Carbonic anhydrase versatility: from pH regulation to CO2 sensing and metabolism

Abstract

While the carbonic anhydrase (CA, EC 4.2.1.1) superfamily of enzymes has been described primarily as involved only in pH regulation for decades, it also has many other important functions. CO2, bicarbonate, and protons, the physiological substrates of CA, are indeed the main buffering system in organisms belonging to all life kingdoms; however, in the last period, relevant progress has been made in the direction of elucidating the involvement of the eight genetically distinct CA families in chemical sensing, metabolism, and several other crucial physiological processes. Interference with CA activity, both by inhibiting and activating these enzymes, has thus led to novel applications for CA inhibitors and activators in the field of innovative biomedicine and environment and health. In this perspective article, I will discuss the recent advances which have allowed for a deeper understanding of the biochemistry of these versatile enzymes and various applications of their modulators of activity.

Novel Carbonic Anhydrase Inhibitors with Dual-Tail Core Sulfonamide Show Potent and Lasting Effects for Glaucoma Therapy

“…4.2.1.1) present in the human body. − Detailed investigation of the active-site composition and architecture of most hCAs has revealed the middle and the rim parts of the active-site cavity as the most variable region among the 12 catalytically active hCAs (hCAs VIII, X, and XI are catalytically inactive). The most fruitful strategy for designing selective CAIs is the tail approach, involving a zinc-binding group scaffold decorated with various “tails” conferring improved physicochemical properties such as increased water solubility or tuning inhibition profiles against target isoforms. − This approach was employed to include two or three tails of diverse nature onto aromatic sulfonamide scaffolds − at a nitrogen atom branching point, allowing distinct binding to the hydrophobic and hydrophilic sections of the hCAs active site. However, the simple hydrophobic/hydrophilic division of the isoforms binding pocket may no longer be sufficient due to a plethora of accessory subpockets differentiating the various CA isoforms.…”

Pharmacological Activation of SIRT3 Modulates the Response of Cancer Cells to Acidic pH

“…In this context, cancer cells can take advantage of the differential expression of several proteins involved in the homeostasis of the intracellular pH, such as carbonic anhydrase IX and carbonic anhydrase XII for their growth and malignant progression. Carbonic anhydrases are zinc enzymes that consist of five distinct families: alpha, beta, gamma, delta, and epsilon [12] that act as catalysts for the hydration of carbon dioxide to bicarbonate, regulating in this way the acid-base balance in cells [13]. Furthermore, these enzymes are related to CO 2 and HCO 3− transport, bone resorption, ureagenesis, gluconeogenesis, and lipogenesis [14,15].…”