What Are Carbonic Anhydrase Inhibitors?

The first zincase discovered in 1940 was also the most important zincase. More than 80 zinc enzymes have been reported, ranking first in all types of metals. It is distributed in human renal tubular epithelial cells, gastric mucosa, pancreas, red blood cells, central nervous cells, and ciliary body epithelial cells.

Carbonic anhydrase

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The first zincase discovered in 1940 was also the most important zincase. More than 80 zinc enzymes have been reported, ranking first in all types of metals. It is distributed in human renal tubular epithelial cells, gastric mucosa, pancreas, red blood cells, central nervous cells, and ciliary body epithelial cells.

To date, at least 8 isoenzymes have been found in mammals. Their structures, distributions and properties are different. Most of them are related to the secretion of H- and bicarbonate from various epithelial cells. They catalyze the CO2 hydration reaction and certain lipids. 3. Hydration reactions of aldehydes, participate in a variety of ion exchange, and maintain the steady state of the body environment.

Chinese name

Carbonic anhydrase

Foreign name

Carbonic Anhydrase (CA)

Category

Carbonic Anhydrase (CA) is a zinc-containing metal enzyme. So far, at least 8 isoenzymes have been found in mammals. They have different structures, distributions, and properties, and they secrete H from various epithelial cells. -It is related to bicarbonate. It catalyzes the CO2 hydration reaction and some lipids and aldehydes hydration reaction, participates in a variety of ion exchanges, and maintains a stable body environment.

CA is widely distributed. CA and were isolated from red blood cells for the first time. CA was first found in skeletal muscle cytoplasm. All three were 29kD cytosolic enzymes in humans; membrane-associated enzyme CAIV has been purified from calf lung, human kidney, and rat lung; CAIV (29kD) was found in mitochondria; CA (42kD) purified from salivary glands by Murakmi in 1987 is a secreted enzyme; a new CA-associated gene CA recently discovered in salivary glands and Purkinje cells in the cerebellum is also an intracellular enzyme. Gastrointestinal tract, distal renal tubules and manifolds, adrenal spherule cells, epididymal stenosis cells, distal head and proximal tail epithelial cells, fast-contracting skeletal muscle cells, cerebral choroid plexus epithelial cells, marrow CA is present in phospholipid-forming cells and eye ciliary processes, cornea, and retinal cells; CA is also distributed in the apical membrane, basal plasma membrane surface of the epithelial cells in the gastrointestinal tract, distal tubules, and thick ascending branches of the myelin. Epithelial microvilli, epidermis, parietal membrane, subcutaneous smooth muscle layer, cerebral capillary epithelial cell cavity surface, myocardium, ocular capillary bed, choroidal vascular layer, skeletal muscle, liver, lacrimal gland, etc.

CA, , and II all have a zinc-containing monomer in the structure, but CA and exist as monomers, and CA exists as a disulfide-linked dimer. The three-dimensional structure of human CA and CA is diffracted by x-ray crystals. The graph test is almost the same. The amino acid sequences of the two are about 60% homologous. CA has 260 amino acids, which is anchored to the plasma membrane by phosphoryl inositol glycerol bonds; it can resist SDS dissociation, and has 30 to 36% homology with CA in cytoplasm, and its structure varies with different species. Human lung CAIV (36kD) lacks an N-linked oligosaccharide chain, while mouse lung CAIV (39kD) and other mammals have this chain. CAVI carries two oligosaccharide chains that are complex.

Carbonic anhydrase is one of the main protein components of red blood cells, and its status in red blood cells is second only to hemoglobin. Contains a coiled protein chain and a zinc (II) ion. The molecular weight is about 30,000. Zinc ions are in the coordination environment of deformed tetrahedron. The most important reaction catalyzed is the reversible hydration of carbon dioxide (carbonic anhydride), which makes it proceed quickly under physiological pH conditions (pH 7). In order to catalyze the reaction of CO2 (g) + H2O H2CO3, the factor that the enzyme accelerates carbon dioxide hydration is about 10 ^ 7. These reactions are extremely important for breathing.

Carbonic anhydrase is a zinc protein (animal origin) and is found in red blood cells of vertebrates and various tissues of many animals and leaves of plants. It has a rapid conversion of carbonate and bicarbonate ions in red blood cells. It has an effect on the secretion of hydrochloric acid in the stomach, and generally has the effect of adjusting the pH of body fluids. It is also thought to be related to photosynthesis of plants.

1. Maintain acid-base balance in blood and other tissues.

2. Help the body's tissues to remove carbon dioxide.

3. Ensure that enzymes that use CO2 and HCO3- as catalytic substrates maintain a moderate substrate concentration.

The main inhibitors of CA are sulfonamides. The inhibitory effect of surfactants such as DDT on CA may be related to facilitation of group dissociation. Different CAs have different sensitivities to sulfa inhibitors. When studying the binding force between CA198 variants and inhibitors, it was found that the charge, hydrophobicity and drug affinity of the side chain of residue 198 are related to the phenylalanine side chain at position CA198. The phenyl on the stuffing hydrophobic "bag", resulting in low catalysis and low sensitivity. In addition, surfactants can inhibit CA from forming polymers at high concentrations, thereby reducing the competitive inhibition of CA renaturation protein formation by polymers, promoting the start-up phase of protein refolding, and ultimately expanding the range of CA activity concentrations.

Research by Chen et al. (1991) showed that estradiol E2 has a certain effect on CA, and the effect varies with tissues: CA on rat duodenal mucosa can reduce activity under the influence of E, while CA in rat kidney Although there is a downward trend under the action of E2, there is no significant difference. In the same year, Pirkko et al.'S experiments found that the levels of CA protein and mRNA in the lateral side of the prostate of castrated rats were decreased, and the dorsal side was reversed. The changes were reversible after treatment with testosterone; the lateral changes were reversed after treatment with no effect on the dorsal side. ; The treatment of uncastrated rats showed that the level of dorsal CA was elevated without the change of lateral CA. The basic structure, general distribution, and basic physiological functions of carbonic anhydrase were initially recognized by humans in the 1960s. The recent researches focus on the exploration of the relationship between CA structure and function. The understanding of CA structure, function and distribution will be further concrete.

CA catalyzes CO2 and H2O to generate HCO3 in ciliary body epithelial cells, which are secreted into the aqueous humor through the luminal membrane. Since the liquid in the aqueous humor must remain electrically neutral, Na + secretion increases to the aqueous humor and at the same time drives Cl- to the aqueous humor. , So that the humorous water forms a high osmotic pressure, and thus promote the flow of H2O to the humorous water; maintain the humorous water balance and the normal pH value. In patients with glaucoma, intraocular pressure increases due to poor return of aqueous humor. CA inhibitors (CAIs) can inhibit the activity of CA, reduce the production of HCO3 and reduce intraocular pressure. It is mainly used to treat glaucoma and reduce intraocular pressure in clinic.

CAIs, as drugs for the treatment of glaucoma, are divided into three generations according to their development process and pharmacological effects: the first generation of oral CAIs, the second generation of topical CAIs, and the third generation of long-acting non-stimulating CAIs.

The first generation of oral CAIs acetazolamide was the first oral treatment for glaucoma. Due to its low fat solubility and less intraocular distribution, a larger dose (1000-2000 mg) is required to be effective, so the concentration of white medicine is high; The medication is prone to hypokalemia and metabolic acidosis (hyperchloremic acidosis), so the clinical application is gradually decreasing. Inhibition of CA by non-ocular tissues with oral CAIs can cause severe systemic adverse reactions. Polyuria, gastrointestinal discomfort and fatigue occurred in the early stage of medication, some patients developed kidney stones, and a few cases of agranulocytosis.

The second generation of topical CAIs was synthesized in the early 1990s. It has strong selective inhibition of CA activity and high water solubility and fat solubility, which is convenient for the preparation of eye drops and can penetrate the cornea to make the drug reach an effective drug concentration in the ciliary body. In 1995, dozolid eye drops were marketed in Germany without systemic adverse reactions. However, because the pH of the aqueous solution is 5.5, it is slightly irritating to the conjunctiva. Brinzolomide was launched in 1998, and its water solubility is poor, so it is formulated as a suspension. Its inhibitory effect on CA is stronger than dolzolamide, and it is less irritating to the eyes. And the action time is short, can only be maintained for 2-3 hours, requiring multiple doses per day to maintain effective drug concentration.

The third-generation long-acting non-stimulating topical CAIs After the scientists modified the structure of the CAIs compound, they obtained two powerful CAIs with a long action time (5-6 hours), but the pH value of the solution was formulated as a drop solution. Around 5.5, it still irritates the eyes. In order to solve the pH problem, the researchers changed the bis carboxyl group at the tail of the compound to an amino acid, so that the pH of the drip solution was between 6.5 and 7, and the eye irritation was basically eliminated. So far, the embryonic form of the third generation of CAIs has basically formed.

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