Ligands zinc enzymes

A large body of work with particular reference to the mimicry of mononuclear zinc enzymes has utilized tris(pyrazolyl)borate ligands. This ligand class offers a facial coordination mode of three pyrazole A-donors and can be functionalized in the three and five positions on the rings to increase steric bulk and vary the electronic properties of the ligand. The synthesis and complex formation with these ligands has been extensively reviewed.2,21 219... 

Pyridyl functionalized tris(pyrazolyl)borate ligands show some interesting properties including the formation of polynuclear zinc complexes.23,1 Some of these contain extensive H bonding and have potential as models for multinuclear zinc enzymes such as phospholipase C or PI nuclease.235 A bis-ligand complex of the hydrotris(5-methyl-3-(3-pyridyl)pyrazolyl)borate ligand (23) shows octahedral coordination of all six pyrazole nitrogen donors despite the steric bulk. 

Bis(pyrazolylethyl)ether derivatives (106) have been coordinated to zinc providing an N20 donor set. The structural data shows that the ligand coordinates in a meridional rather than facial geometry limiting the application for the modeling of N20 zinc enzyme sites, (derivatives R = i-Pr or Me).161... 

In most zinc enzymes, the metal is tetrahedrally coordinated by either nitrogen atoms alone or by a combination of nitrogen and oxygen atoms. To model zinc enzymes having the much rarer S-donor environments, a number of approaches have been pursued. The most direct routes to such ligands involve the replacement of one or more... 

Zinc is the active metal in the largest group of metalloproteins found in the nature. Recently a new class of zinc enzymes with a sulfur-rich environment has emerged the thiolate-alkylating enzimes, the most prominent of which is the cobalamine-independent methionine synthase.126 For these reasons several monothiolate zinc complexes have been prepared for the modelling of these enzymes with different N2S as (13),127 130 N20,13° 132 N3,132,133 S3,134 tripod ligands, or with Cd because of the favourable spectroscopic properties with an S3 tripod ligand.135... 

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,... 

As mentioned earlier, by far the largest number of zinc enzymes are involved in hydrolytic reactions, frequently associated with peptide bond cleavage. Carboxypeptidases and ther-molysins are, respectively, exopeptidases, which remove amino acids from the carboxyl terminus of proteins, and endopeptidases, which cleave peptide bonds in the interior of a polypeptide chain. However, they both have almost identical active sites (Figure 12.4) with two His and one Glu ligands to the Zn2+. It appears that the Glu residue can be bound in a mono- or bi-dentate manner. The two classes of enzymes are expected to follow similar reaction mechanisms. 

It was clear for some time that a number of zinc enzymes required two or more metal ions for full activity, but in the absence of X-ray structural data the location of these metal centres with regard to one another was often uncertain. When the first 3-D structures began to appear, it became clear that the metals were in close proximity. A particular feature of many of these enzymes was the presence of a bridging ligand between two of the metal sites, usually an Asp residue of the protein, which is occasionally replaced by a water molecule. While some of the sites contain only Zn ions, several contain Zn in combination with Cu (in cytosolic superoxide dismutases) Fe (in purple acid phosphatases) or Mg (in alkaline phosphatase and the aminopeptidase of lens). 

The A, AT, 0-binding motif is found in many non-heme iron enzymes as well as in some zinc enzymes as metal-binding motif Thus, to mimic this motif is the purpose of small organic 0-ligands such as... 

Trispyrazolylborates are models for tris-histidine active sites in zinc enzymes, e.g., the matrix metalloproteinases involved in breakdown of extracellular matrices. Inhibition of these metalloproteinases may prove valuable in the treatment of, inter alios, cancer and arthritis, so efforts are being made to find appropriate ligands to block the zinc active site. The search has recently moved on from hydroxamates to hydroxypyridinones - l-hydroxy-2-pyridinone is a cyclic analogue of hydroxamic acid. As reported in Section II.B.2 earlier, hydroxypyridinones form stable five-coordinate complexes on reaction with hydrotris(3,5-phenylmethylpyrazolyl)borate zinc hydroxide. Modeling studies suggest that hydroxypyridinonate ligands should be able to access the active site in the enzyme with ease (110). 

Vallee, B. L., and Auld, D. S. (1990a). Active-site zinc ligands and activated H2O of zinc enzymes. Proc. Natl. Acad. Sci. U.S.A. 87, 220-224. 

Sharma and Reed, 1976)]. In proteins the coordination number 4 is most common, where the zinc ion is typically coordinated in tetrahedral or distorted tetrahedral fashion. The coordination polyhedron of structural zinc is dominated by cysteine thiolates, and the metal ion is typically sequestered from solvent by its molecular environment the coordination polyhedron of catalytic zinc is dominated by histidine ligands, and the metal ion is exposed to bulk solvent and typically binds a solvent molecule (Vallee and Auld, 1990). The inner-sphere coordination number of catalytic zinc may increase to 5 during the course of enzymatic turnover, and several five-coordinate zinc enzyme—substrate, enzyme product, and enzyme-inhibitor complexes have been studied by high-resolution X-ray crystallographic methods (reviewed by Matthews, 1988 Christianson and Lipscomb, 1989). The coordination polyhedron of zinc in five coordinate examples may tend toward either trigonal bipyramid or octahedral-minus-one geometry. 

One of the problems in studying zinc enzymes is that the zinc is silent from both electronic and nuclear points of view, and so provides no information about site symmetry and ligand groups. Accordingly a dominant feature of work on zinc enzymes has been the use of probe metal ions to replace Zn. Co11 has been used with some success, while a more recent innovation is the use of 113Cd2+ as a probe, and the application of Cd NMR techniques. 

Ammonia N-donor Ligands Chromium Inorganic Coordination Chemistry Coordination Numbers Geometries Copper Inorganic Coordination Chemistry Magnetism of Transition Metal Ions Molecular Orbital Theory Nickel Inorganic Coordination Chemistry Zinc Enzymes Zinc Inorganic Coordination Chemistry. 

While zinc can readily form four-, five-, and six-coordinate complexes, structural zinc sites in proteins have 4 protein ligands and no bound water molecule. This type of coordination is also observed in many of the Protein Interface zinc sites. The first zinc enzymes recognized to have a... 

Some of these sites can effect function in zinc proteins as well as stabilizing structure. The hydrolase class of zinc enzymes are good examples of this action. In this case, one or more amino acid residues within the active site may be provided by the amino acid spacers between zinc ligands (Figure 12). The side chain of these amino acids may be involved in substrate binding, bond cleavage or modulating the chemical enviromnent of the active site. In addition, other active-site residues are often provided by... 

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