Carbonic anhydrase I and other non-tumor-associated isoforms (CA1, CA2, CA3, CA4, CA5A, CA5B, CA6, CA7, CA8, CA10, CA11, CA13, CA14)

Carbonic anhydrases (CAs) are a family of zinc-containing metalloenzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate and a proton [1.2.2, 1.5.1]. In humans, the non-tumor-associated isoforms—including cytosolic (CA I, II, III, VII, XIII), mitochondrial (CA VA, VB), and membrane-bound (CA IV, XIV) forms—are essential for systemic pH homeostasis, respiration, and fluid balance [1.2.2, 1.5.2]. CA II is the most widely distributed and catalytically active isoform, playing a key role in the production of aqueous humor in the eye and bicarbonate reabsorption in the kidneys [1.2.3, 1.3.3]. Therapeutic inhibition of these isoforms by drugs like acetazolamide and dorzolamide is used to treat glaucoma, altitude sickness, and certain types of epilepsy [1.3.3, 1.3.5]. However, because these isoforms are ubiquitously expressed in normal tissues, their non-selective inhibition often leads to systemic side effects such as metabolic acidosis, hypokalemia, and paresthesia [1.1.1, 1.1.2]. In modern oncology, these housekeeping isoforms are frequently considered off-targets to be avoided when designing selective inhibitors for the tumor-associated isoforms CA IX and CA XII [1.4.1, 1.4.3].

Other names

Carbonate dehydrataseCarbonic dehydrataseCytosolic carbonic anhydrasesMitochondrial carbonic anhydrasesHousekeeping carbonic anhydrase isoformsCA-ICA-IICA-IVCA-VA/B

Reversible inhibition of the zinc-containing active site of carbonic anhydrase enzymes, which prevents the hydration of carbon dioxide to bicarbonate and protons, thereby altering pH and fluid dynamics in specific tissues [1.2.3, 1.3.3, 1.5.1].