Carbonic anhydrase theory

Few paid any attention to what I said. Because at that time carbonic anhydrase was a popular object of study, and because its presence in parietal cells gave the first glimmer of light regarding the mechanism of acid secretion, I became known as the proprietor of the carbonic anhydrase theory of acid secretion. ... 

The carbonic anhydrase theory is mentioned in Gray JS. The formation of acid in the gastric glands. Fed Proc 1 25 5-260, 1942 and in idem. The physiology of the parietal cell with special reference to the formation of acid. Gastroenterology 1 390-400,1943.1 must say, in fairness to John Gray, that he fully understood the words just quoted. 

Davenport HW. In memoriam The carbonic anhydrase theory of gastric acid secretion. Gastroenterology 1 314-315, 1946. 

Bertini I, Luchinat C, Scozzafava A (1982) Carbonic Anhydrase An Insight into the Zinc Binding Site and into the Active Cavity Through Metal Substitution. 48 45-91 Bertrand P (1991) Application of Electron Transfer Theories to Biological Systems. 75 1-48 Bill E, see Trautwein AX (1991) 78 1-96 Bino A, see Ardon M (1987) 65 1-28 Blanchard M, see Linares C (1977) 33 179-207 Blasse G, see Powell RC (1980) 42 43-96... 

The interaction of carbon disulfide as a substrate in carbonic anhydrase model systems has been studied using density functional theory methods. A higher activation energy of CS2 compared to C02 in the reaction with [L3ZnOH]+ was due to the reduced electrophilicity of CS2. The reversibility of the reaction on the basis of these calculations is questionable with [L3ZnSC(0)SH]+ as intermediate.572... 

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). 

As an example of behavior of a typical Gd-complex and Gd-macromolecule we discuss here the NMRD profiles of a derivative of Gd-DTPA with a built-in sulfonamide (SA) and the profile of its adduct with carbonic anhydrase (see Fig. 37) 100). Other systems are described in Chapter 4. The profile of Gd-DTPA-SA contains one dispersion only, centered at about 10 MHz, and can be easily fit as the sum of the relaxation contributions from two inner-sphere water protons and from diffusing water molecules. Both the reorientational time and the field dependent electron relaxation time contribute to the proton correlation time. The fit performed with the SBM theory, without... 

Cheeseman,J.D. Corbett,A.D. Shu,R. Croteau,J. Gleason,J.L. Kazlauskas, R. J. Amphfication of screening sensitivity through selective destruction Theory and screening of a hbrary of carbonic anhydrase inhibitors. J. Am. Chem. Soc. 2002,124, 5692-5701. 

A third problem with the mitochondrial theory of biomineralization is that many mineralized tissues contain carbonate rather than phosphate. Since bicarbonate ions do not pass across mitochondrial membranes with any ease, it has now been shown that in phosphate-free buffers, calcium will enter mitochondria if dissolved carbon dioxide is available. It appears that some mitochondria possess carbonic an-hydrase activity on the inner membrane or in the mitochondrial matrix and are thus able to synthesize bicarbonate within the organelle. In such cases, inhibitors of carbonic anhydrase block the accumulation of calcium and carbonate ions622) since crystals of calcite have been identified in the mitochondria of earthworms calci-ferous glands623. These cells freqently showed spherical granules in the cytoplasm and lumen of the glands during phases of mineral secretion and it was suggested that they were aspects of cellular breakdown which occurred at these times. 

Ab-initio and density functional theory are used to calculate the probability of proton conduction via a chain of water molecules from Zn+ to its residue in the active site of carbonic anhydrase (Isaev and Scheiner, 2001). They conclude that proton conduction occurs as a concerted process and includes the shortening of each H-bonds as the proton donor and acceptor move towards one other. 

In fact, transient assembly of H-bonded water files is probably common in enzyme function. In carbonic anhydrase, for example, the rate-limiting step is proton transfer from the active-site Zn2+-OH2 complex to the surface, via a transient, H-bonded water network that conducts H+. Analysis of the relationship between rates and free energies (p K differences) by standard Marcus theory shows that the major contribution to the observed activation barrier is in the work term for assembling the water chain (Ren et al., 1995). 

The enzyme has been found in corals (Goreau, 1959), annelids (Clark, 1975), crustaceans (Costlow, 1959), molluscs (Wilbur, 1972, for references), and echinoderms (Heatfield, 1970). In all cases, sulfanilamide inhibitors of the enzyme added to the medium reduced the rate of calcification at least 50%, indicating that catalysis by carbonic anhydrase is required for the normal rate of mineralization. In theory, the reactions should occur without enzyme catalysis and this appears to be true. Various mechanisms of action have been suggested (e.g., Goreau, 1959 Istin and Girard, 1970b) but the exact role of carbonic anhydrase remains uncertain. 

Enzymes are proteins that act as catalysts for specific biochemical reactions in living systems. The reactants in enz)une-catalyzed reactions are called substrates. Thousands of vital processes in our bodies are catalyzed by many distinct enzymes. For instance, the enzyme carbonic anhydrase catalyzes the combination of CO2 and water (the substrates), facilitating most of the transport of carbon dioxide in the blood. This combination reaction, ordinarily uselessly slow, proceeds rapidly in the presence of carbonic anhydrase a single molecule of this enzyme can promote the conversion of more than 1 million molecules of carbon dioxide each second. Each enzyme is extremely specific, catalyzing only a few closely related reactions—or, in many cases, only one particular reaction—for only certain substrates. Modern theories of enzyme action attribute this to the requirement of very specific matching of shapes (molecular geometries) for a particular substrate to bind to a particular enzyme (Figure 16-19). 

Figure 29.19 The reactant (R), transition state (TS) and product (P) configurations for the rate-determining triple proton transfer step of the 58-atom model used to represent the active site of carbonic anhydrase II [18]. The numbers denote bond distances (in A) calculated at two different levels of theory. The arrows in the insert figure represent the tunneling mode and illustrate the degree of synchronicity of the transfer.

R 466 J. G. Kempf and J. P. Loria, Theory and Applications of Protein Dynamics from Solution NMR , Cell Biochem. Biophys., 2002,37,187 R467 E. Kennett and P. Kuchel, Redox Reactions and Electron Transfer Across the Red Cell Membrane , lUBMB Life, 2003,55, 375 R 468 R. G. Khalifah, Reflections on Edsall s Carbonic Anhydrase Paradoxes of an Ultra Fast Enzyme , Biophys. Chem., 2003,100,159 R 469 A. A. Khrapitchev and P. T. Callaghan, Spatial Dependence of Dispersion , Magn. Reson. Imaging, 2003, 21, 373 R 470 I. V. Khudyakov, N. Arsu, S. Jockusch and N. J. Turro, Magnetic and Spin Effects in the Photoinitiation of Polymerization , Des. Monomers Polym., 2003, 6, 91... 

The distribution of carbonic anhydrase is also in accord with the alkaline stress theory. This enzyme is highly active in C3 chloroplasts whereas it is absent from C4 bundle-sheath chloroplasts conducting carboxlation - nor is it needed there. Bicarbonate generated on nitrite reduction in the mesophyll chloroplasts could be transferred to the cytosol at a leisurely rate for PEP carboxylase activity there. ... 

Metallic elements are essential components of many important enzymes operating within our bodies. Carbonic anhydrase, which contains Zn, is responsible for rapidly interconverting dissolved CO2 and bicarbonate ion, HCO3. The zinc in carbonic anhydrase is ccx)idinated by three nitrogen-containing groups and a water molecule. The enzyme s action depends on the fact that the coordinated water molecule is more acidic than the bulk solvent molecules. Explain this fact in terms of Lewis add-base theory (Section 16.11). 

In the late winter of 1938-39, when I was writing my Ph.D. thesis at the California Institute of Technology on the presence of carbonic anhydrase in the parietal cells, I was quite naturally thinking about the mechanism of acid secretion. I encountered two abstracts by Martin E. Hanke, a physiological chemist at the University of Chicago. The first began A new theory has been developed for the chem-... 

However, when CO2 plus carbonic anhydrase were added together, they did not obtain a rate comparable to HCO3 alone, but 50% of the rate. Hence, a discrepancy was noted. In comparable experiments with other carboxylases including RudP carboxylase, the predicted data more nearly agreed with theory. 

Functional differences, such as variations in the occurrence of certain enzymes, may exist between different vascular beds. In brain capillary endothelial cells, the distribution of alkaline phosphatase and Na , K ATPase differs between the luminal and antiluminal cytoplasmic membranes. Cadmium is known to inhibit several SH-containing enzymes and it might be speculated that the content and subcellular distribution of enzymes in ganglionic endothelial cells are of importance for the preferential occurrence of cadmium-induced vascular injury in ganglia. A similar theory has been proposed to explain the vascular damage caused by cadmium in the testis. Thus, Aoki and Hoffer suggested that a cadmium-sensitive testicular isoenzyme of carbonic anhydrase may in some way be associated with the capillary endothelial cells. 

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