scholarly journals Epithelial carbonic anhydrases facilitatePCO2and pH regulation in rat duodenal mucosa

2006 ◽  
Vol 573 (3) ◽  
pp. 827-842 ◽  
Author(s):  
Misa Mizumori ◽  
Justin Meyerowitz ◽  
Tetsu Takeuchi ◽  
Shu Lim ◽  
Paul Lee ◽  
...  
Keyword(s):  
Ph Regulation ◽  
Duodenal Mucosa ◽  
Carbonic Anhydrases

scholarly journals Preclinical Evaluation of Ureidosulfamate Carbonic Anhydrase IX/XII Inhibitors in the Treatment of Cancers

2019 ◽  
Vol 20 (23) ◽  
pp. 6080 ◽  
Author(s):  
Kaye J. Williams ◽  
Roben G. Gieling
Keyword(s):  
Triple Negative ◽  
Ph Regulation ◽  
Treatment Resistance ◽  
Carbonic Anhydrases ◽  
Test Results ◽  
Future Studies ◽  
Clinical Phase ◽  
Chemical Structures ◽  
Catalytic Domains ◽  
Cancer Cell Type

Carbonic anhydrases (CAs) are a family of enzymes involved in the pH regulation of metabolically active cells/tissues. Upregulation of the CAIX/XII isoforms is associated with hypoxic tumours and clinically linked with malignant progression, treatment resistance and poor prognosis. The elucidation of the crystal structure of the catalytic domains of CAIX/XII provided the basis for the generation of CAIX/XII selective inhibitors based on the sulfonamide, sulfamate and coumarins chemical structures. Ureido-substituted benzenesulfonamide CAIX/XII inhibitors have shown significant potential, with U-104 (SLC-0111) currently present in clinical Phase I/II. Ureido-substituted sulfamate CAIX/XII inhibitors have received less attention despite encouraging preclinical test results. In triple-negative breast cancer (TNBC), ureidosulfamates revealed a significant antitumour (FC9-398A) and antimetastatic potential (S4). In small cell lung cancer (SCLC), a cancer cell type very sensitive to a dysregulation in CAIX signaling, S4 treatment was particularly effective when combined with cisplatin with no evidence of acquired cisplatin-resistance. These successful anticancer strategies should provide a solid basis for future studies on ureido-substituted sulfamates.

scholarly journals Transport Metabolons and Acid/Base Balance in Tumor Cells

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 899 ◽  
Author(s):  
Holger M. Becker ◽  
Joachim W. Deitmer
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Drug Targets ◽  
Ph Regulation ◽  
Host Cells ◽  
Bicarbonate Transport ◽  
Carbonic Anhydrases ◽  
Acid Base Balance ◽  
Acid Base ◽  
Base Balance

Solid tumors are metabolically highly active tissues, which produce large amounts of acid. The acid/base balance in tumor cells is regulated by the concerted interplay between a variety of membrane transporters and carbonic anhydrases (CAs), which cooperate to produce an alkaline intracellular, and an acidic extracellular, environment, in which cancer cells can outcompete their adjacent host cells. Many acid/base transporters form a structural and functional complex with CAs, coined “transport metabolon”. Transport metabolons with bicarbonate transporters require the binding of CA to the transporter and CA enzymatic activity. In cancer cells, these bicarbonate transport metabolons have been attributed a role in pH regulation and cell migration. Another type of transport metabolon is formed between CAs and monocarboxylate transporters, which mediate proton-coupled lactate transport across the cell membrane. In this complex, CAs function as “proton antenna” for the transporter, which mediate the rapid exchange of protons between the transporter and the surroundings. These transport metabolons do not require CA catalytic activity, and support the rapid efflux of lactate and protons from hypoxic cancer cells to allow sustained glycolytic activity and cell proliferation. Due to their prominent role in tumor acid/base regulation and metabolism, transport metabolons might be promising drug targets for new approaches in cancer therapy.

scholarly journals Role of Carbonic Anhydrases and Inhibitors in Acid–Base Physiology: Insights from Mathematical Modeling

2019 ◽  
Vol 20 (15) ◽  
pp. 3841 ◽  
Author(s):  
Occhipinti ◽  
Boron
Keyword(s):  
Mathematical Modeling ◽  
Ph Regulation ◽  
Reaction Diffusion ◽  
The Body ◽  
Whole Body ◽  
Facilitated Diffusion ◽  
Carbonic Anhydrases ◽  
Physiological Processes ◽  
Urinary Acid

Carbonic anhydrases (CAs) catalyze a reaction fundamental for life: the bidirectional conversion of carbon dioxide (CO2) and water (H2O) into bicarbonate (HCO3−) and protons (H+). These enzymes impact numerous physiological processes that occur within and across the many compartments in the body. Within compartments, CAs promote rapid H+ buffering and thus the stability of pH-sensitive processes. Between compartments, CAs promote movements of H+, CO2, HCO3−, and related species. This traffic is central to respiration, digestion, and whole-body/cellular pH regulation. Here, we focus on the role of mathematical modeling in understanding how CA enhances buffering as well as gradients that drive fluxes of CO2 and other solutes (facilitated diffusion). We also examine urinary acid secretion and the carriage of CO2 by the respiratory system. We propose that the broad physiological impact of CAs stem from three fundamental actions: promoting H+ buffering, enhancing H+ exchange between buffer systems, and facilitating diffusion. Mathematical modeling can be a powerful tool for: (1) clarifying the complex interdependencies among reaction, diffusion, and protein-mediated components of physiological processes; (2) formulating hypotheses and making predictions to be tested in wet-lab experiments; and (3) inferring data that are impossible to measure.

scholarly journals Insights into Activity Enhancement of H64A Carbonic Anhydrase by Imidazoles

2014 ◽  
Vol 70 (a1) ◽  
pp. C803-C803
Author(s):  
Mayank Aggarwal ◽  
Chingkuang Tu ◽  
David Silverman ◽  
Robert McKenna
Keyword(s):  
Binding Sites ◽  
Ph Regulation ◽  
Side Chain ◽  
Carbonic Anhydrases ◽  
Physiological Processes ◽  
Multiple Binding Sites ◽  
Zinc Metalloenzymes ◽  
Number Of Binding Sites ◽  
Activity Enhancement ◽  
Proton Shuttling

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.

scholarly journals Proton Transport in Cancer Cells: The Role of Carbonic Anhydrases

2021 ◽  
Vol 22 (6) ◽  
pp. 3171
Author(s):  
Holger M. Becker ◽  
Joachim W. Deitmer
Keyword(s):  
Cancer Cells ◽  
Ph Regulation ◽  
Extracellular Ph ◽  
Host Cells ◽  
Carbonic Anhydrases ◽  
Catalytic Function ◽  
Tumor Ph ◽  
Cancer Pathogenesis ◽  
Outward Transport

Intra- and extracellular pH regulation is a pivotal function of all cells and tissues. Net outward transport of H+ is a prerequisite for normal physiological function, since a number of intracellular processes, such as metabolism and energy supply, produce acid. In tumor tissues, distorted pH regulation results in extracellular acidification and the formation of a hostile environment in which cancer cells can outcompete healthy local host cells. Cancer cells employ a variety of H+/HCO3−-coupled transporters in combination with intra- and extracellular carbonic anhydrase (CA) isoforms, to alter intra- and extracellular pH to values that promote tumor progression. Many of the transporters could closely associate to CAs, to form a protein complex coined “transport metabolon”. While transport metabolons built with HCO3−-coupled transporters require CA catalytic activity, transport metabolons with monocarboxylate transporters (MCTs) operate independently from CA catalytic function. In this article, we assess some of the processes and functions of CAs for tumor pH regulation and discuss the role of intra- and extracellular pH regulation for cancer pathogenesis and therapeutic intervention.

scholarly journals Carbonic anhydrases and anion transport in mosquito midgut pH regulation

2009 ◽  
Vol 212 (11) ◽  
pp. 1662-1671 ◽  
Author(s):  
P. J. Linser ◽  
K. E. Smith ◽  
T. J. Seron ◽  
M. Neira Oviedo
Keyword(s):  
Ph Regulation ◽  
Anion Transport ◽  
Carbonic Anhydrases ◽  
Mosquito Midgut ◽  
Midgut Ph

scholarly journals 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 ◽  
2019 ◽  
Vol 17 (3) ◽  
pp. 146 ◽  
Author(s):  
Sonia Del Prete ◽  
Silvia Bua ◽  
Fatmah Alasmary ◽  
Zeid AlOthman ◽  
Sylvie Tambutté ◽  
...  
Keyword(s):  
Plasma Membranes ◽  
Molecular Mechanisms ◽  
Ph Regulation ◽  
Protein Isoforms ◽  
Carbonic Anhydrases ◽  
Recombinant Enzymes ◽  
Stylophora Pistillata ◽  
Bicarbonate Transporters ◽  
Cell Layers ◽  
Inorganic Carbon Transport

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.

scholarly journals Intracellular pH regulation in mantle epithelial cells of the Pacific oyster, Crassostrea gigas

2020 ◽  
Vol 190 (6) ◽  
pp. 691-700 ◽  
Author(s):  
Kirti Ramesh ◽  
Marian Y. Hu ◽  
Frank Melzner ◽  
Markus Bleich ◽  
Nina Himmerkus
Keyword(s):  
Epithelial Cells ◽  
Intracellular Ph ◽  
Crassostrea Gigas ◽  
Pacific Oyster ◽  
Ph Regulation ◽  
Carbonic Anhydrases ◽  
Limited Information ◽  
Acid Base ◽  
Regulatory Machinery ◽  
The Pacific

Abstract Shell formation and repair occurs under the control of mantle epithelial cells in bivalve molluscs. However, limited information is available on the precise acid–base regulatory machinery present within these cells, which are fundamental to calcification. Here, we isolate mantle epithelial cells from the Pacific oyster, Crassostrea gigas and utilise live cell imaging in combination with the fluorescent dye, BCECF-AM to study intracellular pH (pHi) regulation. To elucidate the involvement of various ion transport mechanisms, modified seawater solutions (low sodium, low bicarbonate) and specific inhibitors for acid–base proteins were used. Diminished pH recovery in the absence of Na+ and under inhibition of sodium/hydrogen exchangers (NHEs) implicate the involvement of a sodium dependent cellular proton extrusion mechanism. In addition, pH recovery was reduced under inhibition of carbonic anhydrases. These data provide the foundation for a better understanding of acid–base regulation underlying the physiology of calcification in bivalves.

scholarly journals Carbonic anhydrase IX and acid transport in cancer

2019 ◽  
Vol 122 (2) ◽  
pp. 157-167 ◽  
Author(s):  
Holger M. Becker
Keyword(s):  
Cancer Cells ◽  
Ph Regulation ◽  
Migration And Invasion ◽  
Carbonic Anhydrases ◽  
Hostile Environment ◽  
Proton Extrusion ◽  
Acid Base ◽  
Current State ◽  
Bicarbonate Transporters ◽  
State Of Research

AbstractAlterations in tumour metabolism and acid/base regulation result in the formation of a hostile environment, which fosters tumour growth and metastasis. Acid/base homoeostasis in cancer cells is governed by the concerted interplay between carbonic anhydrases (CAs) and various transport proteins, which either mediate proton extrusion or the shuttling of acid/base equivalents, such as bicarbonate and lactate, across the cell membrane. Accumulating evidence suggests that some of these transporters interact both directly and functionally with CAIX to form a protein complex coined the ‘transport metabolon’. Transport metabolons formed between bicarbonate transporters and CAIX require CA catalytic activity and have a function in cancer cell migration and invasion. Another type of transport metabolon is formed by CAIX and monocarboxylate transporters. In this complex, CAIX functions as a proton antenna for the transporter, which drives the export of lactate and protons from the cell. Since CAIX is almost exclusively expressed in cancer cells, these transport metabolons might serve as promising targets to interfere with tumour pH regulation and energy metabolism. This review provides an overview of the current state of research on the function of CAIX in tumour acid/base transport and discusses how CAIX transport metabolons could be exploited in modern cancer therapy.

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