Role of Carbonic Anhydrases and Inhibitors in Acid–Base Physiology: Insights from Mathematical Modeling

Abstract

Carbonic anhydrases (CAs) catalyze a reaction fundamental for life: the bidirectional conversion of carbon dioxide (CO ₂) and water (H ₂O) into bicarbonate (HCO ₃ ⁻) and protons (H ⁺). These enzymes impact numerous physiological processes that occur within and across the many compartments in the body. Within compartments, CAs promote rapid H ⁺ buffering and thus the stability of pH-sensitive processes. Between compartments, CAs promote movements of H ⁺, CO ₂, HCO ₃ ⁻, and related species. This traffic is central to respiration, digestion, and whole-body/cellular pH regulation. Here, we focus on the role of mathematical modeling in understanding how CA enhances buffering as well as gradients that drive fluxes of CO ₂ and other solutes (facilitated diffusion). We also examine urinary acid secretion and the carriage of CO ₂ by the respiratory system. We propose that the broad physiological impact of CAs stem from three fundamental actions: promoting H ⁺ buffering, enhancing H ⁺ exchange between buffer systems, and facilitating diffusion. Mathematical modeling can be a powerful tool for: (1) clarifying the complex interdependencies among reaction, diffusion, and protein-mediated components of physiological processes; (2) formulating hypotheses and making predictions to be tested in wet-lab experiments; and (3) inferring data that are impossible to measure.