α-carbonic anhydrases

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Α-carbonic anhydrases
Α-carbonic anhydrases
Ribbon model of the CA2, zinc in the center, according to PDB  1MOO

Existing structural data : 1azm , 2cab

Cofactor zinc
Identifier
Gene name (s) CA1 , CA2 , CA3 , CA4 , CA5A , CA5B , CA6 , CA7 , CA9 , CA12 , CA13 , CA14
Enzyme classification
EC, category 4.2.1.1 lyase
Response type (De) hydration
Substrate Carbon dioxide + water
Products Hydrogen carbonate + hydrogen ion

The α-carbonic anhydrases (abbreviation α-CA ) are enzymes that catalyze the hydration of carbon dioxide (CO 2 ) to carbonic acid (H 2 CO 3 ) and vice versa . They are found in animals , plants , bacteria and green algae . Carbon dioxide can be transported more easily in the body in the form of hydrogen carbonate , so a reversible conversion makes sense. In addition, the reaction regulates the pH of the blood plasma and stomach acid . Eleven paralogous isoforms of the enzyme are known in animals , as well as four others without enzyme activity .

The eleven isoforms are divided into:

The enzyme was discovered in 1932 at about the same time by William Christopher Stadie (1886-1959) and Helen O'Brien in the USA and Norman Urquhart Meldrum (1907-1933) and Francis John Worsley Roughton (1899-1972) in Great Britain.

Catalyzed equilibrium

Carbon dioxide is hydrated to carbonic acid and vice versa. Carbonic acid dissociates in aqueous solutions to hydrogen carbonate and a proton:

Carbonic anhydrase is an enzyme that catalyzes very quickly: it can hydrate up to 10 6 molecules of carbon dioxide per second and accelerates the reaction 10 7 times. Their k cat value is 1,000,000 per second. The Michaelis constant K m is in this case 0.012 M .

For the reverse reaction, k cat value = 400,000 per second and K m = 0.026 M.

construction

CA was discovered as the first enzyme that requires a metal as a cofactor in its active center . The protein contains a zinc ion as a cofactor , which determines the actual catalytic activity of the enzyme. It is bound to three imidazole residues of the amino acid histidine . The fourth coordination site is of a hydroxo - ligand occupied.

In rare cases cadmium is bound as a cofactor in the active center of the enzyme (e.g. in Thalassioria weissflogii ).

Functions in the organism

breathing

When breathing , carbon dioxide (CO 2 ) is produced as a metabolic end product. Carbon dioxide is released into the blood and has to be transported to the lungs (in complex organisms). In aqueous solutions, such as. B. in the blood or in the cytoplasm , however, CO 2 reacts with water to form hydrogen carbonate. Although these reactions take place spontaneously even without a catalyst, carbonic anhydrases are found in almost all organisms. Whether CO 2 is absorbed or released depends on the pH value of the cell plasma. In the animal organism, CA is found in erythrocytes (red blood cells), where it is involved in the transport of carbon dioxide. Carbon dioxide diffuses in the capillaries into the erythrocytes, where it is converted into carbonic acid with water and finally reacts to hydrogen carbonate ions and protons. The hydrogen carbonate is exchanged for chloride from the plasma in the so-called hamburger shift in order to preserve electrical neutrality.

eye

In the ciliary body of the eye , the carbonic anhydrase CA_IV is a key enzyme for the production of aqueous humor . Excessive production or impaired drainage of the aqueous humor is regarded as one of the pathogenetic bases of glaucoma . The drug-based inhibition of carbonic anhydrase with active ingredients such as dorzolamide or acetazolamide is therefore a tried and tested option in glaucoma therapy today. Mutations in the CA4 gene can lead to a form of retinitis pigmentosa (RP17).

Kidney function

Among other things, CA is crucial for the regulation of the acid - base balance by the kidneys . For this regulation it is important that around 90 percent of the hydrogen carbonate filtered in the primary urine is reabsorbed. Otherwise acidosis would develop . Without the CA, hydrogen carbonate reabsorption from the primary urine would not work. The mechanism: Protons (H + ) are excreted from the proximal tubular cells of the kidney from intracellular to extracellular (into the lumen of the renal tubule ) in exchange for Na + . Due to the action of CA, filtered hydrogen carbonate reacts with protons to form carbonic acid , which then turns into water and carbon dioxide. In contrast to hydrogen carbonate, carbon dioxide can easily pass through the cell membrane from the tubular lumen (primary urine) into the tubular cell. There the intracellular CA catalyzes the reverse reaction. Protons and hydrogen carbonate are formed from the carbon dioxide in the tubular cell. The hydrogen carbonate is released from the cell into the blood, the proton is available again for the same reaction. Carbonic anhydrase can be inhibited by the drug acetazolamide . The inhibition leads to bicarbonate loss in the urine and thus to acidosis . This can be used to treat metabolic alkalosis .

Gastric function

It is the key enzyme for the production of stomach acid. Carbonic anhydrase is located in the parietal cells of the gastric epithelium. Protons are transported to the apical membrane of the epithelial cell by a proton potassium ATPase (V-ATPase) into the gastric lumen. In the process, potassium is transported into the cell in exchange. In the cell, the CA produces protons and bicarbonate from water and carbon dioxide. On the basolateral membrane, bicarbonate is then brought from the cell into the blood vessel system in exchange for chloride. The chloride reaches the apical membrane through a chloride channel into the gastric lumen and forms gastric acid there with the protons.

The V-ATPase and carbonic anhydrase in the parietal cells of the stomach are suppressed by proton pump inhibitors such. B. omeprazole or pantoprazole inhibited.

pancreas

In the pancreas , carbonic anhydrase is used for hydrogen carbonate secretion.

Medication side effects

The sulfonamides , which are rarely used today , also inhibit carbonic anhydrase.

plants

In plants, carbon dioxide is required for photosynthesis and is absorbed through the stomata of the leaves. This finally gets into the thylakoids and is converted into glucose in the course of photosynthesis . Plants with Crassulacean acid metabolism and C 4 metabolism need carbonic anhydrases so that the carbon dioxide dissolved in the cytosol is converted more quickly into hydrogen carbonate (HCO 3 - ). HCO 3 - is used as a substrate by another enzyme and serves as the first, preliminary carbon dioxide fixation.

More functions

In freshwater fish, carbonic anhydrase enables salt resorption in specialized cells of the gill epithelium and thus serves for osmoregulation .

Reaction mechanism of carbonic anhydrase

Carbonanhyratase Mechanism.png
  • A molecule of water can attach to the zinc (II) ion, which is coordinated to the three nitrogen donor centers of the imidazole ring of the three histidine amino acids. As a result of the coordination to the zinc ion, the pKa value of the water molecule is lowered - so far that a proton can be split off even at the physiological pH value found in the vicinity of carbonic anhydrase (1) .
The negative charge remaining on the oxygen is mesomeric stabilized because it can be transferred to the zinc (II) ion.
  • In a next step (2) , a molecule of carbon dioxide is deposited in the active center of the enzyme in such a way that it can react with the hydroxide ion.
  • The free electron pairs on the oxygen of the OH group nucleophilically attack the carbon dioxide molecule, so that hydrogen carbonate ion is formed (3)
  • Finally, a water molecule can be bound to the active center, so that the hydrogen carbonate ion is released (4) .

With this regeneration of the active center, a new cycle can begin.

literature

  • Jeremy M. Berg, John L. Tymoczko, Lubert Stryer: Biochemistry. 5th edition. Spectrum Akademischer Verlag, Heidelberg 2003, ISBN 3-8274-1303-6 .

Individual evidence

  1. Swiss Institute of Bioinformatics (SIB): PROSITE documentation PDOC00146. Accessed in 2011 .
  2. ^ Interpro: Carbonic anhydrases
  3. Derek Lowe, Das Chemiebuch, Librero 2017, p. 288
  4. ^ Reginald Garrett, Charles M. Grisham: Biochemistry. (International Student Edition). 4th edition. Cengage Learning Services, 2009, ISBN 978-0-495-11464-2 , p. 394.
  5. ^ TW Lane, FM Morel: A biological function for cadmium in marine diatoms . In: Proc. Natl. Acad. Sci. USA . 97, No. 9, April 2000, pp. 4627-4631. doi : 10.1073 / pnas.090091397 . PMID 10781068 . PMC 18283 (free full text).
  6. Norbert Pfeiffer: Glaucoma. Thieme Verlag, Stuttgart 2001, pp. 87-99.
  7. I. Puscas, M. Coltau, M. Baican, G. Domuta: Omeprazole has a dual mechanism of action: it inhibits both H (+) K (+) ATPase and gastric mucosa carbonic anhydrase enzyme in humans (in vitro and in vivo experiments) . In: J. Pharmacol. Exp. Ther. . 290, No. 2, August 1999, pp. 530-534. PMID 10411559 .

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