Role Of Carbonic Anhydrase Research Articles

Potential Novel Role of Membrane-Associated Carbonic Anhydrases in the Kidney.

Carbonic anhydrases (CAs), because they catalyze the interconversion of carbon dioxide (CO2) and water into bicarbonate (HCO3-) and protons (H+), thereby influencing pH, are near the core of virtually all physiological processes in the body. In the kidneys, soluble and membrane-associated CAs and their synergy with acid-base transporters play important roles in urinary acid secretion, the largest component of which is the reabsorption of HCO3- in specific nephron segments. Among these transporters are the Na+-coupled HCO3- transporters (NCBTs) and the Cl--HCO3- exchangers (AEs)-members of the "solute-linked carrier" 4 (SLC4) family. All of these transporters have traditionally been regarded as "HCO3-" transporters. However, recently our group has demonstrated that two of the NCBTs carry CO32- rather than HCO3- and has hypothesized that all NCBTs follow suit. In this review, we examine current knowledge on the role of CAs and "HCO3-" transporters of the SLC4 family in renal acid-base physiology and discuss how our recent findings impact renal acid secretion, including HCO3- reabsorption. Traditionally, investigators have associated CAs with producing or consuming solutes (CO2, HCO3-, and H+) and thus ensuring their efficient transport across cell membranes. In the case of CO32- transport by NCBTs, however, we hypothesize that the role of membrane-associated CAs is not the appreciable production or consumption of substrates but the minimization of pH changes in nanodomains near the membrane.

The whole-cell kinetic metabolic model of the pH regulation mechanisms in human erythrocytes

Mathematical modeling in recent years helped to obtain answers to questions that were difficult or even impossible to answer experimentally, to predict several unexpected connections in cell metabolism and to understand and importance of certain biochemical reactions. Due to the complexity and variety of processes underlying the mechanisms of intracellular pH (pHi) regulation, mathematical modeling and metabolome analysis are powerful tools for their analysis. In this regard, a mathematical metabolic model for human erythrocytes was created, which combines cellular metabolism with acid-base processes and gas exchange. The model consists of the main metabolic pathways, such as glycolysis, the pentose phosphate pathway, some membrane transport systems, and interactions between hemoglobin and metabolites. The Jacobs-Stewart cycle, which is fundamental in gas exchange and pH regulation, was included to these pathways. The model was created in the COPASI environment, consisted of 85 reactions, the rate of which is based on accurate kinetic equations. The time dependences of reaction flows and metabolite concentrations, as an outcome of calculations, allowed us to reproduce the behaviour of the metabolic system after its disturbance in vitro and to establish the recovery mechanisms or approximation to stationary states. The COPASI simulation environment provides model flexibility by reproducing any experimental design by optimizing direct quantitative comparisons between measured and predicted results. Thus, the procedure of parameters optimization (Parameter Estimation) followed by the solution of the model’s differential equations (Time Course procedure) was used to predict the behaviour of all measured and unmeasured variables over time. The initial intracellular concentrations of CO2, HCO3– in human erythrocytes used for incubation in a phosphate buffer medium were calculated. Changes in CO2, HCO3– content over time were shown. It was established that the regulation of pH in erythrocytes placed in a buffer medium takes place with the participation of two types of processes – fast (takes place in 1.3 s) and slow. It is shown that fast processes are aimed at restoring the intracellular balance between CO2 and HCO3–, slow processes are aimed at establishing the balance of H+ between the cell and the extracellular environment. The role of carbonic anhydrase (CA) and hemoglobin in the processes of pH stabilization is shown and analyzed. The physiological role of the metabolon between band 3 protein (AE1), CA, aquaporin and hemoglobin in maintaining pH homeostasis in the conditions of in vitro experiments are discussed.

Transcriptome Analysis to Study the Molecular Response in the Gill and Hepatopancreas Tissues of Macrobrachium nipponense to Salinity Acclimation.

Macrobrachium nipponense is an economically important prawn species and common in Chinese inland capture fisheries. During aquaculture, M. nipponense can survive under freshwater and low salinity conditions. The molecular mechanism underlying the response to salinity acclimation remains unclear in this species; thus, in this study, we used the Illumina RNA sequencing platform for transcriptome analyses of the gill and hepatopancreas tissues of M. nipponense exposed to salinity stress [0.4‰ (S0, control group), 6‰ (S6, low salinity group), and 12‰ (S12, high salinity group)]. Differentially expressed genes were identified, and several important salinity adaptation-related terms and signaling pathways were found to be enriched, such as “ion transport,” “oxidative phosphorylation,” and “glycometabolism.” Quantitative real-time PCR demonstrated the participation of 12 key genes in osmotic pressure regulation in M. nipponense under acute salinity stress. Further, the role of carbonic anhydrase in response to salinity acclimation was investigated by subjecting the gill tissues of M. nipponense to in situ hybridization. Collectively, the results reported herein enhance our understanding of the mechanisms via which M. nipponense adapts to changes in salinity.

'Regulation of photosynthesis' session of the Russian Photobiology Society 9th Congress (Shepsi, September 12-19, 2021).

The 'Regulation of Photosynthesis' session was one of the largest events of the Congress, with 17 talks and 9 poster presentations. It covered many topics on the cutting edge of modern photosynthesis research: from the electron transport within the cytochrome b 6 f-complex to the novel role of carbonic anhydrase in the regulation of pH within the thylakoid lumen, the expanding role of retrograde signaling in all aspects of plant life including the regulation of cell-to-cell traffic via plasmodesmata, and the development of new non-invasive techniques to measure photosynthetic response. Here, a short survey of the presented reports is given.

Roles of Carbonic Anhydrases and Carbonic Anhydrase Related Proteins in Zebrafish.

During recent decades, zebrafish (Danio rerio) have become one of the most important model organisms in which to study different physiological and biological phenomena. The research field of carbonic anhydrases (CAs) and carbonic anhydrase related proteins (CARPs) is not an exception to this. The best-known function of CAs is the regulation of acid–base balance. However, studies performed with zebrafish, among others, have revealed important roles for these proteins in many other physiological processes, some of which had not yet been predicted in the light of previous studies and suggestions. Examples include roles in zebrafish pigmentation as well as motor coordination. Disruption of the function of these proteins may generate lethal outcomes. In this review, we summarize the current knowledge of CA-related studies performed in zebrafish from 1993–2021 that was obtained from PubMed search.

Recent Advances in the Design and Synthesis of Small Molecule Carbonic Anhydrase IX Inhibitors.

Human carbonic anhydrase (CA) IX is a tumor-associated protein since it is scarcely present in normal tissues but highly overexpressed in a large number of solid tumors, where it actively contributes to survival and metastatic spread of tumor cells. A variety of approaches and design strategies were reported that afford CA IX/XII specific inhibitors and avoid the compromising effects of isoforms-promiscuous compounds. CA IX inhibitors hybrids/conjugates have become an important scaffold to design therapeutic agents with both CA inhibition and anti-cancer effects. In this review, we firstly present an overview of the role of CA IX in hypoxic tumors physiopathology, then provide a comprehensive update on the rational design and synthesis of small molecule CA IX inhibitors discovered since 2019. Also, their structure-activity relationship analysis studies are covered. A brief description of applications for CA IX inhibition in other therapeutic areas is also provided.

The Roles of Carbonic Anhydrases in Carbon Concentrating Mechanisms of Aquatic Photoautotrophs

The article surveys the role of carbonic anhydrases (CAs) in inorganic carbon (Ci) acquisition by cyanobacteria, microalgae, and macrophytes under Ci limiting conditions. Slow Ci diffusion in aquatic environments imposes the need for carbon concentrating mechanisms (also named CO2 concentrating mechanisms, CCMs) in aquatic photoautotrophs, to transport Ci against the gradient and ensure a CO2 supply for photosynthesis. There are common requirements for efficient CCM functioning in cyanobacteria, algae, and aquatic angiosperms, including active transport of HCO3- to the Ci-concentrating compartment and CO2 generation from the HCO3- pool in the Rubisco-enriched subcompartment. Facilitating Ci diffusion in aqueous solutions and across lipid bilayers, CAs play essential roles in CCMs that are best studied in cyanobacteria, green algae, and diatoms. Roles of CAs in CCMs depend on their localization and include facilitation of active transmembrane Ci uptake by supplying C1 at the outer surface (Role 1) whilst removing it at the inner surface (Role 2), as well as accelerating CO2 production from HCO3- near Rubisco (Role 3) in a specialised CO2-tight compartment, known as the carboxysome in cyanobacteria or pyrenoid in microalgae. The compartmentalization of CAs is also critical because, if activated in the HCO3- -concentrating compartment, they can easily eliminate the Ci gradient created by the CCMs.

Роль карбоангідраз у механізмах концентрування карбону водних фотоавтотрофів

The article surveys multiple roles of carbonic anhydrases (CAs) in inorganic carbon (Ci) acquisition by cyanobacteria, microalgae, and macrophytes under Ci limiting conditions. Slow Ci diffusion in aquatic environments imposes the need for carbon concentrating mechanisms (also named CO2 concentrating mechanisms, CCMs) in aquatic photoautotrophs to transport Ci against the gradient and ensure CO2 supply to photosynthesis. There are common requirements for efficient CCM functioning in cyanobacteria, algae, and aquatic angiosperms, including active transport of HCO3- to the Ci-concentrating compartment and CO2 generation from the HCO3- pool in the Rubisco-enriched subcompartment. Facilitating Ci diffusion in aqueous solutions and across lipid bilayers, CAs play essential roles in CCMs that are best studied in cyanobacteria, green algae, and diatoms. Roles of CAs in CCMs depend on their localization and include facilitation of active transmembrane Ci uptake by its supplying at the outer surface (Role 1) and removal at the inner surface (Role 2), as well as the acceleration of CO2 production from HCO3- near Rubisco (Role 3) in a special CO2-tight compartment, carboxysome in cyanobacteria or pyrenoid in microalgae. The compartmentalization of CAs is also critical because, if activated in the HCO3- –concentrating compartment, they can easily eliminate the Ci gradient created by CCMs.

The role of carbonic anhydrase III and autophagy in type 2 diabetes with cardio-cerebrovascular disease

Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases among the elderly people. The T2DM increases the risk of cardio-cerebrovascular disease (CCD), and the main pathological change of the CCD is atherosclerosis (AS). Meanwhile, the carbonic anhydrases (CAs) are involved in the formation and progression of plaques in AS. However, the exact physiological mechanism of carbonic anhydrase III (CAIII) has not been clear yet, and there are also no correlation study between CAIII protein and T2DM with CCD. The 8-week old diabetic mice (db/db−/− mice) and wild-type mice (wt mice) were feed by a normal diet till 32 weeks, and detected the carotid artery vascular opening angle using the method of biomechanics; The changes of cerebral cortex and myocardium were watched by the ultrastructure, and the autophagy were observed by electron microscope; The tissue structure, inflammation and cell injury were observed by Hematoxylin and eosin (HE) staining; The apoptosis of cells were observed by TUNEL staining; The protein levels of CAIII, IL-17, p53 were detected by immunohistochemical and Western Blot, and the Beclin-1, LC3, NF-κB were detected by Western Blot. All statistical analysis is performed using PRISM software. Compared with wt mice, db/db−/− mice’ carotid artery open angle increased significantly. Electron microscope results indicated that autophagy in db/db−/− mice cerebral cortex and heart tissue decreased and intracellular organelle ultrastructure were damaged. HE staining indicated that, db/db−/− mice’ cerebral cortex and heart tissue stained lighter, inflammatory cells infiltration, cell edema were obvious, myocardial fibers were disorder, and myocardial cells showed different degrees of degeneration. Compared with wt mice, TUNEL staining showed that there was obviously increase in db/db−/− mice cortex and heart tissue cell apoptosis. The results of immunohistochemistry and Western Blot indicated that CAIII, Beclin-1 and LC3II/I expression levels conspicuously decreased in cortex and heart tissue of db/db−/− mice, and the expression level of IL-17, NF-κB and p53 obviously increased. The carotid artery’ vascular stiffness was increased and which was probably related with formation of AS in diabetic mice. And the autophagy participated in the occurrence and development of diabetic CCD. CAIII protein might somehow be involved in the regulation of autophagy probably through affecting cell apoptosis and inflammation, but the underlying mechanism remains to be further studied.

Role of Carbonic Anhydrase in Cerebral Ischemia and Carbonic Anhydrase Inhibitors as Putative Protective Agents.

Ischemic stroke is a leading cause of death and disability worldwide. The only pharmacological treatment available to date for cerebral ischemia is tissue plasminogen activator (t-PA) and the search for successful therapeutic strategies still remains a major challenge. The loss of cerebral blood flow leads to reduced oxygen and glucose supply and a subsequent switch to the glycolytic pathway, which leads to tissue acidification. Carbonic anhydrase (CA, EC 4.2.1.1) is the enzyme responsible for converting carbon dioxide into a protons and bicarbonate, thus contributing to pH regulation and metabolism, with many CA isoforms present in the brain. Recently, numerous studies have shed light on several classes of carbonic anhydrase inhibitor (CAI) as possible new pharmacological agents for the management of brain ischemia. In the present review we summarized pharmacological, preclinical and clinical findings regarding the role of CAIs in strokes and we discuss their potential protective mechanisms.

Proton Transport in Cancer Cells: The Role of Carbonic Anhydrases.

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.

Carbonic anhydrase influences asymmetric sodium and acetate transport across omasum of sheep.

ObjectiveOmasum is an important site for the absorption of short chain fatty acids. The major route for the transport of acetate is via sodium hydrogen exchanger (NHE). However, a discrepancy in the symmetry of sodium and acetate transport has been previously reported, the mechanism of which is unclear. In this study, we investigated the possible role of carbonic anhydrase (CA) for this asymmetry.MethodsOmasal tissues were isolated from healthy sheep (N = 3) and divided into four groups; pH 7.4 and 6.4 alone and in combination with Ethoxzolamide. Electrophysiological measurements were made using Ussing chamber and the electrical measurements were made using computer controlled voltage clamp apparatus. Effect(s) of CA inhibitor on acetate and sodium transport flux rate of Na22 and 14C-acetate was measured in three different flux time periods. Data were presented as mean±standard deviation and level of significance was ascertained at p≤0.05.ResultsMucosal to serosal flux of Na (JmsNa) was greater than mucosal to serosal flux of acetate (JmsAc) when the pH was decreased from 7.4 to 6.4. However, the addition of CA inhibitor almost completely abolished this discrepancy (JmsNa ≈ JmsAc).ConclusionThe results of the present study suggest that the additional protons required to drive the NHE were provided by the CA enzyme in the isolated omasal epithelium. The findings of this study also suggest that the functions of CA may be exploited for better absorption in omasum.

The role of carbonic anhydrases in extinction of contextual fear memory

Carbonic anhydrases (CAs; EC 4.2.1.1) are metalloenzymes present in mammals with 16 isoforms that differ in terms of catalytic activity as well as cellular and tissue distribution. CAs catalyze the conversion of CO2 to bicarbonate and protons and are involved in various physiological processes, including learning and memory. Here we report that the integrity of CA activity in the brain is necessary for the consolidation of fear extinction memory. We found that systemic administration of acetazolamide, a CA inhibitor, immediately after the extinction session dose-dependently impaired the consolidation of fear extinction memory of rats trained in contextual fear conditioning. d-phenylalanine, a CA activator, displayed an opposite action, whereas C18, a membrane-impermeable CA inhibitor that is unable to reach the brain tissue, had no effect. Simultaneous administration of acetazolamide fully prevented the procognitive effects of d-phenylalanine. Whereas d-phenylalanine potentiated extinction, acetazolamide impaired extinction also when infused locally into the ventromedial prefrontal cortex, basolateral amygdala, or hippocampal CA1 region. No effects were observed when acetazolamide or d-phenylalanine was infused locally into the substantia nigra pars compacta. Moreover, systemic administration of acetazolamide immediately after the extinction training session modulated c-Fos expression on a retention test in the ventromedial prefrontal cortex of rats trained in contextual fear conditioning. These findings reveal that the engagement of CAs in some brain regions is essential for providing the brain with the resilience necessary to ensure the consolidation of extinction of emotionally salient events.

Role of Carbonic Anhydrase in the Regulation of Na‐H exchanger‐1 in Experimental Colitis

A role of carbonic anhydrase (CA) was investigated in the regulation of Na–H exchanger‐1 (NHE‐1) in experimental colitis. Trinitrobenzenesulphonic acid (TNBS) was administered intra‐rectally to induce colitis in rats, and the animals were sacrificed on day 6 post TNBS. The isoforms CA‐I and CA‐II were the abundant isoforms in the colon but expressed as minor ones in the ileum. Both CA isoforms, on co‐immunoprecipitation and confocal microscopy, appeared to be colocalized with the NHE‐1 isoform in the colon. Importantly, inflammation reduced the expression of these proteins in the colon, but not in the ileum. The reduction in the level of co‐immunoprecipitated CA isoforms was more pronounced as compared to their level of expression in the inflamed tissue. Ex‐vivo treatment of uninflamed colonic strips by TNF‐α reduced the expression of CA isoforms. The binding site of the CA‐II isoform was identified in a peptide (83 aa) selected from the NHE‐1 C‐terminus. However, the CA‐I isoform did not bind with the same peptide. Since the tissues used in this study expressed inflammatory markers, the present data suggest that the uncoupling of CA and NHE‐1 is due to inflammation. This uncoupling would lead to a reduction in the NHE‐1 activity and an accumulation of H+ intracellularly, which together cause acidosis and necrosis in the inflamed colon in the present model.Support or Funding InformationResearch Sector, Kuwait University, Kuwait (Grant # MB03/15)

Characterization of Carbonic Anhydrase In Vivo Using Magnetic Resonance Spectroscopy.

Carbonic anhydrase is a ubiquitous metalloenzyme that catalyzes the reversible interconversion of CO2/HCO3−. Equilibrium of these species is maintained by the action of carbonic anhydrase. Recent advances in magnetic resonance spectroscopy have allowed, for the first time, in vivo characterization of carbonic anhydrase in the human brain. In this article, we review the theories and techniques of in vivo 13C magnetization (saturation) transfer magnetic resonance spectroscopy as they are applied to measuring the rate of exchange between CO2 and HCO3− catalyzed by carbonic anhydrase. Inhibitors of carbonic anhydrase have a wide range of therapeutic applications. Role of carbonic anhydrases and their inhibitors in many diseases are also reviewed to illustrate future applications of in vivo carbonic anhydrase assessment by magnetic resonance spectroscopy.

Role of carbonic anhydrase 9 as diagnostic and prognostic marker in clear cell renal cell carcinoma: A single centre study

Background: Carbonic anhydrase 9 (CA-9) is currently being evaluated as prognostic and predictive biomarker for clear cell renal cell carcinomas (ccRCC) and also aids in diagnosis, monitoring tumour progression and clinical outcome. Methods: Descriptive study wherein 100 cases of primary ccRCC and 50 controls tissues were evaluated for CA-9 by immunohistochemistry. Immunoreactivity scores and pattern of staining were correlated with Furhman grading, clinical staging and risk stratification. Results: 88% cases of ccRCC exhibited CA-9 immunopositivity wherein 20% nonclear cell category were positive exhibiting strong statistical correlation between CA-9 immnoexpression and ccRCC. Low grade tumours, lower stage grouping and low risk tumours (UCLA integrated clinical staging) exhibited strong to moderate positivity while high grade, high stage and high risk tumours were either negative or exhibited weak patchy positivity and association was statistically significant. Conclusion: CA-9 is a valuable diagnostic marker for ccRCC and its expression correlates with low grade low risk tumours with favourable prognosis.

Role of carbonic anhydrase in acute recovery following renal ischemia reperfusion injury.

Ischemia reperfusion (IR) injury can cause acute kidney injury. It has previously been reported that kidney oxygen consumption (QO2) in relation to glomerular filtration rate (GFR), and thus tubular sodium load, is markedly increased following IR injury, indicating reduced electrolyte transport efficiency. Since proximal tubular sodium reabsorption (TNa) is a major contributor to overall kidney QO2, we investigated whether inhibition of proximal tubular sodium transport through carbonic anhydrase (CA) inhibition would improve renal oxygenation following ischemia reperfusion. Anesthetized adult male Sprague Dawley rats were administered the CA inhibitor acetazolamide (50 mg/kg bolus iv), or volume-matched vehicle, and kidney function, hemodynamics and QO2 were estimated before and after 45 minutes of unilateral complete warm renal ischemia. CA inhibition per se reduced GFR (-20%) and TNa (-22%), while it increased urine flow and urinary sodium excretion (36-fold). Renal blood flow was reduced (-31%) due to increased renal vascular resistance (+37%) without affecting QO2. IR per se resulted in similar decrease in GFR and TNa, independently of CA activity. However, the QO2/TNa ratio following ischemia-reperfusion was profoundly increased in the group receiving CA inhibition, indicating a significant contribution of basal oxygen metabolism to the total kidney QO2 following inhibition of proximal tubular function after IR injury. Ischemia increased urinary excretion of kidney injury molecule-1, an effect that was unaffected by CA. In conclusion, this study demonstrates that CA inhibition further impairs renal oxygenation and does not protect tubular function in the acute phase following IR injury. Furthermore, these results indicate a major role of the proximal tubule in the acute recovery from an ischemic insult.

Role of Carbonic Anhydrases and Inhibitors in Acid-Base Physiology: Insights from Mathematical Modeling.

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.

Protective roles of carbonic anhydrase 8 in Machado-Joseph Disease.

Machado-Joseph disease (MJD)/Spinocerebellar ataxia type 3 (SCA3) is an inherited neurodegenerative disease that can lead to a regression of motor coordination and muscle control in the extremities. It is known that expansion of CAG repeats encodes abnormally long polyQ in mutant ataxin-3, the disease protein. It is also noted that mutant ataxin-3 interacts with 1,4,5-trisphosphate receptor type 1 (IP3R1) and induces abnormal Ca2+ release. Previously, we have shown a significant increase in the expression of carbonic anhydrase VIII (CA8) in SK-N-SH-MJD78 cells, which are human neuroblastoma cells overexpressing mutant ataxin-3 with 78 glutamine repeats. In the current study, we showed the presence of significantly increased CA8 expression in MJD mouse cerebellum in either early or late disease stage, with a gradual decrease in CA8 expression as the MJD mice naturally aged. By immunofluorescence and immunoprecipitation analysis, we also found that CA8 co-localized and interacted with mutant ataxin-3 in SK-N-SH-MJD78 cells harboring overexpressed CA8 (SK-MJD78-CA8). In addition, we found that SK-MJD78-CA8 cells, as well as cerebellar granule neurons (CGNs) of MJD transgenic (Tg) mouse with overexpressed CA8, were more resistant to reactive oxygen species (ROS) stress than the control cells. Importantly, overexpression of CA8 in SK-MJD78-CA8 cells and in MJD CGNs rescued abnormal Ca2+ release and caused an increase in cell survival. In summary, we demonstrate the protective function of CA8 in MJD disease models and speculate that the declining expression of CA8 following an initial increased expression may be related to the late onset phenomenon of MJD.

Carbonic Anhydrases and Metabolism

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.