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Carbonic Anhydrases and Metabolism Carbonic Anhydrases and Metabolism Edited by Claudiu T. Supuran Printed Edition of the Special Issue Published in Metabolites www.mdpi.com/journal/metabolites Carbonic Anhydrases and Metabolism Carbonic Anhydrases and Metabolism Special Issue Editor Claudiu T. Supuran MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade Special Issue Editor Claudiu T. Supuran Universita` degli Studi di Firenze Italy Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Metabolites (ISSN 2218-1989) from 2017 to 2019 (available at: https://www.mdpi.com/journal/ metabolites/special issues/Carbonic Anhydrases Metabolism) For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year, Article Number, Page Range. ISBN 978-3-03897-800-8 (Pbk) ISBN 978-3-03897-801-5 (PDF) c 2019 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND. Contents About the Special Issue Editor ...................................... vii Claudiu T. Supuran Carbonic Anhydrases and Metabolism Reprinted from: Metabolites 2018, 8, 25, doi:10.3390/metabo8020025 ................. 1 Claudiu T. Supuran Carbonic Anhydrase Inhibition and the Management of Hypoxic Tumors Reprinted from: Metabolites 2017, 7, 48, doi:10.3390/metabo7030048 ................. 6 Paul C. McDonald, Mridula Swayampakula and Shoukat Dedhar Coordinated Regulation of Metabolic Transporters and Migration/Invasion by Carbonic Anhydrase IX Reprinted from: Metabolites 2018, 8, 20, doi:10.3390/metabo8010020 ................. 19 Mam Y. Mboge, Brian P. Mahon, Robert McKenna and Susan C. Frost Carbonic Anhydrases: Role in pH Control and Cancer Reprinted from: Metabolites 2018, 8, 19, doi:10.3390/metabo8010019 ................. 30 Carol Ward, James Meehan, Mark Gray, Ian H. Kunkler, Simon P. Langdon and David J. Argyle Carbonic Anhydrase IX (CAIX), Cancer, and Radiation Responsiveness Reprinted from: Metabolites 2018, 8, 13, doi:10.3390/metabo8010013 ................. 61 Elisabetta Iessi, Mariantonia Logozzi, Davide Mizzoni, Rossella Di Raimo, Claudiu T. Supuran and Stefano Fais Rethinking the Combination of Proton Exchanger Inhibitors in Cancer Therapy Reprinted from: Metabolites 2018, 8, 2, doi:10.3390/metabo8010002 .................. 79 Niccol`o Chiaramonte, Maria Novella Romanelli, Elisabetta Teodori and Claudiu T. Supuran Amino Acids as Building Blocks for Carbonic Anhydrase Inhibitors Reprinted from: Metabolites 2018, 8, 36, doi:10.3390/metabo8020036 ................. 99 Morteza Abdoli, Murat Bozdag, Andrea Angeli and Claudiu T. Supuran Benzamide-4-Sulfonamides Are Effective Human Carbonic Anhydrase I, II, VII, and IX Inhibitors Reprinted from: Metabolites 2018, 8, 37, doi:10.3390/metabo8020037 .................121 Ashok Aspatwar, Susanna Haapanen and Seppo Parkkila An Update on the Metabolic Roles of Carbonic Anhydrases in the Model Alga Chlamydomonas reinhardtii Reprinted from: Metabolites 2018, 8, 22, doi:10.3390/metabo8010022 .................132 Silvia Bua, Susanna Haapanen, Marianne Kuuslahti, Seppo Parkkila and Claudiu T. Supuran Activation Studies of the β-Carbonic Anhydrase from the Pathogenic Protozoan Entamoeba histolytica with Amino Acids and Amines Reprinted from: Metabolites 2019, 9, 26, doi:10.3390/metabo9020026 .................148 Claudiu T. Supuran and Clemente Capasso An Overview of the Bacterial Carbonic Anhydrases Reprinted from: Metabolites 2017, 7, 56, doi:10.3390/metabo7040056 .................156 v About the Special Issue Editor Claudiu T. Supuran has been the Professor of Medicinal and Pharmaceutical Chemistry at the University of Florence, Italy, since 1995. He completed his PhD at the University of Bucharest, Romania, and was a visiting scholar at the University of Florida, Gainesville, USA, and at Griffith University, Brisbane, Australia. He was a visiting professor at the University of La Plata, Argentina, and at the University of New South Wales, Sydney, Australia. His main research interest is the medicinal chemistry/biochemistry of carbonic anhydrases, a field in which he has made contributions to the design of many novel classes of enzyme inhibitors and activators, deciphering their mechanism of action at the molecular level; the discovery of new isoforms and their role in disease (cancer, obesity, epilepsy, neuropathic pain, and cognition); and the discovery and characterization of carbonic anhydrases from various organisms (bacteria, fungi, corals, vertebrates other than humans and rodents, etc). Other research interests of his include the X-ray crystallography of metalloenzymes, biologically active organoelement derivatives, QSAR studies, metal-based drugs, cyclooxygenases, serine proteases, matrix metalloproteinases, bacterial proteases, amino acid derivatives, heterocyclic chemistry, and the chemistry of sulfonamides, sulfamates, and sulfamides, among others. He has published more than 1500 papers in these fields, and his Hirsch index is 134. One of the compounds discovered in his laboratory (SLC-0111) is in Phase II clinical trials for the treatment of advanced metastatic solid tumors. vii H OH metabolites OH Editorial Carbonic Anhydrases and Metabolism Claudiu T. Supuran ID Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche, Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Polo Scientifico, Via U. Schiff 6, Sesto Fiorentino, 50019 Florence, Italy; claudiu.supuran@unifi.it Received: 18 March 2018; Accepted: 20 March 2018; Published: 21 March 2018 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. Keywords: carbonic anhydrase; hypoxic tumor; metabolism; carboxylation; bicarbonate; pH regulation; antitumor agent; sulfonamide; bacterial enzymes Carbonic anhydrases (CAs, EC 4.2.1.1) are a superfamily of metalloenzymes present in all life kingdoms, as they equilibrate the reaction between three simple but essential chemical species: CO2, bicarbonate, and protons [1–6]. Although discovered 85 years ago, these enzymes are still extensively investigated due to the biomedical application of their inhibitors [7–12] and activators [13] 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, the α-, β-, γ-, δ-, ζ-, η-, and θ-CAs [2,4,5,14–16]. CAs are also among the most efficient enzymes known in nature, probably due to the fact that uncatalyzed CO2 hydration is a very slow process at neutral pH, and the physiologic demands for its conversion to ionic, soluble species (i.e., bicarbonate and protons) are very high [1–6]. Indeed, CO2 is generated in most metabolic oxidative processes, and being a gas, it must be converted to soluble products quickly and efficiently. Otherwise, it would tend to accumulate and provoke damage to cells and other organelles in the gaseous state without such an efficient hydration catalyst as the CAs [2,6–8]. Inhibition of the CAs has pharmacologic applications in many fields, such as diuretics [9], antiglaucoma [10], anticonvulsant [7,8,11], antiobesity [11], and anticancer agents/diagnostic tools [1,2,12], but it is also emerging for designing anti-infectives, i.e., antifungal, antibacterial, and antiprotozoan agents with a novel mechanism of action [4,5,8,17,18]. For a long period it has been considered that the pharmacologic effects of CA inhibition or activation are mainly due to effects on pH regulation in cells or tissues where the enzymes are present [1]. Although these phenomena are undoubtedly relevant and take place in most organisms/tissues/cells where these ubiquitous enzymes are found, a lot of recent evidence points to the fact that CAs are true metabolic enzymes at least for two different reasons: (i) due to their direct participation in carboxylating reactions which provide bicarbonate and/or CO2 to carboxylating enzymes, such as pyruvate carboxylase, acetyl-coenzyme A Metabolites 2018, 8, 25; doi:10.3390/metabo80200251 www.mdpi.com/journal/metabolites Metabolites 2018, 8,25 carboxylase [19,20], phosphoenolpyruvate
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