Carbonic anhydrase II, CAII

Osteopetrosis (marble bone disease), characterized by increased bone density, is due to inability to resorb bone. One form occurs along with renal tubular acidosis and cerebral calcification. It is due to mutations in the gene (located on chromosome 8q22) encoding carbonic anhydrase II (CAII), one of four isozymes of carbonic anhydrase present in human tissues. The reaction catalyzed by carbonic anhydrase is shown below ... 

As an illustration, we briefly discuss the SCC-DFTB/MM simulations of carbonic anhydrase II (CAII), which is a zinc-enzyme that catalyzes the interconversion of CO2 and HCO [86], The rate-limiting step of the catalytic cycle is a proton transfer between a zinc-bound water/hydroxide and the neutral/protonated His64 residue close to the protein/solvent interface. Since this proton transfer spans at least 8-10 A depending on the orientation of the His 64 sidechain ( in vs. out , both observed in the X-ray study [87]), the transfer is believed to be mediated by the water molecules in the active site (see Figure 7-1). To carry out meaningful simulations for the proton transfer in CAII, therefore, it is crucial to be able to describe the water structure in the active site and the sidechain flexibility of His 64 in a satisfactory manner. 

In our selected example, Lehn and coworkers [80] reported the synthesis of a dynamic 12-member, template-directed imine library 1, obtained from the reversible condensation of three aldehydes (monomer set M, Figure 7.11), with four primary amines (monomer set M2, Figure 7.11) in buffered aqueous conditions, followed by irreversible reduction to amines 2 with sodium cyanoborohydride. The library was prepared in the presence of a large excess of M2, to prevent further condensation of an aldehyde onto the secondary amine product. A template-driven imine library 1 was prepared in the presence of the metalloenzyme carbonic anhydrase II (CAII). After the template-assisted, reversible dynamic reaction was complete, the reducing agent was added and the amine library 2 was produced (Figure 7.11). Without any... 

FIGURE 2.3 (A) ESI-FTICR mass spectrum of a mixture of carbonic anhydrase II (CAII) and combinatorial library (289 components, 1). (B) MS-MS spectrum of the isolated complex of ions [CAII + Zn + 1] ". The expanded view shows the region of the singly charged inhibitors l , and the doubly expanded region shows the high resolution achieved in the experiment and the amino acid residue composition of the inhibitor ions. (Reprinted from Gao et al. [18], used with permission. Copyright 1996 by the American Chemical Society.)... 

Human carbonic anhydrase II (CAII) is present in red blood cells and catalyses the reversible hydration of CO2 (reaction... 

Fig. 28.22 (a) Schematic representation of the active site in human carbonic anhydrase II (CAII). (b) The catalytic cycle for the hydration of CO2 catalysed by CAII. 

Human carbonic anhydrase II (CAII) is present in red blood cells and catalyses the reversible hydration of CO2 (reaction 29.17). This process is slow k = 0.037s ) but is fundamental to the removal of CO2 from actively metabolizing sites. CAII increases the rate of hydrolysis by a factor of 10 at physiological pH. 

Carbonic anhydrase (CA) exists in three known soluble forms in humans. All three isozymes (CA I, CA II, and CA III) are monomeric, zinc metalloenzymes with a molecular weight of approximately 29,000. The enzymes catalyze the reaction for the reversible hydration of C02. The CA I deficiency is known to cause renal tubular acidosis and nerve deafness. Deficiency of CA II produces osteopetrosis, renal tubular acidosis, and cerebral calcification. More than 40 CA II-defi-cient patients with a wide variety of ethnic origins have been reported. Both syndromes are autosomal recessive disorders. Enzymatic confirmation can be made by quantitating the CA I and CA II levels in red blood cells. Normally, CA I and CAII each contribute about 50% of the total activity, and the CAI activity is completely abolished by the addition of sodium iodide in the assay system (S22). The cDNA and genomic DNA for human CA I and II have been isolated and sequenced (B34, M33, V9). Structural gene mutations, such as missense mutation, nonsense... 

Human CAII (carbonic anhydrase isozyme II) ZnNsO 9.8 1 CP/QCPMG [53]... 

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