Abstract
Carbonic anhydrases (CAs) catalyze a reaction fundamental for life: the bidirectional conversion of carbon dioxide (CO2) and water (H2O) into bicarbonate (HCO3−) 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+, CO2, HCO3−, 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 CO2 and other solutes (facilitated diffusion). We also examine urinary acid secretion and the carriage of CO2 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.
Highlights
Carbonic anhydrases (CAs) are ubiquitous metalloenzymes that catalyze one of the most important reactions in life: the interconversion of carbon dioxide (CO2) and water (H2O) to bicarbonate (HCO3−) and protons (H+)
Viewed from the perspective of Region 1, these are: (i) the difference, which establishes the fraction of CO2 consumed to form HCO3−; (ii) CA, which accelerates this consumption of incoming CO2; (iii) the total concentration of the mobile buffer, [TB], which influences the velocity of H+ consumption and the magnitudes of the gradients for B− and HB; and (iv) the difference, which influences the same parameters as (iii)
Since the time of Roughton, we have appreciated that the rapid CA-catalyzed interconversion of CO2 and HCO3− makes it possible for red blood cells (RBCs) to transfer CO2 from the systemic tissues to the alveoli (Figure 9)
Summary
Carbonic anhydrases (CAs) are ubiquitous metalloenzymes that catalyze one of the most important reactions in life: the interconversion of carbon dioxide (CO2) and water (H2O) to bicarbonate (HCO3−) and protons (H+). Because CAs catalyze a reaction that is so fundamental in life, these enzymes affect a wide range of physiological processes in a variety of tissues and cellular compartments These processes include respiration (e.g., transmembrane CO2 movements, O2 exchange in red blood cells via the pH and CO2 Bohr effects), transepithelial fluid secretion, transepithelial acid–base transport (e.g., gastric-acid secretion and pancreatic HCO3− secretion), and acid secretion by osteoclasts in bone resorption [18,19,20,21,22]. Sci. 2019, 20, 3841 include the contents of renal tubules in which urine formation occurs, alveoli in which pulmonary gas exchange occurs, and the entire gastrointestinal tract, including structures that diverge from the intestines (e.g., ducts of the pancreas) Most of these countless compartments, and many of the membranes that surround them, contain CAs. Mathematical modeling holds the potential of helping us understand physiology in areas of the body where processes are currently impossible to measure or difficult to interpret. In this review, we consider how mathematical modeling can provide insights on CA functions in tissues—that is, complex compartments—taking as specific examples renal proximal tubules as well as alveoli and their adjacent capillaries
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