Carbonic anhydrase action

The most powerful and specific inhibitors of carbonic anhydrase are certain aromatic or heterocyclic sulfonamides containing an unsubstituted R—SO2NH2 group (28). Inhibitors of this type are of great value in biochemical and physiological studies of carbonic anhydrase action and have found some therapeutic applications (28). As the various factors involved in their interaction with the enzyme have been extensively discussed at a recent symposium (51, 52) they will only be briefly mentioned here. 

Carbonic anhydrase is an enzyme that produces free hydrogen ions, which are then exchanged for sodium ions in the kidney tubules. Carbonic anhydrase inhibitors inhibit the action of the enzyme carbonic anhydrase This effect results in the excretion of sodium, potassium, bicarbonate, and water. Carbonic anhydrase inhibitors also decrease the production of aqueous humor in the eye, which in turn decreases intraocular pressure (IOP) (ie, the pressure within the eye). 

Figure 48-12. Schematic illustration of some aspects of the role of the osteoclast in bone resorption. Lysosomal enzymes and hydrogen ions are released into the confined microenvironment created by the attachment between bone matrix and the peripheral clear zone of the osteoclast. The acidification of this confined space facilitates the dissolution of calcium phosphate from bone and is the optimal pH for the activity of lysosomal hydrolases. Bone matrix is thus removed, and the products of bone resorption are taken up into the cytoplasm of the osteoclast, probably digested further, and transferred into capillaries. The chemical equation shown in the figure refers to the action of carbonic anhydrase II, described in the text. (Reproduced, with permission, from Jun-queira LC, Carneiro J BasicHistology. Text Atlas, 10th ed. McGraw-Hill, 2003.)...

The system illustrated by (272) forms the basis of a model for the zinc-containing metalloenzyme, carbonic anhydrase (Tabushi Kuroda, 1984). It contains Zn(n) bound to imidazole groups at the end of a hydrophobic pocket, as well as basic (amine) groups which are favourably placed to interact with a substrate carbon dioxide molecule. These are both features for the natural enzyme whose function is to catalyze the reversible hydration of carbon dioxide. The synthetic system is able to mimic the action of the enzyme (although side reactions also occur). Nevertheless, the formation of bicarbonate is still many orders of magnitude slower than occurs for the enzyme. 

The answer is c. (Hardman, pp 6917 693 J Acetazolamide is a carbonic anhydrase inhibitor with its primary site of action at the proximal tubule of the nephron. Acetazolamide promotes a urinary excretion of Na, K, and bicarbonate There is a decrease in loss of Cl ions The increased excretion of bicarbonate makes the urine alkaline and may produce metabolic acidosis as a consequence of the loss of bicarbonate from the blood. None of the other diuretic drugs promote a reduction in the excretion of the Cl ion... 

In turn, the concentration of C02 in the atmosphere depends on the mass of the biosphere and its rate of decay after death, and on the carbonic-anhydrase concentrations in the sea surface. In future predictions of the rate of increase of C02 partial pressure in the atmosphere due to burning fossil fuels, it will be important to include the interaction of the atmospheric C02 with the bio-organic reservoir and the catalyzation of its absorption into the sea by means of the action of carbonic-anhydrase dissolved in sea water, considerations which have not been taken into account in past computations. 

The identification of different carbonate binding modes in copper(II) and in zinc(II)/2,2 -bipyridine or tris(2-aminoethyl)amine/(bi)carbonate systems, specifically the characterization by X-ray diffraction techniques of both r)1 and r 2 isomers of [Cu(phen)2(HC03)]+ in their respective perchlorate salts, supports theories of the mechanism of action of carbonic anhydrase which invoke intramolecular proton transfer and thus participation by r)1 and by r 2 bicarbonate (55,318). 

The first zinc enzyme to be discovered was carbonic anhydrase in 1940, followed by car-boxypeptidase A some 14 years later. They both represent the archetype of mono-zinc enzymes, with a central catalytically active Zn2+ atom bound to three protein ligands, and the fourth site occupied by a water molecule. Yet, despite the overall similarity of catalytic zinc sites with regard to their common tetrahedral [(XYZ)Zn2+-OH2] structure, these mononuclear zinc enzymes catalyse a wide variety of reactions, as pointed out above. The mechanism of action of the majority of zinc enzymes centres around the zinc-bound water molecule,... 

Figure 12.3 (a) The active site of human carbonic anhydrase and (b) a simplified mechanism of action for the enzyme B = general base, probably His64. (Reprinted with permission from Parkin, 2004. Copyright (2004) American Chemical Society.)... 

Structure and physiology of the kidney glomerular filtration tubular activity selective reabsorption and secretion, often using specific carrier mechanisms carbonic anhydrase and acid-base balance. The kidney also produces, and is sensitive to, hormones actions of the hormones ADH, aldosterone and PTH the kidney as a secretory organ erythropoietin, the renin-angiotensin system vitamin D3. 

Part of the metabolic machinery of an osteoclast resembles the red cell and the renal tubule cells because all of these cell types contain the enzyme carbonic anhydrase (carbonate dehydratase) which generates acid, that is protons, and have ion pumps in their plasma membranes. The mechanism of bone resorption requires the action of cathepsin and metalloproteinase-9 working in an acidic environment (Figure 9.8). 

The plot in (b) refers to a similar interaction with the carboxymethylated derivative of carbonic anhydrase (Prob. 19). Aromatic sulfonamides are powerful inhibitors of the action of the enzyme and are useful probes of the site characteristics. 

Drugs of this group inhibit activity of carbonic anhydrase, an enzyme that catalyzes the reversible reaction of water and carbon dioxide, which forms carbonic acid. The mechanism of action of this group of drags is not fuUy understood. However, inhibition of carbonic anhydrase activity leads to a reduction of carbonic acid formation and an increase in bicarbonate, sodium, and potassium excretion with urine, which eventually leads to a significant increase in the process of excreting water from the organism. 

Pharmacology These agents are nonbacteriostatic sulfonamides that inhibit the enzyme carbonic anhydrase. This action reduces the rate of aqueous humor formation, resulting in decreased lOP. 

The most convincing proposal is that camosine plays one or more roles in control of intracellular hydrogen ion concentration (Abe, 2000 Vaughan-Jones et al, 2006). Camosine is an effective physiological buffer it is presumed that this property explains its predominant association with white, glycolytic, muscles which possess relatively few mitochondria and thereby generate lactic acid. Not only may camosine, also possible in its acetylated form, help to directly suppress the rise in hydrogen ion concentration but its ability to activate the enzyme carbonic anhydrase (Temperini et al, 2005) would increase bicarbonate buffer capacity. These properties may help explain camosine s protective action in ischaemia, a condition associated with severe intracellular acidosis. 

Dorzolamide (Trusopt) [Carbonic Anhydrase Inhibitor, Sul-fonamide/Glaucoma A9ent] Uses Glaucoma Action Carbonic anhydrase inhibitor Dose 1 gtt in eye(s) tid Caution [C, ] Contra Component sensitivity Disp Soln SE Irritation, bitter taste, punctate k atitis, ocular all gic Rxn EMS t Effects W/ oral carbonic anhydrase inhibitors, salicylates EMS Drug is absorbed systemicaUy OD May cause electrolyte disturbances (K) and acidosis monitor ECG... 

Dorzolamide Timolol (Cosopt) [Carbonic Anhydrase Inhibitor/Beta Adrener9ic Bloclcer] Uses Glaucoma Action Carbonic anhydrase inhibitor w/ i-adrenergic blocks Dose 1 gtt in eye(s) bid... 

Memantine (Namenda) [Anti Alzheimer Agent/NMDA Receptor Antagonist] Uses Mod/ evere Alzheimer Dz Action N-methyl-D-aspartate recqjtor antagonist Dose Target 20 mg/d, start 5 mg/d, t 5 mg/d to 20 mg/d, wait >1 wk before t dose use doses if >5mg/d Caution [B, /-] Hqjatic/mild-mod renal impair Disp Tabs, sol SE Dizziness Interactions t Effects W amantadine, carbonic anhydrase inhibitors, dextromethorphan, ketamine, Na bicarbonate t effects W/ any drug, herb, food that alkalinizes urine EMS Use NaHCOs w/ caution OD May cause restlessness, hallucinations, drowsiness, and fainting symptomatic and supportive... 

The thiazidelike compounds, including chlorthalidone Hygrown), quinethazone (Hydromox), and metolazone (Zaroxolyn) have similar mechanisms of action, but they differ substantially from one another in their duration of action, the degree of carbonic anhydrase inhibition, and the dose required for maximum natriuretic activity. 

Mechanism of Action A carbonic anhydrase inhibitor that reduces formation of hydrogen and bicarbonate ions from carbon dioxide and water by inhibiting, in proximal renal tubule, the enzyme carbonic anhydrase, thereby promoting renal excretion of sodium, potassium, bicarbonate, and water. Ocular Reduces rate of aqueous humor formation, lowers intraocular pressure. Therapeutic Effect Produces anticonvulsant activity. 

MecHanism of Action An ophthalmic agent that inhibits carbonic anhydrase. Decreases aqueous humor secretion. Therapeutic Effect Reduces intraocular pressure (lOP). 

Mechanism of Action A noncompetitive inhibitor of carbonic anhydrase that inhibits the enzyme at the luminal border of cells of the proximal tubule. Increases urine volume and changes to an alkaline pH with subsequent decreases in the excretion of ti-tratable acid and ammonia Therapeutic Effect Produces a diuretic and antiglaucoma effect. 

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