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Carbonic Anhydrases as Key Biocatalysts in CO2 Dynamics: From Biochemistry to Biomedical and Biotechnological Applications

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 20 February 2025 | Viewed by 8051

Special Issue Editor

Prof. Dr. Marc A. Ilies

E-Mail Website
Guest Editor
Lewis Katz School of Medicine, Philadelphia, PA, USA
Interests: medicinal chemistry; chemical biology; drug and nucleic acid delivery systems
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Carbon dioxide is the end product of aerobic catabolism in many organisms, from simple unicellular organisms to mammals and humans. It is also the starting point of many anabolic and biosynthetic processes in simple or complex organisms, thus occupying a central role in carbon-based life. It combines spontaneously with water to yield carbonic acid, which ionizes to a proton and a bicarbonate ion (CO2 + H2O ⇄ H2CO3 ⇄ H+ + HCO3-). This reversible process allows for both efficient elimination of CO2 as a biochemical waste and the use of CO2 as a simple biochemical one-carbon synthon. However, the rate of this hydration reaction is too slow for the biochemical needs and specific dynamics of living organisms. Consequently, carbonic anhydrases (CAs) evolved to catalyze the reversible CO2 hydration reaction, with efficiencies approaching the diffusion limit for certain representatives. CAs can instantaneously equilibrate CO2/HCO3- pools internally, inside cytoplasm and in different cellular organelles, and also externally, in different tissues and organs of complex organisms, including humans.

Due to the diversity of the environments in which they operate, and the importance of the reaction catalyzed, it is not surprising that the CA superfamily contains at least seven classes of CAs, namely α-, β-, γ-, δ-, ζ-, η-, and ɵ-CAs, in a typical example of convergent evolution. One goal of this Special Issue is to highlight the newest contributions towards the elucidation of structure, catalytic properties and physiological roles played by these different CAs within their host organisms, with an emphasis on understanding their unique properties and structural similarities, but especially the differences between different members induced by adaptation to the specific environments in which they operate.  

Another goal of this Special Issue is to present new studies regarding the role played by the 15 α-CAs in humans and their contribution to key physiological and pathological processes, as well as the impact of the inhibition and activation of these α-CAs in human health. Special emphasis will be placed on studies dealing with selective CA inhibitors and activators, either within the α-CAs class or between different CA classes, with a focus on improving human health.

We also welcome contributions from research groups studying the impact of CAs in the dynamic of CO2 in the biosphere, and from teams focused on developing CA-based biotechnological solutions to optimize and decarbonize industrial processes that involve CO2.

Prof. Dr. Marc A. Ilies
Guest Editor

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Keywords

  • metalloenzyme
  • catalysis
  • inhibitor
  • activator
  • selective toxicity
  • biomedical applications
  • biotechnological applications

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Published Papers (4 papers)

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15 pages, 3381 KiB  
Article
Alpha Carbonic Anhydrase from Nitratiruptor tergarcus Engineered for Increased Activity and Thermostability
by Colleen Varaidzo Manyumwa, Chenxi Zhang, Carsten Jers and Ivan Mijakovic
Int. J. Mol. Sci. 2024, 25(11), 5853; https://doi.org/10.3390/ijms25115853 - 28 May 2024
Viewed by 760
Abstract
The development of carbon capture and storage technologies has resulted in a rising interest in the use of carbonic anhydrases (CAs) for CO2 fixation at elevated temperatures. In this study, we chose to rationally engineer the α-CA (NtCA) from the thermophilic bacterium [...] Read more.
The development of carbon capture and storage technologies has resulted in a rising interest in the use of carbonic anhydrases (CAs) for CO2 fixation at elevated temperatures. In this study, we chose to rationally engineer the α-CA (NtCA) from the thermophilic bacterium Nitratiruptor tergarcus, which has been previously suggested to be thermostable by in silico studies. Using a combination of analyses with the DEEPDDG software and available structural knowledge, we selected residues in three regions, namely, the catalytic pocket, the dimeric interface and the surface, in order to increase thermostability and CO2 hydration activity. A total of 13 specific mutations, affecting seven amino acids, were assessed. Single, double and quadruple mutants were produced in Escherichia coli and analyzed. The best-performing mutations that led to improvements in both activity and stability were D168K, a surface mutation, and R210L, a mutation in the dimeric interface. Apart from these, most mutants showed improved thermostability, with mutants R210K and N88K_R210L showing substantial improvements in activity, up to 11-fold. Molecular dynamics simulations, focusing particularly on residue fluctuations, conformational changes and hydrogen bond analysis, elucidated the structural changes imposed by the mutations. Successful engineering of NtCA provided valuable lessons for further engineering of α-CAs. Full article
(This article belongs to the Special Issue Carbonic Anhydrases as Key Biocatalysts in CO2 Dynamics: From Biochemistry to Biomedical and Biotechnological Applications)
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17 pages, 3333 KiB  
Article
Fluconazole-Induced Protein Changes in Osteogenic and Immune Metabolic Pathways of Dental Pulp Mesenchymal Stem Cells of Osteopetrosis Patients
by Zikra Alkhayal, Zakia Shinwari, Ameera Gaafar and Ayodele Alaiya
Int. J. Mol. Sci. 2023, 24(18), 13841; https://doi.org/10.3390/ijms241813841 - 8 Sep 2023
Cited by 3 | Viewed by 1431
Abstract
Osteopetrosis is a rare inherited disease caused by osteoclast failure, resulting in increasing bone density in humans. Patients with osteopetrosis possess several dental and cranial complications. Since carbonic anhydrase II (CA-II) deficiency is a major cause of osteopetrosis, CA-II activators might be an [...] Read more.
Osteopetrosis is a rare inherited disease caused by osteoclast failure, resulting in increasing bone density in humans. Patients with osteopetrosis possess several dental and cranial complications. Since carbonic anhydrase II (CA-II) deficiency is a major cause of osteopetrosis, CA-II activators might be an attractive potential treatment option for osteopetrosis patients. We conducted comprehensive label-free quantitative proteomics analysis on Fluconazole-treated Dental Pulp Mesenchymal Stem/Stromal Cells from CA-II-Deficient Osteopetrosis Patients. We identified 251 distinct differentially expressed proteins between healthy subjects, as well as untreated and azole-treated derived cells from osteopetrosis patients. Twenty-six (26) of these proteins were closely associated with osteogenesis and osteopetrosis disease. Among them are ATP1A2, CPOX, Ap2 alpha, RAP1B and some members of the RAB protein family. Others include AnnexinA1, 5, PYGL, OSTF1 and PGAM4, all interacting with OSTM1 in the catalytic reactions of HCO3 and the Cl- channel via CAII regulation. In addition, the pro-inflammatory/osteoclast regulatory proteins RACK1, MTSE, STING1, S100A13, ECE1 and TRIM10 are involved. We have identified proteins involved in osteogenic and immune metabolic pathways, including ERK 1/2, phosphatase and ATPase, which opens the door for some CA activators to be used as an alternative drug therapy for osteopetrosis patients. These findings propose that fluconazole might be a potential treatment agent for CAII- deficient OP patients. Altogether, our findings provide a basis for further work to elucidate the clinical utility of azole, a CA activator, as a therapeutic for OP. Full article
(This article belongs to the Special Issue Carbonic Anhydrases as Key Biocatalysts in CO2 Dynamics: From Biochemistry to Biomedical and Biotechnological Applications)
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18 pages, 10362 KiB  
Article
Propranolol, Promising Chemosensitizer and Candidate for the Combined Therapy through Disruption of Tumor Microenvironment Homeostasis by Decreasing the Level of Carbonic Anhydrase IX
by Barbora Puzderova, Petra Belvoncikova, Katarina Grossmannova, Lucia Csaderova, Martina Labudova, Silvia Fecikova, Jaromir Pastorek and Monika Barathova
Int. J. Mol. Sci. 2023, 24(13), 11094; https://doi.org/10.3390/ijms241311094 - 4 Jul 2023
Cited by 5 | Viewed by 2003
Abstract
Resistance to chemotherapy represents a persisting medical problem, ranking among main causes of chemotherapy failure and cancer mortality. There is a possibility to utilize and repurpose already existing therapeutics which were not primarily intended for oncological treatment. Overactivation of adrenergic receptors and signaling [...] Read more.
Resistance to chemotherapy represents a persisting medical problem, ranking among main causes of chemotherapy failure and cancer mortality. There is a possibility to utilize and repurpose already existing therapeutics which were not primarily intended for oncological treatment. Overactivation of adrenergic receptors and signaling dysregulation promotes tumor progression, metastatic potential, immune system evasion, tumor angiogenesis and drug resistance. The non-selective beta-blocker propranolol, approved in infantile haemangioma treatment, has a high potential for use in cancer therapy. We analyzed the effects of propranolol and 5-fluorouracil combination on sensitive and resistant cells derived from colorectal carcinoma in monolayers, single-component and co-culture spheroids and in vivo mouse models. Our results revealed that propranolol is able to exert its effect not only in chemosensitive colorectal cells, but also in 5-fluorouracil resistant cells. Propranolol disrupts the hypoxic adaptation machinery by inhibiting HIF1α, carbonic anhydrase IX, and activates apoptosis, which may be important in the management of chemo-resistant patients. We showed that propranolol slows down the growth of xenografts formed from colorectal cancer cells, even from cells already adapted to the β-blocker. We provide clear evidence that blockade of β-adrenergic receptors affects essential signaling pathways modulating tumor microenvironment and thus the response to anticancer therapy. Our findings indicate that propranolol could be repurposed to serve as chemosensitizer in combined therapy aimed at disrupting homeostasis of tumor microenvironment. Full article
(This article belongs to the Special Issue Carbonic Anhydrases as Key Biocatalysts in CO2 Dynamics: From Biochemistry to Biomedical and Biotechnological Applications)
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18 pages, 2521 KiB  
Article
Expression Dynamics of CA IX Epitope in Cancer Cells under Intermittent Hypoxia Correlates with Extracellular pH Drop and Cell Killing by Ureido-Sulfonamide CA IX Inhibitors
by Md. Abu Sufian, Sabina Zamanova, Ahmed M. Shabana, Brianna Kemp, Utpal K. Mondal, Claudiu T. Supuran and Marc A. Ilies
Int. J. Mol. Sci. 2023, 24(5), 4595; https://doi.org/10.3390/ijms24054595 - 27 Feb 2023
Cited by 5 | Viewed by 3074
Abstract
Carbonic anhydrase IX (CA IX) is a membrane-bound CA isozyme over-expressed in many hypoxic tumor cells, where it ensures pH homeostasis and has been implicated in tumor survival, metastasis and resistance to chemotherapy and radiotherapy. Given the functional importance of CA IX in [...] Read more.
Carbonic anhydrase IX (CA IX) is a membrane-bound CA isozyme over-expressed in many hypoxic tumor cells, where it ensures pH homeostasis and has been implicated in tumor survival, metastasis and resistance to chemotherapy and radiotherapy. Given the functional importance of CA IX in tumor biochemistry, we investigated the expression dynamics of CA IX in normoxia, hypoxia and intermittent hypoxia, which are typical conditions experienced by tumor cells in aggressive carcinomas. We correlated the CA IX epitope expression dynamics with extracellular pH acidification and with viability of CA IX-expressing cancer cells upon treatment with CA IX inhibitors (CAIs) in colon HT-29, breast MDA-MB-231 and ovarian SKOV-3 tumor cell models. We observed that the CA IX epitope expressed under hypoxia by these cancer cells is retained in a significant amount upon reoxygenation, probably to preserve their proliferation ability. The extracellular pH drop correlated well with the level of CA IX expression, with the intermittent hypoxic cells showing a similar pH drop to fully hypoxic ones. All cancer cells showed higher sensitivity to CA IX inhibitors (CAIs) under hypoxia as compared to normoxia. The tumor cell sensitivity to CAIs under hypoxia and intermittent hypoxia were similar and higher than in normoxia and appeared to be correlated with the lipophilicity of the CAI. Full article
(This article belongs to the Special Issue Carbonic Anhydrases as Key Biocatalysts in CO2 Dynamics: From Biochemistry to Biomedical and Biotechnological Applications)
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