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Carbonic anhydrase plays an important role in respiration by influencing the transport of CO2 in the blood.
Carbonic anhydrase or carbonic anhydride is an enzyme found in red blood cells , gastric mucosa, pancreatic cells, and kidney tubules that catalyze the interconversion of carbon dioxide (CO2) and carbonic acid (H2CO3).
The enzyme also works in the formation of hydrochloric acid by the stomach.
Carbonic anhydrase is a crucial enzyme that operates in animal cells, plant cells, and in the environment to stabilize carbon dioxide concentrations.
Without this enzyme, the conversion of carbon dioxide to bicarbonate , and vice versa, would be extremely slow, and it would be almost impossible to carry out vital processes, such as photosynthesis in plants and people who exhale carbon dioxide during respiration.
Although it performs many beneficial functions, it can also harm the human body, even causing some forms of cancer.
Due to the essential nature of this enzyme, nature has developed the catalytic ability to hydrate dehydrated carbon dioxide / bicarbonate multiple times.
There are three recognized classes of carbonic anhydrase enzymes, alpha, beta, and gamma, which do not have significant sequence identity, and have structurally distinct global folds.
However, despite their structural differences, the active sites of all three classes function with a single zinc atom that is essential for catalysis.
These enzymes are of ancient origin, and appear to have evolved independently of each other, thus providing an excellent example of convergent evolution.
The three classes have different distributions in different organisms: in mammals, all isozymes discovered so far belong to the alpha class; plants mainly produce the beta class; prokaryotes encode all three classes of enzymes, with the beta and gamma classes predominating.
Alpha class carbonic anhydrases
The alpha class of the enzyme has been studied most intensively in mammals, but it also occurs in prokaryotes.
This class is characterized by its high affinity for zinc, where the geometry of the conserved histidine residues favors the binding of zinc and is destabilized by the binding of other metals.
Certain proteins from Vaccinia and other Poxviruses appear to be related to alpha-class carbonic anhydrases, but have lost two of the zinc-binding histidines and other conserved residues; these proteins are involved in cell surface binding and are expressed late in infection.
In mammals, the different isoenzymes vary in their tissue and subcellular distributions and in their susceptibility to inhibitors.
In addition to their participation in the regulation of pH, the reabsorption of bicarbonate and the expiration of carbon dioxide, carbonic anhydrase enzymes have a great variety of functions in mammals, involved in the transport of ammonia, bone resorption, gastric acidity, contraction muscle, gluconeogenesis, kidney acidification and brain development.
For example, carbonic anhydrase functions as an effective attentional gate that controls signal transfer through the neural network, as well as being involved in signal processing and memory storage.
Several isozymes have been implicated in disease states.
Carbonic anhydrase II is required by the kidney for renal acidification, and its absence in an inherited syndrome leads to osteoporosis, renal tubular acidosis, and cerebral calcification.
Two isozymes, carbonic anhydrases IX and XII, are expressed in a variety of malignant tumors and appear to be associated with a poor prognosis, which may be indicative of an aggressive malignant phenotype.
In the brain, carbonic anhydrase dysfunction affects cognition and is associated with mental retardation, Alzheimer’s disease, and aging.
Treatment often involves the use of sulfonamides that inhibit carbonic anhydrase activity, such as for the treatment of glaucoma, epilepsy, gastroduodenal ulcers, and possibly cancer.
Carbonic anhydrase activators could have important uses in the treatment of genetic carbonic anhydrase deficiencies and memory disorders.
Beta-class carbonic anhydrases
The beta class of carbonic anhydrase is found in plants, algae, bacteria, and archaea, and has a much more diverse sequence than the other two classes, with only five residues (three that make up the zinc ligand) that are fully conserved.
Enzymes of the beta class can be divided into seven clades (AG) based on sequence identity, and plant enzymes form two clades representing dicot and monocot plants.
The enzymes within these clades can vary with respect to structure and their response to inhibitors, suggesting different functional mechanisms of action.
Characterization of these enzymes reveals sharp differences between the beta class, which forms dimers, tetramers, hexamers, and octomers, and the alpha and gamma classes, which strictly form monomers and trimers.
Carbonic anhydrase expression in prokaryotes is influenced by growth rate and is expressed at the highest levels in slow-growing, high-density cultures.
Bacteria demand for bicarbonate is 1,000 to 10,000 times greater than uncatalyzed hydration can provide.
Various metabolic processes require either carbon dioxide or bicarbonate.
For example, in E. coli carbonic anhydrase CynT, which is normally repressed, is required during cyanate metabolism to replace the bicarbonate used during bicarbonate-dependent hydrolysis of cyanate by the enzyme cyanase.
In photosynthetic bacteria and plant chloroplasts, carbonic anhydrase is essential for photosynthetic carbon fixation.
Gamma-class carbonic anhydrases
The gamma class may be the oldest form of carbonic anhydrases, having evolved long before the alpha class, to which it is more closely related than the beta class.
The reaction mechanism of the gamma class is similar to that of the alpha class, although the global folds are different and the active site residues differ (apart from those that bind zinc).
Gamma-class carbonic anhydrase is a zinc-bound enzyme that is produced at a high level in E. coli.
There is a possibility that iron and cobalt may substitute for zinc in certain archaea species, as these metals were found to exhibit higher rates of carbon dioxide hydration when substituted in the enzyme than the enzyme bound to zinc.
In humans
Carbon dioxide is produced as waste from the breakdown of sugars and fats and in respiration, so it must be transported through the body to the lungs.
Carbonic anhydrase converts CO2 to carbonic acid as it is transported by blood cells, before it is converted back to carbon dioxide.
Since many bodily functions depend on a certain pH, carbonic anhydrase adjusts the acidity of the chemical environment to prevent damage to the body.
In the plants
Like animal cells, plant cells transport carbon dioxide gas in the form of bicarbonate before converting it back to use in photosynthesis to generate nutrition for the plant.
One difference is that plant cells get carbon dioxide from the air and soil instead of producing it.
The structure can be almost completely different as it has a different amino acid sequence, and uses a zinc metal ion, which interacts with oxygen atoms, also in a different mechanism than humans and animals.
The plant version is found in the liquid part of the cell, while the animal version is found in the cellular mitochondria.
In the ocean
Atmospheric CO2 is absorbed into the ocean by carbonic anhydrase and converted to carbonic acid, which reduces the overall pH of the ocean over time.
As more and more carbon dioxide is released and then removed from the atmosphere, the ocean becomes more acidic and has potential detrimental effects on marine life.
The seaweed then takes dissolved bicarbonate ions and converts them to carbon dioxide.
Is it necessary to stop carbonic anhydrase?
Although the enzyme is beneficial in many cases, it also catalyzes negative impacts on the body, and a special type of medication, called a carbonic anhydrase inhibitor, is available to counteract this activity.
A disease caused by the activity of this enzyme, but not the enzyme itself, is glaucoma , in which the pressure of acidic fluid build-up decreases vision over time.
Some forms of cancer are also accelerated by carbonic anhydrase, including ovarian, breast, colon, and kidney cancers.
