Zinc ions models

Uncovering of the three dimentional structure of catalytic groups at the active site of an enzyme allows to theorize the catalytic mechanism, and the theory accelerates the designing of model systems. Examples of such enzymes are zinc ion containing carboxypeptidase A 1-5) and carbonic anhydrase6-11. There are many other zinc enzymes with a variety of catalytic functions. For example, alcohol dehydrogenase is also a zinc enzyme and the subject of intensive model studies. However, the topics of this review will be confined to the model studies of the former hydrolytic metallo-enzymes. 

Fig. 9.1. Left panel A model zinc finger obtained using the second domain of the transcription factor IIIA. The zinc ion (gray sphere) is coordinated tetrahedrally by two histidine (H) and two cysteine (C) residues. Right panel Results showing the free energy change for displacing Zn2+ by other comparable ions Fe2+ and Co2+ from different binding motifs CCHH, CCHC, and CCCC, respectively...

Errecalde, O., Seidl, M. and Campbell, P. G. C. (1998). Influence of a low molecular weight metabolite (citrate) on the toxicity of cadmium and zinc to the unicellular green alga Selenastrum capricornutum an exception to the free-ion model, Water Res., 32, 419 -29. 

More advanced semiempirical molecular orbital methods have also been used in this respect in modeling, e.g., the structure of a diphosphonium extractant in the gas phase, and then the percentage extraction of zinc ion-pair complexes was correlated with the calculated energy of association of the ion pairs [29]. Semiempirical SCF calculations, used to study structure, conformational changes and hydration of hydroxyoximes as extractants of copper, appeared helpful in interpreting their interfacial activity and the rate of extraction [30]. Similar (PM3, ZINDO) methods were also used to model the structure of some commercial extractants (pyridine dicarboxylates, pyridyloctanoates, jS-diketones, hydroxyoximes), as well as the effects of their hydration and association with modifiers (alcohols, )S-diketones) on their thermodynamic and interfacial activity [31 33]. In addition, the structure of copper complexes with these extractants was calculated [32]. 

This zinc metalloenzyme [EC 1.1.1.1 and EC 1.1.1.2] catalyzes the reversible oxidation of a broad spectrum of alcohol substrates and reduction of aldehyde substrates, usually with NAD+ as a coenzyme. The yeast and horse liver enzymes are probably the most extensively characterized oxidoreductases with respect to the reaction mechanism. Only one of two zinc ions is catalytically important, and the general mechanistic properties of the yeast and liver enzymes are similar, but not identical. Alcohol dehydrogenase can be regarded as a model enzyme system for the exploration of hydrogen kinetic isotope effects. 

Zinc may function to promote the nucleophilicity of a bound solvent molecule in both small-molecule and protein systems. The p/Ca of metal-free H2O is 15.7, and the p/Ca of hexaaquo-zinc, Zn (OH2)6. is about 10 (Woolley, 1975) (Table III). In a novel small-molecule complex the coordination of H2O to a four-coordinate zinc ion reduces the to about 7 (Groves and Olson, 1985) (Fig. 2). This example is particularly noteworthy since it has a zinc-bound solvent molecule sterically constrained to attack a nearby amide carbonyl group as such, it provides a model for the carboxypeptidase A mechanism (see Section IV,B). To be sure, the zinc ligands play an important role in modulating the chemical function of the metal ion in biological systems and their mimics. 

Fig. 47. Model of the a-helical peptide HSaj. showing backbone atoms and three histidine zinc ligands. The bound zinc ion is represented by a sphere. [Reprinted with permission from Handel, T., DeGrado, W. F. (1990) J. Am. Chem. Soc. 112,6710—6711. Copyright 1990 American Chemical Society.]...

Zn-organometallic compound and the complex was synthesized with the aim of modeling the active site of carbonic anhydrase during its first catalytic step, the acquisition of the NMR properties of nucleus at this Zn complex could be further exploited in studies where the zinc ion would be replaced by a Zn nucleus. 

Figure 13-7 Interaction of the bound zinc ion of L-fuculose-l-phosphate aldolase and catalytic side chains with the substrate in the active site of the enzyme as revealed by X-ray crystallography and modeling. See Dreyer and Schulz.193...

The NAD+-dependent alcohol dehydrogenase from horse liver contains one catalytically essential zinc ion at each of its two active sites. An essential feature of the enzymic catalysis appears to involve direct coordination of the enzyme-bound zinc by the carbonyl and hydroxyl groups of the aldehyde and alcohol substrates. Polarization of the carbonyl group by the metal ion should assist nucleophilic attack by hydride ion. A number of studies have confirmed this view. Zinc(II) catalyzes the reduction of l,10-phenanthroline-2-carbaldehyde by lV-propyl-l,4-dihy-dronicotinamide in acetonitrile,526 and provides an interesting model reaction for alcohol dehydrogenase (Scheme 45). The model reaction proceeds by direct hydrogen transfer and is absolutely dependent on the presence of zinc(II). The zinc(II) ion also catalyzes the reduction of 2- and 4-pyridinecarbaldehyde by Et4N BH4-.526 The zinc complex of the 2-aldehyde is reduced at least 7 x 105 times faster than the free aldehyde, whereas the zinc complex of the 4-aldehyde is reduced only 102 times faster than the free aldehyde. A direct interaction of zinc(II) with the carbonyl function is clearly required for marked catalytic effects to be observed. 

Fig. 10. View of the region around the zinc ion and the SH-group in the complex of human carbonic anhydrase C and acetoxy-mercurisulfanilamide. The model was built on the basis of crystal structure data to 5.5 A resolution. Two inhibitor molecules are bound via the Hg atom to the SH-group and via the SC>2NH2-group to the zinc ion. From Fridborg et at. (61)...

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