Carbonic anhydrase activators: Activation of the archaeal β-class (Cab) and γ-class (Cam) carbonic anhydrases with amino acids and amines

Carbonic Anhydrases (CAs) are a superfamily of metalloenzymes widespread in all life kingdoms, classified into seven genetically different families (α-θ). These enzymes catalyse the reversible hydration of carbonic anhydride (CO2), generating bicarbonate (HCO3-) and protons (H+). Fifteen isoforms of human CA (hCA I-XV) have been isolated, their presence being fundamental for the regulation of many physiological processes. In addition, overexpression of some isoforms has been associated with the outbreak or the progression of several diseases. For this reason, for a long time CA inhibitors (CAIs) are used in the control of glaucoma and as diuretics. Furthermore, the search for new potential CAIs for other pharmacological applications is a very active field. Amino acids constitute the smallest fundamental monomers of protein and, due to their useful bivalent chemical properties, are widely used in organic chemistry. Both proteinogenic and non-proteinogenic amino acids have been extensively used to synthesize CAIs. This article provides an overview of the different strategies that have been used to design new CAIs containing amino acids, and how these bivalent molecules influence the properties of the inhibitors.

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Are Carbonic Anhydrases Suitable Targets to Fight Protozoan Parasitic Diseases?

Current Medicinal Chemistry ◽

10.2174/0929867325666180326160121 ◽

2019 ◽

Vol 25 (39) ◽

pp. 5266-5278 ◽

Cited By ~ 9

Author(s):

Katia D'Ambrosio ◽

Claudiu T. Supuran ◽

Giuseppina De Simone

Keyword(s):

Drug Resistance ◽

Animal Models ◽

Carbonic Anhydrase ◽

Drug Target ◽

Treatment Options ◽

Parasitic Diseases ◽

Carbonic Anhydrases ◽

Extensive Drug Resistance ◽

Protozoan Infections

Protozoans belonging to Plasmodium, Leishmania and Trypanosoma genera provoke widespread parasitic diseases with few treatment options and many of the clinically used drugs experiencing an extensive drug resistance phenomenon. In the last several years, the metalloenzyme Carbonic Anhydrase (CA, EC 4.2.1.1) was cloned and characterized in the genome of these protozoa, with the aim to search for a new drug target for fighting malaria, leishmaniasis and Chagas disease. P. falciparum encodes for a CA (PfCA) belonging to a novel genetic family, the η-CA class, L. donovani chagasi for a β-CA (LdcCA), whereas T. cruzi genome contains an α-CA (TcCA). These three enzymes were characterized in detail and a number of in vitro potent and selective inhibitors belonging to the sulfonamide, thiol, dithiocarbamate and hydroxamate classes were discovered. Some of these inhibitors were also effective in cell cultures and animal models of protozoan infections, making them of considerable interest for the development of new antiprotozoan drugs with a novel mechanism of action.

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Anticonvulsant Effects of Carbonic Anhydrase Inhibitors: The Enigmatic Link Between Carbonic Anhydrases and Electrical Activity of the Brain

Neurochemical Research ◽

10.1007/s11064-021-03390-2 ◽

2021 ◽

Author(s):

Hatice Zehra Ozsoy

Keyword(s):

Carbonic Anhydrase ◽

Electrical Activity ◽

Carbonic Anhydrases ◽

Carbonic Anhydrase Inhibitors ◽

The Brain ◽

Anticonvulsant Effects

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Synthesis and Human Carbonic Anhydrase I, II, IX, and XII Inhibition Studies of Sulphonamides Incorporating Mono-, Bi- and Tricyclic Imide Moieties

Pharmaceuticals ◽

10.3390/ph14070693 ◽

2021 ◽

Vol 14 (7) ◽

pp. 693

Author(s):

Kalyan K. Sethi ◽

KM Abha Mishra ◽

Saurabh M. Verma ◽

Daniela Vullo ◽

Fabrizio Carta ◽

...

Keyword(s):

Molecular Docking ◽

Carbonic Anhydrase ◽

Docking Studies ◽

Carbonic Anhydrases ◽

Molecular Docking Studies ◽

Structure Activity Relationships ◽

Structure Activity ◽

Carbonic Anhydrase I ◽

Human Carbonic Anhydrase ◽

Inhibition Studies

New derivatives were synthesised by reaction of amino-containing aromatic sulphonamides with mono-, bi-, and tricyclic anhydrides. These sulphonamides were investigated as human carbonic anhydrases (hCAs, EC 4.2.1.1) I, II, IX, and XII inhibitors. hCA I was inhibited with inhibition constants (Kis) ranging from 49 to >10,000 nM. The physiologically dominant hCA II was significantly inhibited by most of the sulphonamide with the Kis ranging between 2.4 and 4515 nM. hCA IX and hCA XII were inhibited by these sulphonamides in the range of 9.7 to 7766 nM and 14 to 316 nM, respectively. The structure–activity relationships (SAR) are rationalised with the help of molecular docking studies.

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Polypharmacology of epacadostat: a potent and selective inhibitor of the tumor associated carbonic anhydrases IX and XII

Chemical Communications ◽

10.1039/c8cc09568j ◽

2019 ◽

Vol 55 (40) ◽

pp. 5720-5723 ◽

Cited By ~ 9

Author(s):

Andrea Angeli ◽

Marta Ferraroni ◽

Alessio Nocentini ◽

Silvia Selleri ◽

Paola Gratteri ◽

...

Keyword(s):

Carbonic Anhydrase ◽

Selective Inhibitor ◽

Carbonic Anhydrase Inhibitor ◽

Carbonic Anhydrases ◽

Indoleamine 2,3 Dioxygenase

Epacadostat (EPA), a selective indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor, has been investigatedin vitroas a human (h) Carbonic Anhydrase Inhibitor (CAI).

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Carbonic Anhydrases in Photosynthesizing Cells of C3 Higher Plants

Metabolites ◽

10.3390/metabo9040073 ◽

2019 ◽

Vol 9 (4) ◽

pp. 73 ◽

Cited By ~ 5

Author(s):

Lyudmila Ignatova ◽

Natalia Rudenko ◽

Elena Zhurikova ◽

Maria Borisova-Mubarakshina ◽

Boris Ivanov

Keyword(s):

Plasma Membrane ◽

Carbonic Anhydrase ◽

Environmental Conditions ◽

Organic Molecules ◽

Higher Plants ◽

C3 Plants ◽

Coherent System ◽

Carbonic Anhydrases ◽

Chloroplast Stroma ◽

Different Parts

The review presents data on the location, nature, properties, number, and expression of carbonic anhydrase genes in the photosynthesizing cells of C3 plants. The available data about the presence of carbonic anhydrases in plasma membrane, cytoplasm, mitochondria, chloroplast stroma and thylakoids are scrutinized. Special attention was paid to the presence of carbonic anhydrase activities in the different parts of thylakoids, and on collation of sources of these activities with enzymes encoded by the established genes of carbonic anhydrases. The data are presented to show that the consistent incorporation of carbonic anhydrases belonging to different families of these enzymes forms a coherent system of CO2 molecules transport from air to chloroplasts in photosynthesizing cells, where they are included in organic molecules in the carboxylation reaction. It is discussed that the manifestation of the activity of a certain carbonic anhydrase depends on environmental conditions and the stage of ontogenesis.

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Human Carbonic Anhydrases and Carbonic Anhydrase Deficiencies

Annual Review of Biochemistry ◽

10.1146/annurev.bi.64.070195.002111 ◽

1995 ◽

Vol 64 (1) ◽

pp. 375-401 ◽

Cited By ~ 563

Author(s):

William S. Sly ◽

Peiyi Y. Hu

Keyword(s):

Carbonic Anhydrase ◽

Carbonic Anhydrases

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Polymorphisms in Brucella Carbonic anhydrase II mediate CO2 dependence and fitness in vivo

10.1101/804740 ◽

2019 ◽

Author(s):

JM García-Lobo ◽

Y Ortiz ◽

C González-Riancho ◽

A Seoane ◽

B Arellano-Reynoso ◽

...

Keyword(s):

Carbonic Anhydrase ◽

Primary Cultures ◽

Low Frequency ◽

Carbonic Anhydrase Ii ◽

Carbonic Anhydrases ◽

Significant Difference ◽

Dependent Strain

AbstractSome Brucella isolates are known to require an increased concentration of CO2 for growth, especially in the case of primary cultures obtained directly from infected animals. Moreover, the different Brucella species and biovars show a characteristic pattern of CO2 requirement, and this trait has been included among the routine typing tests used for species and biovar differentiation. By comparing the differences in gene content among different CO2-dependent and CO2-independent Brucella strains we have confirmed that carbonic anhydrase II (CA II), is the enzyme responsible for this phenotype in all the Brucella strains tested. Brucella species contain two carbonic anhydrases of the β family, CA I and CA II; genetic polymorphisms exist for both of them in different isolates, but only those putatively affecting the activity of CA II correlate with the CO2 requirement of the corresponding isolate. Analysis of these polymorphisms does not allow the determination of CA I functionality, while the polymorphisms in CA II consist of small deletions that cause a frameshift that changes the C-terminus of the protein, probably affecting its dimerization status, essential for the activity.CO2-independent mutants arise easily in vitro, although with a low frequency ranging from 10−6 to 10−10 depending on the strain. These mutants carry compensatory mutations that produce a full length CA II. At the same time, no change was observed in the sequence coding for CA I. A competitive index assay designed to evaluate the fitness of a CO2-dependent strain compared to its corresponding CO2-independent strain revealed that while there is no significant difference when the bacteria are grown in culture plates, growth in vivo in a mouse model of infection provides a significant advantage to the CO2-dependent strain. This could explain why some Brucella isolates are CO2-dependent in primary isolation. The polymorphism described here also allows the in silico determination of the CO2 requirement status of any Brucella strain.

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