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Carbonic Anhydrase and Biomarker Research 2020
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Carbonic Anhydrase and Biomarker Research 2020

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

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 33841

Special Issue Editor

Dr. Maria Giulia Lionetto

E-Mail Website
Guest Editor
Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Itay
Interests: carbonic anhydrase; antioxidant; biomarkers; oxidative stress
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Carbonic anhydrase is a widely distributed metalloenzyme catalysing the reversible hydration of CO2 to HCO3- and H+. It plays a fundamental role in a number of physiological processes, including gas exchange, pH homeostasis, electrolyte transport, metabolic reactions, bone resorption, and calcification. Recently, its involvement in several pathological conditions, as well as sensitivity to chemical pollutants, has advanced the research on carbonic anhydrase in the biomarker discovery field.

A biomarker is defined as a cellular, biochemical, or molecular alteration that is measurable in biological media as an indicator of normal biological process, pathogenic processes, or response to an exposure or intervention. Biomarkers are useful tools in a wide range of fields, including medicine, drug discovery, environmental health, and ecotoxicology.

In recent years, alteration in the expression of specific carbonic anhydrase isoforms has been proposed as diagnostic or prognostic biomarkers in the clinical field, mainly in cancer research.

Moreover, the sensitivity of specific carbonic anhydrase isoforms to environmental pollutants has given rise to new perspectives in the potential use of carbonic anhydrase as a pollution biomarker.

This Special Issue of IJMS is aimed to cover the more recent insights into the research of carbonic anhydrase as a promising biomarker in several areas of interest, from human health to environmental sciences, opening new perspectives for the translation of advances in basic sciences on this ancient enzyme into innovative applications.

Prof. Dr. Maria Giulia Lionetto
Guest Editor

Manuscript Submission Information

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Keywords

  • carbonic anhydrase
  • biomarker
  • pH regulation
  • cancer
  • tumor microenvironment
  • heavy metals
  • pollutant
  • biomonitoring

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Related Special Issue

Published Papers (10 papers)

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Editorial

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4 pages, 210 KiB  
Editorial
Carbonic Anhydrase and Biomarker Research: New Insights
by Maria Giulia Lionetto
Int. J. Mol. Sci. 2023, 24(11), 9687; https://doi.org/10.3390/ijms24119687 - 2 Jun 2023
Cited by 6 | Viewed by 1555
Abstract
Carbonic anhydrase (CA) is a widespread metalloenzyme with eight genetically distinct families catalyzing the reversible hydration of CO2 to HCO3− and H+ [...] Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Biomarker Research 2020)

Research

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26 pages, 6658 KiB  
Article
Inhibitory Monoclonal Antibodies and Their Recombinant Derivatives Targeting Surface-Exposed Carbonic Anhydrase XII on Cancer Cells
by Dovile Stravinskiene, Aiste Sliziene, Lina Baranauskiene, Vilma Petrikaite and Aurelija Zvirbliene
Int. J. Mol. Sci. 2020, 21(24), 9411; https://doi.org/10.3390/ijms21249411 - 10 Dec 2020
Cited by 8 | Viewed by 3234
Abstract
Monoclonal and recombinant antibodies are widely used for the diagnostics and therapy of cancer. They are generated to interact with cell surface proteins which are usually involved in the development and progression of cancer. Carbonic anhydrase XII (CA XII) contributes to the survival [...] Read more.
Monoclonal and recombinant antibodies are widely used for the diagnostics and therapy of cancer. They are generated to interact with cell surface proteins which are usually involved in the development and progression of cancer. Carbonic anhydrase XII (CA XII) contributes to the survival of tumors under hypoxic conditions thus is considered a candidate target for antibody-based therapy. In this study, we have generated a novel collection of monoclonal antibodies (MAbs) against the recombinant extracellular domain of CA XII produced in HEK-293 cells. Eighteen out of 24 MAbs were reactive with cellular CA XII on the surface of live kidney and lung cancer cells as determined by flow cytometry. One MAb 14D6 also inhibited the enzymatic activity of recombinant CA XII as measured by the stopped-flow assay. MAb 14D6 showed the migrastatic effect on human lung carcinoma A549 and renal carcinoma A498 cell lines in a ‘wound healing’ assay. It did not reduce the growth of multicellular lung and renal cancer spheroids but reduced the cell viability by the ATP Bioluminescence assay. Epitope mapping revealed the surface-exposed amino acid sequence (35-FGPDGENS-42) close to the catalytic center of CA XII recognized by the MAb 14D6. The variable regions of the heavy and light chains of MAb 14D6 were sequenced and their complementarity-determining regions were defined. The obtained variable sequences were used to generate recombinant antibodies in two formats: single-chain fragment variable (scFv) expressed in E. coli and scFv fused to human IgG1 Fc fragment (scFv-Fc) expressed in Chinese Hamster Ovary (CHO) cells. Both recombinant antibodies maintained the same specificity for CA XII as the parental MAb 14D6. The novel antibodies may represent promising tools for CA XII-related cancer research and immunotherapy. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Biomarker Research 2020)
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23 pages, 2865 KiB  
Article
PIMT Binding to C-Terminal Ala459 of CAIX Is Involved in Inside-Out Signaling Necessary for Its Catalytic Activity
by Veronika Simko, Petra Belvoncikova, Lucia Csaderova, Martina Labudova, Katarina Grossmannova, Miriam Zatovicova, Ivana Kajanova, Ludovit Skultety, Monika Barathova and Jaromir Pastorek
Int. J. Mol. Sci. 2020, 21(22), 8545; https://doi.org/10.3390/ijms21228545 - 12 Nov 2020
Cited by 4 | Viewed by 2736
Abstract
Human carbonic anhydrase IX (CAIX), a unique member of the α carbonic anhydrase family, is a transmembrane glycoprotein with high enzymatic activity by which CAIX contributes to tumorigenesis through pH regulation. Due to its aberrant expression, CAIX is considered to be a marker [...] Read more.
Human carbonic anhydrase IX (CAIX), a unique member of the α carbonic anhydrase family, is a transmembrane glycoprotein with high enzymatic activity by which CAIX contributes to tumorigenesis through pH regulation. Due to its aberrant expression, CAIX is considered to be a marker of tumor hypoxia and a poor prognostic factor of several human cancers. Hypoxia-activated catalytic function of CAIX is dependent on posttranslational modification of its short intracellular domain. In this work, we have identified that C-terminal Ala459 residue, which is common across CAIX of various species as well as additional transmembrane isoforms, plays an important role in CAIX activation and in pH regulation. Moreover, structure prediction I-TASSER analysis revealed involvement of Ala459 in potential ligand binding. Using tandem mass spectrometry, Protein-L-isoaspartyl methyltransferase (PIMT) was identified as a novel interacting partner, further confirmed by an in vitro pulldown assay and an in situ proximity ligation assay. Indeed, suppression of PIMT led to increased alkalinization of culture media of C33a cells constitutively expressing CAIX in hypoxia. We suggest that binding of PIMT represents a novel intracellular signal required for enzymatic activity of CAIX with a potential unidentified downstream function. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Biomarker Research 2020)
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20 pages, 2783 KiB  
Article
Biophysical Characterization of Cancer-Related Carbonic Anhydrase IX
by Katarina Koruza, A. Briana Murray, Brian P. Mahon, Jesse B. Hopkins, Wolfgang Knecht, Robert McKenna and S. Zoë Fisher
Int. J. Mol. Sci. 2020, 21(15), 5277; https://doi.org/10.3390/ijms21155277 - 25 Jul 2020
Cited by 4 | Viewed by 3361
Abstract
Upregulation of carbonic anhydrase IX (CA IX) is associated with several aggressive forms of cancer and promotes metastasis. CA IX is normally constitutively expressed at low levels in selective tissues associated with the gastrointestinal tract, but is significantly upregulated upon hypoxia in cancer. [...] Read more.
Upregulation of carbonic anhydrase IX (CA IX) is associated with several aggressive forms of cancer and promotes metastasis. CA IX is normally constitutively expressed at low levels in selective tissues associated with the gastrointestinal tract, but is significantly upregulated upon hypoxia in cancer. CA IX is a multi-domain protein, consisting of a cytoplasmic region, a single-spanning transmembrane helix, an extracellular CA catalytic domain, and a proteoglycan-like (PG) domain. Considering the important role of CA IX in cancer progression and the presence of the unique PG domain, little information about the PG domain is known. Here, we report biophysical characterization studies to further our knowledge of CA IX. We report the 1.5 Å resolution crystal structure of the wild-type catalytic domain of CA IX as well as small angle X-ray scattering and mass spectrometry of the entire extracellular region. We used matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry to characterize the spontaneous degradation of the CA IX PG domain and confirm that it is only the CA IX catalytic domain that forms crystals. Small angle X-ray scattering analysis of the intact protein indicates that the PG domain is not randomly distributed and adopts a compact distribution of shapes in solution. The observed dynamics of the extracellular domain of CA IX could have physiological relevance, including observed cleavage and shedding of the PG domain. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Biomarker Research 2020)
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18 pages, 6518 KiB  
Article
CAIX-Mediated Control of LIN28/let-7 Axis Contributes to Metabolic Adaptation of Breast Cancer Cells to Hypoxia
by Adriana Gibadulinova, Petra Bullova, Hynek Strnad, Kamil Pohlodek, Dana Jurkovicova, Martina Takacova, Silvia Pastorekova and Eliska Svastova
Int. J. Mol. Sci. 2020, 21(12), 4299; https://doi.org/10.3390/ijms21124299 - 16 Jun 2020
Cited by 31 | Viewed by 4504
Abstract
Solid tumors, including breast cancer, are characterized by the hypoxic microenvironment, extracellular acidosis, and chemoresistance. Hypoxia marker, carbonic anhydrase IX (CAIX), is a pH regulator providing a selective survival advantage to cancer cells through intracellular neutralization while facilitating tumor invasion by extracellular acidification. [...] Read more.
Solid tumors, including breast cancer, are characterized by the hypoxic microenvironment, extracellular acidosis, and chemoresistance. Hypoxia marker, carbonic anhydrase IX (CAIX), is a pH regulator providing a selective survival advantage to cancer cells through intracellular neutralization while facilitating tumor invasion by extracellular acidification. The expression of CAIX in breast cancer patients is associated with poor prognosis and metastases. Importantly, CAIX-positive hypoxic tumor regions are enriched in cancer stem cells (CSCs). Here we investigated the biological effects of CA9-silencing in breast cancer cell lines. We found that CAIX-downregulation in hypoxia led to increased levels of let-7 (lethal-7) family members. Simultaneously with the increase of let-7 miRNAs in CAIX-suppressed cells, LIN28 protein levels decreased, along with downstream metabolic pathways: pyruvate dehydrogenase kinase 1 (PDK1) and phosphorylation of its substrate, pyruvate dehydrogenase (PDH) at Ser-232, causing attenuation of glycolysis. In addition to perturbed glycolysis, CAIX-knockouts, in correlation with decreased LIN28 (as CSC reprogramming factor), also exhibit reduction of the further CSC-associated markers NANOG (Homeobox protein NANOG) and ALDH1 (Aldehyde dehydrogenase isoform 1). Oppositely, overexpression of CAIX leads to the enhancement of LIN28, ALDH1, and NANOG. In conclusion, CAIX-driven regulation of the LIN28/let-7 axis augments glycolytic metabolism and enhances stem cell markers expression during CAIX-mediated adaptation to hypoxia and acidosis in carcinogenesis. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Biomarker Research 2020)
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22 pages, 2494 KiB  
Article
Synthetic Strategies and Computational Inhibition Activity Study for Triazinyl-Substituted Benzenesulfonamide Conjugates with Polar and Hydrophobic Amino Acids as Inhibitors of Carbonic Anhydrases
by Mária Bodnár Mikulová, Dáša Kružlicová, Daniel Pecher, Claudiu T. Supuran and Peter Mikuš
Int. J. Mol. Sci. 2020, 21(10), 3661; https://doi.org/10.3390/ijms21103661 - 22 May 2020
Cited by 8 | Viewed by 2717
Abstract
Various sulfonamide derivatives are intensively studied as anticancer agents owing to their inhibitory activity against human tumor-associated carbonic anhydrase isoforms. In this work, different synthetic procedures for the series of 1,3,5-triazinyl-aminobenzenesulfonamide conjugates with amino acids, possessing polar uncharged, negatively charged, and hydrophobic side [...] Read more.
Various sulfonamide derivatives are intensively studied as anticancer agents owing to their inhibitory activity against human tumor-associated carbonic anhydrase isoforms. In this work, different synthetic procedures for the series of 1,3,5-triazinyl-aminobenzenesulfonamide conjugates with amino acids, possessing polar uncharged, negatively charged, and hydrophobic side chain, were studied and optimized with respect to the yield/purity of the synthesis/product as well as the time of synthetic reaction. These procedures were compared to each other via characteristic HPLC-ESI-DAD/QTOF/MS analytical product profiles, and their benefits as well as limitations were discussed. For new sulfonamide derivatives, incorporating s-triazine with a symmetric pair of polar and some less-polar proteinogenic amino acids, inhibition constants (KIs) against four human carboanhydrases (hCAs), namely cytosolic hCA I, II, transmembrane hCA IV, and the tumor-associated, membrane-bound hCA IX isoforms, were computationally predicted applying various methods of the advanced statistical analysis. Quantitative structure-activity relationship (QSAR) analysis indicated an impressive KI ratio (hCA II/hCA IX) 139.1 and hCA IX inhibition constant very similar to acetazolamide (KI = 29.6 nM) for the sulfonamide derivative disubstituted with Gln. The derivatives disubstituted with Ser, Thr, and Ala showed even lower KIs (8.7, 13.1, and 8.4 nM, respectively). Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Biomarker Research 2020)
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Review

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15 pages, 828 KiB  
Review
Carbonic Anhydrase IX in Renal Cell Carcinoma, Implications for Disease Management
by Jean Courcier, Alexandre de la Taille, Maya Nourieh, Ingrid Leguerney, Nathalie Lassau and Alexandre Ingels
Int. J. Mol. Sci. 2020, 21(19), 7146; https://doi.org/10.3390/ijms21197146 - 28 Sep 2020
Cited by 40 | Viewed by 4621
Abstract
Carbonic Anhydrase IX (CAIX) is a well-described enzyme in renal cell carcinoma, with its expression being regulated by the hypoxia-inducible factor 1 alpha, it is known for interfering with hypoxia processes. Renal carcinoma encompasses a broad spectrum of histological entities and is also [...] Read more.
Carbonic Anhydrase IX (CAIX) is a well-described enzyme in renal cell carcinoma, with its expression being regulated by the hypoxia-inducible factor 1 alpha, it is known for interfering with hypoxia processes. Renal carcinoma encompasses a broad spectrum of histological entities and is also described as a heterogeneous malignant tumor. Recently, various combinations of checkpoint inhibitors and targeted therapies have been validated to manage this disease. Reliable markers to confirm the diagnosis, estimate the prognosis, predict or monitor the treatment response are required. Molecular imaging developments allow a comprehensive analysis of the tumor, overcoming the spatial heterogeneity issue. CAIX, being highly expressed at the tumor cell surfaces of clear cell renal carcinoma, also represents a potential treatment target. In this manuscript we reviewed the current knowledge from the literature on the pathophysiological interactions between renal cell carcinoma and CAIX, the role of CAIX as a marker for diagnosis, prognosis, treatment monitoring and molecular imaging, and the potential target for therapeutic strategies. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Biomarker Research 2020)
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24 pages, 4904 KiB  
Review
Interplay between Carbonic Anhydrases and Metallothioneins: Structural Control of Metalation
by Daisy L. Wong, Amelia T. Yuan, Natalie C. Korkola and Martin J. Stillman
Int. J. Mol. Sci. 2020, 21(16), 5697; https://doi.org/10.3390/ijms21165697 - 9 Aug 2020
Cited by 7 | Viewed by 3636
Abstract
Carbonic anhydrases (CAs) and metallothioneins (MTs) are both families of zinc metalloproteins central to life, however, they coordinate and interact with their Zn2+ ion cofactors in completely different ways. CAs and MTs are highly sensitive to the cellular environment and play key [...] Read more.
Carbonic anhydrases (CAs) and metallothioneins (MTs) are both families of zinc metalloproteins central to life, however, they coordinate and interact with their Zn2+ ion cofactors in completely different ways. CAs and MTs are highly sensitive to the cellular environment and play key roles in maintaining cellular homeostasis. In addition, CAs and MTs have multiple isoforms with differentiated regulation. This review discusses current literature regarding these two families of metalloproteins in carcinogenesis, with a dialogue on the association of these two ubiquitous proteins in vitro in the context of metalation. Metalation of CA by Zn-MT and Cd-MT is described. Evidence for protein–protein interactions is introduced from changes in metalation profiles of MT from electrospray ionization mass spectrometry and the metalation rate from stopped-flow kinetics. The implications on cellular control of pH and metal donation is also discussed in the context of diseased states. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Biomarker Research 2020)
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16 pages, 1558 KiB  
Review
Carbonic Anhydrase Sensitivity to Pesticides: Perspectives for Biomarker Development
by Maria Giulia Lionetto, Roberto Caricato and Maria Elena Giordano
Int. J. Mol. Sci. 2020, 21(10), 3562; https://doi.org/10.3390/ijms21103562 - 18 May 2020
Cited by 12 | Viewed by 2913
Abstract
Carbonic anhydrase (CA) is a widespread metalloenzyme playing a pivotal role in several physiological processes. Many studies have demonstrated the in vitro and in vivo sensitivity of CA to the exposure to several classes of pesticides in both humans and wildlife. This review [...] Read more.
Carbonic anhydrase (CA) is a widespread metalloenzyme playing a pivotal role in several physiological processes. Many studies have demonstrated the in vitro and in vivo sensitivity of CA to the exposure to several classes of pesticides in both humans and wildlife. This review aims to analyze and to discuss the literature available in this field, providing a comprehensive view useful to foresee perspectives for the development of novel CA-based pesticide biomarkers. The analysis of the available data highlighted the ability of several pesticide molecules to interact directly with the enzyme in humans and wildlife and to inhibit CA activity in vitro and in vivo, with possible alterations of key physiological functions. The analysis disclosed key areas of further research and, at the same time, identified some perspectives for the development of novel CA-based sensitive biomarkers to pesticide exposure, suitable to be used in several fields from human biomonitoring in occupational and environmental medicine to environmental monitoring on non-target species. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Biomarker Research 2020)
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16 pages, 3341 KiB  
Review
Characterization of Carbonic Anhydrase In Vivo Using Magnetic Resonance Spectroscopy
by Jyoti Singh Tomar and Jun Shen
Int. J. Mol. Sci. 2020, 21(7), 2442; https://doi.org/10.3390/ijms21072442 - 1 Apr 2020
Cited by 5 | Viewed by 3789
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Biomarker Research 2020)
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