Dear Colleagues,

Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes present in all life kingdoms, as they equilibrate the reaction between three simple but essential chemical species: CO₂, bicarbonate, and protons. Discovered more than 80 year ago, in 1933, these enzymes were extensively investigated due to the biomedical application of their inhibitors, but also because they are an extraordinary example of convergent evolution, with seven genetically-distinct CA families that evolved independently in Bacteria, Archaea, and Eukarya. CAs are also among the most efficient enzymes known in nature, due to the fact that the uncatalyzed CO₂ hydration is a very slow process, and the physiologic demands for its conversion to ionic, soluble species is very high. Inhibition of the CAs has pharmacologic applications in many fields, such as antiglaucoma, anticonvulsant, antiobesity, and anticancer agents/diagnostic tools, but is also emerging for designing anti-infectives, i.e., antifungal, antibacterial and antiprotozoan agents with a novel mechanism of action. Mitochondrial CAs are implicated in de novo lipogenesis allowing the ability to consider selective inhibitors of such enzymes as useful for the development of new antiobesity drugs. As the tumor metabolism is diverse form that of normal cells, ultimately, relevant contributions on the role of the tumor-associated isoforms CA IX and XII in these phenomena have been published, and the two isoforms have been validated as novel antitumor/antimetastatic drug targets, with antibodies and small molecule inhibitors in various stages of clinical development. CAs also play a crucial role in other metabolic processes connected with urea biosynthesis, gluconeogenesis, etc., since many carboxylation reactions catalyzed by acetyl-coenzyme A carboxylase or pyruvate carboxylase use bicarbonate not CO₂ as a substrate. In organisms other than mammals, e.g., plants, algae, and cyanobacteria, CAs are involved in photosynthesis, whereas, in many parasites (fungi, protozoa), they are involved in the de novo synthesis of important metabolites (lipids, nucleic acids, etc.). The metabolic effects related to interference with CA activity were, however, scarcely investigated. The present Special Issue of Metabolites has the goal of filling this gap, by presenting the latest developments in the field of CAs and their role in metabolism.

Prof. Dr. Claudiu T. Supuran
Guest Editor

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• carbonic anhydrase
• inhibitors
• activators
• metabolism