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 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 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 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 Na+/H+-exchangers differentially contribute to midgut fluid sodium and proton concentration in the sea urchin larva

2021 ◽  
pp. jeb.240705
Author(s):  
Inga Petersen ◽  
William W. J. Chang ◽  
Marian Y. Hu
Keyword(s):  
Sea Urchin ◽  
Epithelial Transport ◽  
Sea Water ◽  
Ph Regulation ◽  
Ionic Composition ◽  
Immunohistochemical Analysis ◽  
Midgut Epithelium ◽  
Larval Stages ◽  
Alkaline Conditions ◽  
Midgut Ph

Regulation of ionic composition and pH is a requisite of all digestive systems in the animal kingdom. Larval stages of the marine superphylum ambulacraria, including echinoderms and hemichordates, were demonstrated to have highly alkaline conditions in their midgut with the underlying epithelial transport mechanisms being largely unknown.Using ion-selective microelectrodes, the present study demonstrated that pluteus larvae of the purple sea urchin have highly alkaline pH (pH ∼9) and low [Na+] ( ̴120 mM) in their midgut fluids, compared to the ionic composition of the surrounding sea water. We pharmacologically investigated the role of Na+/H+-exchangers in intracellular pH regulation and midgut proton and sodium maintenance using the NHE inhibitor 5-(n-ethyl-n-isopropyl)amiloride (EIPA). Basolateral EIPA application decreased midgut pH while luminal application, via micro-injections increased midgut [Na+], without affecting pH. Immunohistochemical analysis demonstrated a luminal localization of NHE-2 (SpSlc9a2) in the midgut epithelium. Specific knockdown of spslc9a2 using vivo morpholinos led to an increase in midgut [Na+] without affecting pH. Acute acidification experiments in combination with qPCR analysis and measurements of midgut pH and [Na+] identified two other NHE isoforms, Spslc9a7 and SpSlc9a8 that potentially contribute to the regulation of [Na+] and pH in midgut fluids.This work provides new insights to ion regulatory mechanisms in the midgut epithelium of sea urchin larvae. The involvement of NHEs in regulating pH and Na+ balance in midgut fluids shows conserved features to insect and vertebrate digestive systems and may contribute to the ability of sea urchin larvae to cope with changes in seawater pH.

scholarly journals Glucose-mediated expansion of a gut commensal bacterium promotes Plasmodium infection through alkalizing mosquito midgut

2020 ◽  
Author(s):  
Mengfei Wang ◽  
Yanpeng An ◽  
Shengzhang Dong ◽  
Yuebiao Feng ◽  
Li Gao ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Malaria Parasite ◽  
Commensal Bacterium ◽  
Mosquito Midgut ◽  
Major Energy Source ◽  
Metabolic Interactions ◽  
Dietary Sugar ◽  
Ph Increase ◽  
Midgut Ph ◽  
Hemolymph Sugar

SUMMARYDietary sugar is the major energy source for mosquitoes, but its influence on mosquitoes’ capability to transmit malaria parasite remains unclear. Here we show that Plasmodium berghei infection changes global metabolism of Anopheles stephensi with the most significant impact on glucose metabolism. Supplementation of glucose or trehalose (the main hemolymph sugar) to mosquito increases Plasmodium infection by alkalizing the mosquito midgut. The glucose/trehalose diets promote rapid growth of a commensal bacterium, Asaia bogorensis, which remodels glucose metabolism and consequently increases midgut pH. The pH increase in turn promotes Plasmodium gametogenesis. We also demonstrate the sugar composition from different natural plants influences A. bogorensis growth and Plasmodium infection is associated with their capability to expand A. bogorensis. Altogether, our results demonstrate that dietary glucose is an important factor that determines mosquito’s competency to transmit Plasmodium and further highlight a key role for mosquito-microbiota metabolic interactions in regulating development of malaria parasite.

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.

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