Carbonic anhydrase

Carbonic anhydrase is an enzyme found in copious quantities in algae, bacteria, plants, and mammalian tissues. It occurs in three distinct types, known as classes, which include alpha, beta, and gamma carbonic anhydrase. These classes are collectively known as carbonic anhydrases, and they all perform related biological functions despite major structural and sequential differences: facilitating the rapid hydration of carbon dioxide into bicarbonate ions, carbonic acid, and protons.

In humans, carbonic anhydrase helps regulate pH levels and fluid balance and plays a role in the formation of hydrochloric acid in the stomach, which breaks down food during the digestion process. It also supports the transportation of carbon dioxide in the bloodstream, thus aiding respiration.

Since carbonic anhydrase was first identified in the early 1930s, scientists have developed two classes of medications that impact its effects on the body. These medications offer multiple known and potential therapeutic benefits. They are carbonic anhydrase inhibitors (CAIs) and carbonic anhydrase activators (CAAs).

Background

Carbonic anhydrase was formally identified as the result of a concerted scientific effort to find the compound responsible for converting carbon dioxide into bicarbonate in the human bloodstream. Histories of the search for this enzyme note that two research teams—one based at Cambridge University in the United Kingdom and the other at the University of Pennsylvania in the United States—isolated carbonic anhydrase at virtually the same time in 1932–1933.

In humans and other mammals, bicarbonate ions play an essential role in controlling bodily pH levels. The pH scale is a feature of chemistry, which specifies the relative acidity or alkalinity of an aqueous (water-containing) solution. In regulating pH levels, carbonic anhydrase helps prevent respiratory or metabolic acidosis and alkalosis. Acidosis occurs when the body’s acid levels are too high, potentially resulting in extreme fatigue, somnolence, disorientation, and severe headache. Left untreated, it can progress to coma or death. Alkalosis is the functional opposite: It results from disproportionately high alkalinity and can cause symptoms including muscle cramps, involuntary muscle movements (twitching), tingling sensations in the extremities and lips, and extreme irritability. Carbonic acid, which is produced when carbonic anhydrase interacts with carbon dioxide in the bloodstream, also assists in the regulation of bodily pH levels by acting as a stabilizing maintenance buffer. The protons released by the biological action of carbonic anhydrase ionize bicarbonate, facilitating its pH regulatory function.

Carbonic anhydrase additionally helps mammals manage their fluid balance, a term used to describe the correct equilibrium of fluid input and output. Fluid balance is critical to many metabolic processes and also helps the body maintain the correct proportions of nutrients, oxygen levels, and water.

Hydrochloric acid is created by the parietal cells found in the stomach lining. Carbonic anhydrase is also involved in its production. It activates after parietal cell cytoplasm mixes with water and carbon dioxide to produce carbonic acid, which carbonic anhydrase then converts into ionized hydrogen and bicarbonate to yield hydrochloric acid. Hydrochloric acid breaks down ingested food in the stomach, facilitating its digestion and the subsequent extraction of nutrients.

The final major role of carbonic anhydrase in mammals covers respiration, specifically the transportation of carbon dioxide in the bloodstream. Carbon dioxide regulates the body’s natural respiratory drive, which controls breathing, and also impacts hemoglobin’s affinity for oxygen, helping deliver oxygen to tissues and organs more efficiently.

Overview

The alpha class of carbonic anhydrase is found in mammals, where it performs functions related to the interconversion of carbon dioxide and water into bicarbonate ions, carbonic acid, and protons. A total of sixteen alpha isoforms have been identified, each of which maintains a specific regulatory function. Beta-class carbonic anhydrase enzymes are found in plants, where they provide essential support for photosynthesis processes and regulate stomatal closure functions in leaves, which occur in response to cold temperatures and droughts. The enzyme’s gamma class is found in bacteria and algae (a subtype of bacteria), but its function in microorganisms is not well understood relative to mammals and plants. Beyond concentrating, carbon dioxide stores and prevents carbon dioxide depletion as a means of regulating certain biological processes. Researchers have yet to identify the precise set of purposes specific to gamma-class carbonic anhydrase.

In humans, medications that inhibit or promote the function of carbonic anhydrase enzymes have a significant and growing list of known and potential applications. Carbonic anhydrase inhibitors (CAIs) are used to treat glaucoma, an eye condition that results from fluid imbalances that impact optic nerves. The targeted application of CAIs in the eye impedes the effects of this fluid imbalance, reducing the buildup of excess fluid and relieving the optic nerve pressure that causes glaucoma symptoms. CAIs also have therapeutic applications as diuretics, a class of substances that enhance the kidney’s ability to excrete water by promoting urination. Their effects on fluid balance can help treat and manage conditions such as peptic ulcers, heart failure, liver failure, kidney stones and other kidney disorders, and edema (tissue swelling). Recent studies suggest that CAIs may have uses in treating obesity and also display properties that inhibit tumor growth, making them an emerging focus of cancer therapy research. However, current generations of CAIs have multiple side effects, including diarrhea, increased frequency of urination, nausea or vomiting, loss of appetite, weight loss, fatigue and weakness, and tingling, burning, or numbness in the mouth, lips, tongue, appendages, and digits. Scientists are working to develop new CAIs capable of more selective and targeted action, which could theoretically lead to effective treatments with fewer side effects.

Medicines that promote or enhance the function of carbonic anhydrase are known as carbonic anhydrase activators (CAAs). These drugs bind at the enzymes’ active sites, allowing them to expedite the rate-determining stage of carbonic anhydrase’s catalytic cycle. Scientists have developed CAAs from multiple compounds, using kinetic quantification and X-ray-powered crystallography to characterize them. Researchers believe the derivative substances that result from CAA development could have applications in memory enhancement and thus hold promise as a potential breakthrough treatment for conditions including dementia and Alzheimer’s disease.

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