Carbonic Anhydrases: A Superfamily of Ubiquitous Enzymes

Dear Colleagues,

The superfamily of carbonic anhydrases (CAs, EC 4.2.1.1) represents a group of ubiquitous proteins, which catalyze the physiologically important hydration–dehydration reaction of carbon dioxide to bicarbonate and protons: CO₂ + H₂O ⇄ HCO₃^- + H⁺. Their crucial role is to equilibrate the reaction between three essential chemical species: CO₂, bicarbonate (HCO₃⁻), and protons (H⁺). These chemical species are metabolites distributed throughout the fluids of all living organisms and are involved in a large number of physiologic and biosynthetic processes, such as respiration, photosynthesis, gluconeogenesis, lipogenesis, ureagenesis, carboxylation, and biochemical pathways involving pH homeostasis. Furthermore, processes such as secretion of electrolytes, calcification, bone resorption, transport of CO₂ and bicarbonate are assisted by these enzymes. Up to date, the CA superfamily contains seven genetically distinct families (or classes), named α-, β-, γ-, δ-, ζ-, η-, and ɵ-CAs. The α-CAs were discovered in vertebrates, eubacteria, algae, and in the cytoplasm of green plants; the β-CAs were identified in eubacteria, algae, and in the chloroplasts of both mono- and dicotyledons; the γ-CAs were found mainly in Archaea and some eubacteria; the δ- and ζ-CAs are typical of the marine diatoms. The η- and q-CAs were recently discovered. The η-CA was recognized in the genome of the protozoa Plasmodia falciparum, while the q-CA was identified in the lumen of the pyrenoid-penetrating thylakoid of the unicellular alga Phaeodactylum tricornutum. From a phylogenetic viewpoint, the seven classes are an example of convergent evolution, since all classes show low sequence similarity and different folds and structures, while having a common CO₂ hydratase activity, with the catalytically active species represented by a metal hydroxide derivative. These enzymes are also characterized by the presence of a large number of isoforms in most organisms investigated so far.

Drugs interfering with CAs activity have been clinically used for more than 70 years, most of them belonging to the sulfonamide class. Many CA inhibitors (CAI) exist, which could be classified as: inhibitors binding the metal ion (anion, sulfonamides and their bioisosteres, dithiocarbamates, xanthates); inhibitors anchoring to the water molecule/hydroxide ion coordinated to the metal (phenols, polyamines, thioxocoumarins, sulfocumarins); inhibitors occluding the active site entrance (coumarins and their isosteres); inhibitors binding outside of the active site. Inhibition of CAs has many pharmacologic applications, such as against glaucoma, convulsions, obesity, and in the therapy and diagnosis of cancer.  An emerging area is studying CAI as anti-infectives, i.e., as antifungal, antibacterial, and antiprotozoan agents with a novel mechanism of action, since it has been seen that the inhibition of pathogens’ CAs leads to growth impairment or growth defects in the host microorganisms.

The CA superfamily can bind molecules known as “activators” (CAA) through the middle-exit part of the active site. CAA are biogenic amines (histamine, serotonin, and catecholamines), amino acids, oligopeptides, or small proteins. CAAs enhance the catalytic constant (k_cat) of the enzyme, with no effect on the K_M. CAAs may have pharmacologic applications in the therapy of memory-related disorders, neurodegenerative diseases (Alzheimer’s disease), and genetic CA-deficiency syndromes.

Moreover, since most bacteria are incredibly abundant in environments that are hostile to all other forms of life, CAs from extremophiles are exciting candidates for industrial and medical applications, such as the post-combustion carbon-capture process and the realization of artificial lungs and biosensors. The ancient CAs can be considered as a biotechnological multitasking superfamily because the various CA classes are potentially able to both fight the increase of CO₂ in the atmosphere produced by anthropogenic activities and ameliorate human health because of their biomedical applications.

This Special Issue is dedicated to all the important advances in the field of carbonic anhydrases, their inhibitors and activators, and their potential use in medical and biotechnological applications, since the CA superfamily represents a very promising target for the scientific community for its ubiquity and crucial role in many physiologic and pathologic processes.

Original papers, reviews articles, and perspectives from experts in the field are welcome.

Prof. Dr. Clemente Capasso
Guest Editor

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