| Carbonic anhydrase 3 (CA3) is a cytosolic α‑carbonic anhydrase isozyme encoded by the CA3 gene and enriched in mesoderm-derived tissues, particularly skeletal muscle, liver and adipocytes, where it catalyzes the reversible hydration of carbon dioxide but also performs specialized roles in pH regulation, oxidative stress handling and tissue remodeling. The protein shares the conserved zinc metalloenzyme fold of α‑CAs, with a zinc ion coordinated in the active site and residues forming a proton-transfer network, yet it displays markedly lower catalytic activity than ubiquitous isoforms such as CA II, in part because a phenylalanine at position 198 creates steric constriction near the zinc-bound solvent and alters interactions needed for efficient proton transfer. Substitution of Phe198 with leucine increases activity toward CO2 hydration, and exogenous imidazole-containing proton donors can rescue catalytic efficiency, indicating that CA3’s active-site architecture is tuned away from maximal hydration turnover and that proton transfer sites closer to the zinc are critical modulators of its enzymatic profile. Beyond catalysis, CA3 contains surface-exposed cysteine residues that undergo glutathionylation and other redox modifications under oxidative stress, and CA3 overexpression modulates redox-sensitive signaling and protects muscle cells from stress, suggesting a role as a redox sensor and buffer rather than solely as a CO2 hydrase. CA3 is a mesodermal marker: its mRNA is present in primitive mesoderm before myogenesis and later defines subsets of mesodermal cell types, including slow-twitch skeletal muscle fibers, notochord and adipocytes, with expression patterns consistent with regulation by myogenic determination factors and roles in facilitated CO2 diffusion and processes involving proton and bicarbonate transport during muscle function. In mouse skeletal muscle, CA3 contributes to fatigue resistance by supporting intracellular pH homeostasis; muscles lacking CA3 display lower intracellular pH under fatigue conditions, and transgenic expression in cardiomyocytes enhances tolerance to acidosis, maintaining ventricular pressure, systolic and diastolic velocities, and stroke volume under low pH stress, supporting a broader role for CA3 in muscle and cardiac adaptation to metabolic acidosis. In the context of cardiac injury, CA3 is required for appropriate fibrosis and repair after myocardial infarction via regulation of Smad7–Smad2/3 signaling in cardiac fibroblasts, with CA3 deficiency leading to impaired fibrotic responses and adverse remodeling, linking its CO2/pH regulatory function and redox activity to TGF‑β/Smad pathway control during tissue repair. In oral squamous cell carcinoma, CA3 overexpression promotes cell migration and epithelial–mesenchymal transition, with associated changes in E‑cadherin and EMT markers. |
