A zinc(II) complex of 1,5,9-triazacyclododecane ([12]aneN3) as a model for carbonic anhydrase

Kimura, Eiichi; Shiota, Takeshi; Koike, Takao; Shiro, Motoo; Kodama, Mutsuo

doi:10.1021/ja00171a020

Cited by 366 publications

(229 citation statements)

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“…331,335,350,351 The investigators measured potentio-metrically the value of pK a to be 7.3 for the Zn-bound water in this complex; this value is very close to that found in CA II (~6.9 for BCA II, 6.8 for HCA II). 331 Using either the tri(amine) or tetra(amine) macrocyclic scaffold, the investigators could vary the number of nitrogen ligands to Zn II from 3 to 4 and, thus, were able to demonstrate that increasing the coordination state of Zn II increased the value of pK a of Zn II -OH 2 + . Thus, they were able to show that the value of pK a of the Zn II -OH 2 + group in the native protein is mainly determined by the coordination number of Zn II , rather than by the hydrophobic environment in the binding pocket.…”

Section: Physical-organic Models Of the Active Site Of Casupporting

confidence: 69%

“…Thus, they were able to show that the value of pK a of the Zn II -OH 2 + group in the native protein is mainly determined by the coordination number of Zn II , rather than by the hydrophobic environment in the binding pocket. 331 Kimura et al also demonstrated that [12]aneN 3 , like CA, was able to catalyze the hydration of acetylaldehyde and hydrolysis of methyl acetate or p-nitrophenyl acetate, albeit with second-order rate constant 1 order of magnitude lower than those of BCA II. The pH profile of the rate of these reactions showed an inflection point near pH = 7.3, agreeing with potentiometric measurements for the value of pK a and indicating that the reaction mechanism involves a nucleophilic attack by Zn II -OH.…”

Section: Physical-organic Models Of the Active Site Of Camentioning

confidence: 99%

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Carbonic Anhydrase as a Model for Biophysical and Physical-Organic Studies of Proteins and Protein−Ligand Binding

et al. 2008

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I. Introduction to Carbonic Anhydrase (CA) and to the Review 948 1. Introduction: Overview of CA as a Model 948 1.1. Value of Models 950 1.2. Objectives and Scope of the Review 950 2. Overview of Enzymatic Activity 950 3. Medical Relevance 951 II. Structure and Structure−Function Relationships of CA 953 4. Global and Active-Site Structure 953 4.1. Structure of Isoforms 953 4.2. Isolation and Purification 954 4.3. Crystallization 954 4.4. Structures Determined by X-ray Crystallography and NMR 955 4.4.1. Structures Determined by X-ray Crystallography 955 4.4.2. Structure Determined by NMR 955 4.5. Global Structural Features 963 4.6. Structure of the Binding Cavity 964 4.7. Zn II -Bound Water 965 5. Metalloenzyme Variants 966 6. Structure−Function Relationships in the Catalytic Active Site of CA 968 6.1. Effects of Ligands Directly Bound to Zn II 968 6.2. Effects of Indirect Ligands 969 7. Physical-Organic Models of the Active Site of CA 969 III. Using CA as a Model to Study Protein−Ligand Binding 970 8. Assays for Measuring Thermodynamic and Kinetic Parameters for Binding of Substrates and Inhibitors 970 8.1. Overview 970 8.

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Section: Physical-organic Models Of the Active Site Of Casupporting

confidence: 69%

Section: Physical-organic Models Of the Active Site Of Camentioning

confidence: 99%

Carbonic Anhydrase as a Model for Biophysical and Physical-Organic Studies of Proteins and Protein−Ligand Binding

et al. 2008

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“…252,270 The pK a values reported for Zn(II)-bound water molecules in a range of model complexes depend strongly on the coordination environment and range from 7.3 to 10.8. [290][291][292][293][294][295][296] Since E. coli 5′-NT is an efficient catalyst even at pH 6, it seems likely that the pK a of the terminal water molecule is lowered through hydrogen bonding interactions with His117 ( Figure 22A). The pH dependence of kinetic parameters for 5′-NT-catalyzed reactions has not yet been analyzed in detail, but based on pH optima ranging from 5.5 to 9 for different enzymes, it appears that in some 5′-NTs the likely candidate for the role of a nucleophile is the bridging water ligand, which is expected to have a lower pK a value.…”

Section: Catalytic Mechanismmentioning

confidence: 99%

The Catalytic Mechanisms of Binuclear Metallohydrolases

et al. 2006

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“…Indeed, the data in Table 2 show the rates as a function of the nature of the specific metal ions added. The reasons for the metal effects are not clear, but we believe that the efficiency is partly correlated with the Lewis acidity of the metals when combining with strong ligands, such as the nitrogen on the polyethylenimine backbone or the imidazoles (14,28).…”

Section: Resultsmentioning

confidence: 99%

Deoxypolypeptides bind and cleave RNA

Cheng

Mahendran

Gonzalez

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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We have prepared L-and D-deoxypolypeptides (DOPPs) by selective reduction of appropriately protected polyhistidines with borane, reducing the carbonyl groups to methylenes. The result is a chiral polyamine, not amide, with a mainly protonated backbone and chirally mounted imidazolylmethylene side chains that are mostly unprotonated at neutrality because of the nearby polycationic backbone. We found that, in contrast with the D-octahistidine DOPP, the L-octahistidine DOPP is able to cooperatively bind to a D-polyuridylic acid RNA; this is consistent with results of previous studies showing that, relative to D-histidine, L-histidine is able to more strongly bind to RNA. The L-DOPP was also a better catalyst for cleaving the RNA than the D-DOPP, consistent with evidence that the L-DOPP uses its imidazole groups for catalysis, in addition to the backbone cations, but the D-DOPP does not use the imidazoles. The L-DOPP bifunctional process probably forms a phosphorane intermediate. This is a mechanism we have proposed for models of ribonuclease cleavage and for the ribonuclease A enzyme itself, based on our studies of the cleavage and isomerization of UpU catalyzed by imidazole buffers as well as other relevant studies. This mechanism contrasts with earlier, generally accepted ribonuclease cleavage mechanisms where the proton donor coordinates with the oxygen of the leaving group as the 2-hydroxyl of ribose attacks the unprotonated phosphate. T he enzyme ribonuclease A (RNase A) hydrolyzes RNA with bifunctional catalysis, using His-12 as a base and protonated His-119 as an acid to form the first products, a 2,3-cyclic phosphate of one ribose and the free next ribose with a new terminal 5′-hydroxyl group (1, 2). Lys-41 is also involved in stabilizing intermediate anions (3). In a second step the cyclic phosphate is hydrolyzed using the now-protonated His-12 and now-deprotonated His-119 in essentially a reverse of the cyclization step, with water replacing the second ribose unit (4). In the classical mechanism of this process it had been generally accepted, including in textbooks, that the protonated His-119 donates its proton to the leaving group whereas the 2′-hydroxyl group attacks the phosphate (1, 2) [isotope studies show that two protons are "in flight" during the hydrolysis step, essentially the reverse of the cyclization, both moving at the same time (5)]. We also showed the two-proton-in-flight process in a model system (6).However, our extensive studies on the cleavage of RNA with imidazole-imidazolium catalysts and on catalysis by RNase A itself indicated that a different mechanism is used ( Fig. 1) (7, 8). The proton donor BH + hydrogen binds to a phosphate oxyanion and donates the proton to the phosphate as the ribose 2′-hydroxyl adds while losing a proton to base :B. This process results in an intermediate phosphorane species. This then expels the 5′-hydroxyl group of the second nucleotide to cleave the P-O bond in a second step. We proposed this two-step phosphorane process to be the preferred path for th...

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A zinc(II) complex of 1,5,9-triazacyclododecane ([12]aneN3) as a model for carbonic anhydrase

Cited by 366 publications

References 0 publications

Carbonic Anhydrase as a Model for Biophysical and Physical-Organic Studies of Proteins and Protein−Ligand Binding

Carbonic Anhydrase as a Model for Biophysical and Physical-Organic Studies of Proteins and Protein−Ligand Binding

The Catalytic Mechanisms of Binuclear Metallohydrolases

Deoxypolypeptides bind and cleave RNA

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