Carbonic Anhydrase

Carbonic anhydrases are enzymes that catalyze the hydration of carbon dioxide and the dehydration of bicarbonate:

CO₂ + H₂O <-----> HCO₃^- + H⁺

These carbonic anhydrase-driven reactions are of great importance in a number of tissues. Examples include:

• Parietal cells in the stomach secrete massive amounts of acid (i.e. hydrogen ions or protons) into the lumen and a corresponding amount of bicarbonate ion into blood.
• Pancreatic duct cells do essentially the opposite, with bicarbonate as their main secretory product.
• Secretion of hydrogen ions by the renal tubules is a critical mechanism for maintaining acid-base and fluid balance.
• Carbon dioxide generated by metabolism in all cells is removed from the body by red blood cells that convert most of it to bicarbonate for transport, then back to carbon dioxide to be exhaled from the lungs.

Carbonic anhydrase isozymes are metalloenzymes consisting of a single polypeptide chain (Mr ~ 29,000) complexed to an atom of zinc. They are incredibly active catalysts, with a turnover rate (kcat) of about 10⁶ reactions per second! Catalytic activity depends on ionization of a group of pK_a 7 and, as you might expect from thinking about when and where the above reactions take place, the hydration reaction depends on the ionized group being in the basic form, and for dehydration in the acidic form.

Carbonic anhydrase inhibitors have been used theraputically. The prototype of such drugs is acetazolamide, which is still sometimes used as a diuretic to treat certain edematous conditions and for therapy of some types of glaucoma. The discovery of this drug is actually an interesting story. It is a member of the sulfonamides, a group of antibacterial agents which, when intially investigated, were shown to induce a metabolic acidosis because they inhibited excretion of hydrogen ion from the kidney.

Send comments to Richard.Bowen@colostate.edu