Carbonic anhydrase and

This is not really a treatment but there is a view that glial cells can protect against seizures since the enzyme systems they possess (e.g. Na-K+ATPase and carbonic anhydrase) facilitate the regulation of ion movements and reduce the spread of seizures. Certainly ageing, a fatty diet, and phenytoin itself increase glial cell count while decreasing seizure susceptibility. In fact inhibition of carbonic anhydrase and the production of bicarbonate was one of the first treatments for epilepsy and a recent discovery that under certain circumstances intracellular bicarbonate can depolarise neurons has created a fresh interest in it. 

Fig. 10. Examples of coordination geometry in the entatic state (34) where the Lewis acidity of Zn(II) in its metalloprotein is considerably altered as compared with that for (a) the Zn2t aquo ion (30), (b) Zn(II) in alcohol dehydrogenase, (c) Zn(II) in carbonic anhydrase, and (d) Zn(II) in carboxypeptidase. Redrawn after Ref. (22).

The zinc acetate complex of tris(3-/-butyl-5-methylpyrazol-l-yl)borate was prepared as a structural model for carbonic anhydrase and comparison with the enzyme active site structures confirmed that the complexes are excellent structural models.239 A mononuclear zinc hydroxide complex can also be formed with the tris(pyrazolyl) borate ligand system as a structural model for carbonic anhydrase.240... 

The ligand tris[2-(l-methylbenzimidazol-2-yl)ethyl] nitromethane (25) has been used in the formation of zinc complexes as models of the active site of carbonic anhydrase, and the formed complexes reveal affinity for the sulfonamide-containing enzyme inhibitor acetazolamide.248... 

Diamox (acetazolamide) inhibits carbonic anhydrase, and this, in turn, increases the blood acidity. The increased blood acidity stimulates breathing and... 

Figure 14.4 Gel image of proteins extracted from a mixed carbonic anhydrase lysozyme tissue surrogate. Lane M, molecular weight marker lane 1, a 1 2 mol ratio mixture of native, non-formalin-treated carbonic anhydrase and lysozyme lane 2, mixed surrogate with 1 2 mol ratio carbonic anhydrase lysozyme, solubilized and retrieved in 20mM Tris-HCl, pH 4.0, with 2% SDS lane 3, mixed surrogate with 1 2 mol ratio carbonic anhydrase lysozyme, solubilized and retrieved in 20mM Tris-HCl, pH 6.0, with 2% SDS. Protein bands corresponding to lysozyme monomer (a), carbonic anhydrase monomer (b), and the putative lysozyme-carbonic anhydrase heterodimer (c) are indicated. For more detail, see Reference 25.

Zonisamide is a broad-spectrum sulfonamide AED that blocks voltage-sensitive sodium channels by reducing voltage-dependent T-type Ca channels it also weakly inhibits carbonic anhydrase, and inhibits glutamate release. 

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. 

Segments of human aorta obtained fresh at autopsy were freed from blood and covering connective tissue and analyzed manometrically for carbonic anhydrase activity. Twelve specimens from 7 males and 5 females yielded nearly a 9-fold spread in values (0.12 to 1.05 units).31 This is interesting in view of the zinc content of carbonic anhydrase and the extremely wide variations in the zinc content of blood plasma and spleens which have been observed (pp. 55 and 72). 

A few gases may be involved in some enzyme reactions, e.g., C02 and 02 as used by carbonic anhydrase and produced by catalase, respectively. If the presence of such dissolved gases affects rates and equilibria at ordinary pressure, their importance will increase at higher pressure. Henry s law says that the partial pressure of a gas above a solution is proportional to its mole fraction in the solution. At high pressure it is more correct to speak of the fugacity / of a gas, instead of partial pressure, in the same sense that one uses activity instead of concentration in solution calculations. In dilute solutions, the fugacity of the dissolved gas is given by... 

One approach to compartmentalize hemoglobin is to encapsulate hemoglobin in biodegradable polymer-PEG-polylactide (30). These nanocapsules have a diameter of 80-150 nm and contain superoxide dismutase, catalase, carbonic anhydrase, and other enzymes of Embden-Meyerhof pathway that are needed for long-term function of an oxygen carrier (31,32). The polylactide capsules are metabolized in vivo to water and carbon... 

Zinc is a microelement essential for proper functioning of the human body. The level of daily demand for zinc was established as 13 to 16 mg (Ziemlahski, 2001). Zinc plays a role in protein and carbohydrate metabolism and is a component of over 60 metaloenzymes, including alkaline phosphatase, pancreatic carboxypeptidases A and B, alcoholic and lactic dehydrogenases, carbonate anhydrase, and proteases. It also forms bonds with nucleic acids -which is very important for their functioning (Prasad, 1983 Valee and Falchuk, 1993). 

Figure 7.1 (a) The denatured conformation of the zinc metalloenzyme carbonic anhydrase and the ESI mass spectra obtained under acidic denaturing conditions, (b) The ESI mass spectra obtained under native-state conditions. The decon-voluted ESI mass spectra of carbonic anhydrase reveals the protein molecular weight. The three dimensional structure is protein Data Bank ID IBNl. 

Human carbonic anhydrase II, found primarily in the erythrocyte, is the prototypical member of the family of carbonic anhydrases and has been extensively reviewed (Pocker and Sarkanen, 1978 Lindskog, 1983, 1986 Silverman and Lindskog, 1988). Within the erythrocyte carbonic anhydrase II hydrates CO2 to form bicarbonate ion plus a proton via tandem chemical processes (Silverman and Lindskog, 1988) (Scheme 2). Most of the carbon dioxide generated during the process of respiration requires this carbonic anhydrase Il-catalyzed event for transport out of the cell. The resultant protons of CO2 hydration are taken up by His-146)8, His-122a, and the amino terminus of the a subunits of the hemoglobin tetramer. As a reference. Scheme 3 outlines the interconversions... 

In humans, only the jV-desethyl metabolite is detected in whole blood, although trace amounts of the other two metabolites are found in urine. All three of the above exhibit binding to carbonic anhydrase and prolonged half-lives in whole blood. In rats, a carboxylic acid metabolite formed by oxidation of the O-desmethyl analog is the predominant urinary metabolite. Small amounts of this compound are also found in human urine. 

Acetazolamide inhibits the enzyme carbonic anhydrase, and interferes with the ability of the renal tubules to produce and secrete hydrogen ions. And, the diuretic action is due to the decreased sodium biocarbonate absorption in proximal tubules and diminished hydrogensodium exchange in the distal tubules. 

Figure 12.2 Mechanism of action of carbonic anhydrase inhibitors on the proximai convoiuted tubuie. Carbonic anhydrase is an enzyme that cataiyses the interconversion of C02and H20 to H2C03and is found in the iuminai epitheiium of the proximai, and to a iesser extent, the distai convoiuted tubuie. It is essentiai for the conservation of body base in the form of HCO-3. An antiporter (1) mechanism (the movement of substances across a barrier in opposite directions) exchanges fiitrate Na+for ceiiuiar H+. The H+combines with fiitrate HCO-3to form carbonic acid which is converted to C02and H20 in the presence of carbonic anhydrase (CA). The C02is reabsorbed by the ceii thereby conserving HCO-3. Acetazoiamide inhibits the activity of carbonic anhydrase and limits the conversion of HCO-3to absorbable C02. The concentration of HCO-3in the filtrate increases as does the urinary loss. P, the sodium pump ECF, extracellular fluid.

Sodium sulfacetamide ophthalmic solution or ointment is effective in the treatment of bacterial conjunctivitis and as adjunctive therapy for trachoma. Another sulfonamide, mafenide acetate, is used topically but can be absorbed from burn sites. The drug and its primary metabolite inhibit carbonic anhydrase and can cause metabolic acidosis, a side effect that limits its usefulness. Silver sulfadiazine is a much less toxic topical sulfonamide and is preferred to mafenide for prevention of infection of burn wounds. 

The results of site-directed mutagenesis analysis of zinc ligands of higher plant p-carbonic anhydrase and of P. purpureum carbonic anhydrase have confirmed that zinc is essential for catalysis. X-ray fine structure data indicated that a water molecule is hydrogen bonded to the zinc-ligated Asp-151 and Asp-405. The water molecule is not directly coordinated to the zinc atom. A possible catalytic mechanism of C02 hydration cycle (211) has been proposed as given in Scheme 10. 

Supuran, . T. Carbonic Anhydrase and Modulation of Physiologic and Pathologic Processes in the Organism Ed. Puscas, I. Helicon, Timisoara, Romania, 1994, pp. 29-111. 

The present volume is a non-thematic issue and includes seven contributions. The first chapter byAndreja Bakac presents a detailed account of the activation of dioxygen by transition metal complexes and the important role of atom transfer and free radical chemistry in aqueous solution. The second contribution comes from Jose Olabe, an expert in the field of pentacyanoferrate complexes, in which he describes the redox reactivity of coordinated ligands in such complexes. The third chapter deals with the activation of carbon dioxide and carbonato complexes as models for carbonic anhydrase, and comes from Anadi Dash and collaborators. This is followed by a contribution from Sasha Ryabov on the transition metal chemistry of glucose oxidase, horseradish peroxidase and related enzymes. In chapter five Alexandra Masarwa and Dan Meyerstein present a detailed report on the properties of transition metal complexes containing metal-carbon bonds in aqueous solution. Ivana Ivanovic and Katarina Andjelkovic describe the importance of hepta-coordination in complexes of 3d transition metals in the subsequent contribution. The final chapter by Sally Brooker and co-workers is devoted to the application of lanthanide complexes as luminescent biolabels, an exciting new area of development. 

We can use the two hypothetical steps of section Clb i.e., that kcJKM be maximized and that KM be greater than [S], to set up criteria for judging the state of evolution of an enzyme whose function is to maximize rate. We recall from Chapter 3 that the maximum value of kcJKM is the rate constant for the diffusion-controlled encounter of the enzyme and substrate, and from Chapter 4 that this is about 108 to 109 s "1 M l. A perfectly evolved enzyme should have a kcJKM in the range of 108 to 109 s"1 and a KM greater than [S]. Using the data for kcJKM listed in Table 4.4 and the substrate concentrations and KM values mentioned in this chapter, it appears that carbonic anhydrase and triosephosphate isomerase are perfectly evolved for the maximization of rate, which agrees with the conclusions of W. J. Albery and J. R. Knowles on triosephosphate isomerase.5... 

It was once thought that the rate of equilibrium of the catalytic acid and basic groups on an enzyme with the solvent limited the rates of acid- and base-catalyzed reactions to turnover numbers of 103 s 1 or less. This is because the rate constants for the transfer of a proton from the imidazolium ion to water and from water to imidazole are about 2 X 103 s 1. However, protons are transferred between imidazole or imidazolium ion and buffer species in solution with rate constants that are many times higher than this. For example, the rate constants with ATP, which has a pKa similar to imidazole s, are about I0 J s 1 M-1, and the ATP concentration is about 2 mM in the cell. Similarly, several other metabolites that are present at millimolar concentrations have acidic and basic groups that allow catalytic groups on an enzyme to equilibrate with the solvent at 107 to 108 s-1 or faster. Enzyme turnover numbers are usually considerably lower than this, in the range of 10 to 103 s-1, although carbonic anhydrase and catalase have turnover numbers of 106 and 4 X 107 s 1, respectively. 

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