs. As the tumor metabolism is diverse form that of normal cells, ultimately, relevant contributions on the role of the tumor-associated isoforms CA IX and XII in these phenomena have been published, and the two isoforms have been validated as novel antitumor/antimetastatic drug targets, with antibodies and small molecule inhibitors in various stages of clinical development. CAs also play a crucial role in other metabolic processes connected with urea biosynthesis, gluconeogenesis, etc., since many carboxylation reactions catalyzed by acetyl-coenzyme A carboxylase or pyruvate carboxylase use bicarbonate not CO₂as a substrate. In organisms other than mammals, e.g., plants, algae, and cyanobacteria, CAs are involved in photosynthesis, whereas, in many parasites (fungi, protozoa), they are involved in the de novo synthesis of important metabolites (lipids, nucleic acids, etc.). The metabolic effects related to interference with CA activity were, however, scarcely investigated. The present Special Issue of Metabolites has the goal of filling this gap, by presenting the latest developments in the field of CAs and their role in metabolism.

Prof. Dr. Claudiu T. Supuran
Guest Editor

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Keywords

carbonic anhydrase
mitochondrial isoforms
tumor-associated isoforms
antiobesity drug
anticancer drug
antiinfectives

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Published Papers (11 papers)

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Editorial

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5 pages, 239 KiB

Open AccessEditorial

Carbonic Anhydrases and Metabolism

by Claudiu T. Supuran

Metabolites 2018, 8(2), 25; https://doi.org/10.3390/metabo8020025 - 21 Mar 2018

Cited by 173 | Viewed by 7942

Abstract

Although the role of carbonic anhydrases (CAs, EC 4.2.1.1) in metabolism is well-established, pharmacological applications of this phenomenon started to be considered only recently. In organisms all over the phylogenetic tree, the seven CA genetic families known to date are involved in biosynthetic processes and pH modulation, which may influence metabolism in multiple ways, with both processes being amenable to pharmacologic intervention. CA inhibitors possess antiobesity action directly by inhibiting lipogenesis, whereas the hypoxic tumor metabolism is highly controlled by the transmembrane isoforms CA IX and XII, which contribute to the acidic extracellular environment of tumors and supply bicarbonate for their high proliferation rates. Many of the articles from this special issue deal with the role of cancer CAs in tumor metabolism and how these phenomena can be used for designing innovative antitumor therapies/imaging agents. The metabolic roles of CAs in bacteria and algae are also discussed. Full article

(This article belongs to the Special Issue Carbonic Anhydrases and Metabolism)

Research

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8 pages, 442 KiB

Open AccessArticle

Activation Studies of the β-Carbonic Anhydrase from the Pathogenic Protozoan Entamoeba histolytica with Amino Acids and Amines

by Silvia Bua, Susanna Haapanen, Marianne Kuuslahti, Seppo Parkkila and Claudiu T. Supuran

Metabolites 2019, 9(2), 26; https://doi.org/10.3390/metabo9020026 - 1 Feb 2019

Cited by 10 | Viewed by 3311

Abstract

The β-carbonic anhydrase (CA, EC 4.2.1.1) from the pathogenic protozoan Entamoeba histolytica, EhiCA, was investigated for its activation with a panel of natural and non-natural amino acids and amines. EhiCA was potently activated by D-His, D-Phe, D-DOPA, L- and D-Trp, L- and D-Tyr, 4-amino-L-Tyr, histamine and serotonin, with K_As ranging between 1.07 and 10.1 µM. The best activator was D-Tyr (K_A of 1.07 µM). L-Phe, L-DOPA, L-adrenaline, L-Asn, L-Asp, L-Glu and L-Gln showed medium potency activation, with K_As of 16.5–25.6 µM. Some heterocyclic- alkyl amines, such as 2-pyridyl-methyl/ethyl-amine and 4-(2-aminoethyl)-morpholine, were devoid of EhiCA activating properties with K_As > 100 µM. As CA activators have poorly been investigated for their interaction with protozoan CAs, our study may be relevant for an improved understanding of the role of this enzyme in the life cycle of E. histolytica. Full article

(This article belongs to the Special Issue Carbonic Anhydrases and Metabolism)

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11 pages, 605 KiB

Open AccessArticle

Benzamide-4-Sulfonamides Are Effective Human Carbonic Anhydrase I, II, VII, and IX Inhibitors

by Morteza Abdoli, Murat Bozdag, Andrea Angeli and Claudiu T. Supuran

Metabolites 2018, 8(2), 37; https://doi.org/10.3390/metabo8020037 - 1 Jun 2018

Cited by 20 | Viewed by 4652

Abstract

A series of benzamides incorporating 4-sulfamoyl moieties were obtained by reacting 4-sulfamoyl benzoic acid with primary and secondary amines and amino acids. These sulfonamides were investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The human (h) isoforms hCA II, VII, and IX were inhibited in the low nanomolar or subnanomolar ranges, whereas hCA I was slightly less sensitive to inhibition (K_Is of 5.3–334 nM). The β- and γ-class CAs from pathogenic bacteria and fungi, such as Vibrio cholerae and Malassezia globosa, were inhibited in the micromolar range by the sulfonamides reported in the paper. The benzamide-4-sulfonamides are a promising class of highly effective CA inhibitors. Full article

(This article belongs to the Special Issue Carbonic Anhydrases and Metabolism)

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Review

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22 pages, 8029 KiB

Open AccessReview

Amino Acids as Building Blocks for Carbonic Anhydrase Inhibitors

by Niccolò Chiaramonte, Maria Novella Romanelli, Elisabetta Teodori and Claudiu T. Supuran

Metabolites 2018, 8(2), 36; https://doi.org/10.3390/metabo8020036 - 24 May 2018

Cited by 22 | Viewed by 7520

Abstract

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

(This article belongs to the Special Issue Carbonic Anhydrases and Metabolism)

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16 pages, 2691 KiB

Open AccessReview

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

by Ashok Aspatwar, Susanna Haapanen and Seppo Parkkila

Metabolites 2018, 8(1), 22; https://doi.org/10.3390/metabo8010022 - 13 Mar 2018

Cited by 41 | Viewed by 6739

Abstract

Carbonic anhydrases (CAs) are metalloenzymes that are omnipresent in nature. CAs catalyze the basic reaction of the reversible hydration of CO₂ to HCO₃⁻ and H⁺ in all living organisms. Photosynthetic organisms contain six evolutionarily different classes of CAs, which are namely: α-CAs, β-CAs, γ-CAs, δ-CAs, ζ-CAs, and θ-CAs. Many of the photosynthetic organisms contain multiple isoforms of each CA family. The model alga Chlamydomonas reinhardtii contains 15 CAs belonging to three different CA gene families. Of these 15 CAs, three belong to the α-CA gene family; nine belong to the β-CA gene family; and three belong to the γ-CA gene family. The multiple copies of the CAs in each gene family may be due to gene duplications within the particular CA gene family. The CAs of Chlamydomonas reinhardtii are localized in different subcellular compartments of this unicellular alga. The presence of a large number of CAs and their diverse subcellular localization within a single cell suggests the importance of these enzymes in the metabolic and biochemical roles they perform in this unicellular alga. In the present review, we update the information on the molecular biology of all 15 CAs and their metabolic and biochemical roles in Chlamydomonas reinhardtii. We also present a hypothetical model showing the known functions of CAs and predicting the functions of CAs for which precise metabolic roles are yet to be discovered. Full article

(This article belongs to the Special Issue Carbonic Anhydrases and Metabolism)

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11 pages, 1436 KiB

Open AccessReview

Coordinated Regulation of Metabolic Transporters and Migration/Invasion by Carbonic Anhydrase IX

by Paul C. McDonald, Mridula Swayampakula and Shoukat Dedhar

Metabolites 2018, 8(1), 20; https://doi.org/10.3390/metabo8010020 - 8 Mar 2018

Cited by 42 | Viewed by 5112

Abstract

Hypoxia is a prominent feature of the tumor microenvironment (TME) and cancer cells must dynamically adapt their metabolism to survive in these conditions. A major consequence of metabolic rewiring by cancer cells in hypoxia is the accumulation of acidic metabolites, leading to the perturbation of intracellular pH (pHi) homeostasis and increased acidosis in the TME. To mitigate the potentially detrimental consequences of an increasingly hypoxic and acidic TME, cancer cells employ a network of enzymes and transporters to regulate pH, particularly the extracellular facing carbonic anhydrase IX (CAIX) and CAXII. In addition to the role that these CAs play in the regulation of pH, recent proteome-wide analyses have revealed the presence of a complex CAIX interactome in cancer cells with roles in metabolite transport, tumor cell migration and invasion. Here, we explore the potential contributions of these interactions to the metabolic landscape of tumor cells in hypoxia and discuss the role of CAIX as a hub for the coordinated regulation of metabolic, migratory and invasive processes by cancer cells. We also discuss recent work targeting CAIX activity using highly selective small molecule inhibitors and briefly discuss ongoing clinical trials involving SLC-0111, a lead candidate small molecule inhibitor of CAIX/CAXII. Full article

(This article belongs to the Special Issue Carbonic Anhydrases and Metabolism)

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31 pages, 5013 KiB

Open AccessReview

Carbonic Anhydrases: Role in pH Control and Cancer

by Mam Y. Mboge, Brian P. Mahon, Robert McKenna and Susan C. Frost

Metabolites 2018, 8(1), 19; https://doi.org/10.3390/metabo8010019 - 28 Feb 2018

Cited by 187 | Viewed by 11485

Abstract

The pH of the tumor microenvironment drives the metastatic phenotype and chemotherapeutic resistance of tumors. Understanding the mechanisms underlying this pH-dependent phenomenon will lead to improved drug delivery and allow the identification of new therapeutic targets. This includes an understanding of the role pH plays in primary tumor cells, and the regulatory factors that permit cancer cells to thrive. Over the last decade, carbonic anhydrases (CAs) have been shown to be important mediators of tumor cell pH by modulating the bicarbonate and proton concentrations for cell survival and proliferation. This has prompted an effort to inhibit specific CA isoforms, as an anti-cancer therapeutic strategy. Of the 12 active CA isoforms, two, CA IX and XII, have been considered anti-cancer targets. However, other CA isoforms also show similar activity and tissue distribution in cancers and have not been considered as therapeutic targets for cancer treatment. In this review, we consider all the CA isoforms and their possible role in tumors and their potential as targets for cancer therapy. Full article

(This article belongs to the Special Issue Carbonic Anhydrases and Metabolism)

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18 pages, 2295 KiB

Open AccessReview

Carbonic Anhydrase IX (CAIX), Cancer, and Radiation Responsiveness

by Carol Ward, James Meehan, Mark Gray, Ian H. Kunkler, Simon P. Langdon and David J. Argyle

Metabolites 2018, 8(1), 13; https://doi.org/10.3390/metabo8010013 - 10 Feb 2018

Cited by 60 | Viewed by 9402

Abstract

Carbonic anhydrase IX has been under intensive investigation as a therapeutic target in cancer. Studies demonstrate that this enzyme has a key role in pH regulation in cancer cells, allowing these cells to adapt to the adverse conditions of the tumour microenviroment. Novel CAIX inhibitors have shown efficacy in both in vitro and in vivo pre-clinical cancer models, adversely affecting cell viability, tumour formation, migration, invasion, and metastatic growth when used alone. In co-treatments, CAIX inhibitors may enhance the effects of anti-angiogenic drugs or chemotherapy agents. Research suggests that these inhibitors may also increase the response of tumours to radiotherapy. Although many of the anti-tumour effects of CAIX inhibition may be dependent on its role in pH regulation, recent work has shown that CAIX interacts with several of the signalling pathways involved in the cellular response to radiation, suggesting that pH-independent mechanisms may also be an important basis of its role in tumour progression. Here, we discuss these pH-independent interactions in the context of the ability of CAIX to modulate the responsiveness of cancer to radiation. Full article

(This article belongs to the Special Issue Carbonic Anhydrases and Metabolism)

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1060 KiB

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Rethinking the Combination of Proton Exchanger Inhibitors in Cancer Therapy

by Elisabetta Iessi, Mariantonia Logozzi, Davide Mizzoni, Rossella Di Raimo, Claudiu T. Supuran and Stefano Fais

Metabolites 2018, 8(1), 2; https://doi.org/10.3390/metabo8010002 - 23 Dec 2017

Cited by 55 | Viewed by 6918

Abstract

Microenvironmental acidity is becoming a key target for the new age of cancer treatment. In fact, while cancer is characterized by genetic heterogeneity, extracellular acidity is a common phenotype of almost all cancers. To survive and proliferate under acidic conditions, tumor cells up-regulate proton exchangers and transporters (mainly V-ATPase, Na⁺/H⁺ exchanger (NHE), monocarboxylate transporters (MCTs), and carbonic anhydrases (CAs)), that actively extrude excess protons, avoiding intracellular accumulation of toxic molecules, thus becoming a sort of survival option with many similarities compared with unicellular microorganisms. These systems are also involved in the unresponsiveness or resistance to chemotherapy, leading to the protection of cancer cells from the vast majority of drugs, that when protonated in the acidic tumor microenvironment, do not enter into cancer cells. Indeed, as usually occurs in the progression versus malignancy, resistant tumor clones emerge and proliferate, following a transient initial response to a therapy, thus giving rise to more malignant behavior and rapid tumor progression. Recent studies are supporting the use of a cocktail of proton exchanger inhibitors as a new strategy against cancer. Full article

(This article belongs to the Special Issue Carbonic Anhydrases and Metabolism)

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5728 KiB

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An Overview of the Bacterial Carbonic Anhydrases

by Claudiu T. Supuran and Clemente Capasso

Metabolites 2017, 7(4), 56; https://doi.org/10.3390/metabo7040056 - 11 Nov 2017

Cited by 180 | Viewed by 9332

Abstract

Bacteria encode carbonic anhydrases (CAs, EC 4.2.1.1) belonging to three different genetic families, the α-, β-, and γ-classes. By equilibrating CO₂ and bicarbonate, these metalloenzymes interfere with pH regulation and other crucial physiological processes of these organisms. The detailed investigations of many such enzymes from pathogenic and non-pathogenic bacteria afford the opportunity to design both novel therapeutic agents, as well as biomimetic processes, for example, for CO₂ capture. Investigation of bacterial CA inhibitors and activators may be relevant for finding antibiotics with a new mechanism of action. Full article

(This article belongs to the Special Issue Carbonic Anhydrases and Metabolism)

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3200 KiB

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Carbonic Anhydrase Inhibition and the Management of Hypoxic Tumors

by Claudiu T. Supuran

Metabolites 2017, 7(3), 48; https://doi.org/10.3390/metabo7030048 - 16 Sep 2017

Cited by 216 | Viewed by 11283

Abstract

Hypoxia and acidosis are salient features of many tumors, leading to a completely different metabolism compared to normal cells. Two of the simplest metabolic products, protons and bicarbonate, are generated by the catalytic activity of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), with at least two of its isoforms, CA IX and XII, mainly present in hypoxic tumors. Inhibition of tumor-associated CAs leads to an impaired growth of the primary tumors, metastases and reduces the population of cancer stem cells, leading thus to a complex and beneficial anticancer action for this class of enzyme inhibitors. In this review, I will present the state of the art on the development of CA inhibitors (CAIs) targeting the tumor-associated CA isoforms, which may have applications for the treatment and imaging of cancers expressing them. Small molecule inhibitors, one of which (SLC-0111) completed Phase I clinical trials, and antibodies (girentuximab, discontinued in Phase III clinical trials) will be discussed, together with the various approaches used to design anticancer agents with a new mechanism of action based on interference with these crucial metabolites, protons and bicarbonate. Full article

(This article belongs to the Special Issue Carbonic Anhydrases and Metabolism)

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