Zinc carbonyl interaction

Zinc proteases, such as carboxypeptidases A and B or thermolysin, contain a tightly bound zinc which is bound to two imidazole residues (His), a carboxylate (Glu), and a molecule of H20. Zinc interacts with the substrate carbonyl oxygen and increases its polarization, thereby displacing water. 

The peptide carbonyl oxygen interacts with zinc, withdrawing electrons from carbon. Water is displaced from zinc. Glu270 accepts a proton from water - it acts as a general base - and the hydroxyl anion of water acts as a nucleophile to attack the carbonyl carbon of the peptide bond and forms a negatively charged tetrahedral... 

This preparation illustrates the Reformatsky reaction, which consists in the interaction of a carbonyl compound, an a-halogen ester (e.g., ethyl bromo-acetate) and zinc In the presence of ether or benzene, followed by hydrolysis. 

Carboxypeptidase A was the first zinc enzyme to yield a three-dimensional structure to the X-ray crystallographic method, and the structure of an enzyme-pseudosubstrate complex provided a model for a precatalytic zinc-carbonyl interaction (Lipscomb etai, 1968). Comparative studies have been performed between carboxypeptidase A and thermolysin based on the results of X-ray crystallographic experiments (Argosetai, 1978 Kesterand Matthews, 1977 Monzingoand Matthews, 1984 Matthews, 1988 Christianson and Lipscomb, 1988b). Models of peptide-metal interaction have recently been utilized in studies of metal ion participation in hydrolysis (see e.g., Schepartz and Breslow, 1987). In these examples a dipole-ion interaction is achieved by virtue of a chelate interaction involving the labile carbonyl and some other Lewis base (e.g.. 

Fig. 31. Mechanistic proposal for peptide hydrolysis catalyzed by carboxypeptidase A (Christianson and Lipscomb, 1989). (a) The precatalytic Michaelis complex with substrate carbonyl hydrogen bonded to Arg-127 allows for nucleophilic attack by a water molecule promoted by zinc and assisted by Glu-270 (an outer-sphere C==O Zn interaction is not precluded), (b) Tbe stabilized tetrahedral intermediate collapses, with required proton donation by Glu-270 (Monzingo and Matthews, 1984) Glu-270 may play a bifunctional catalytic role (Schepartz and Breslow, 1987), which results in the product complex (c). [Reprinted with permission from Christianson, D. W., Lipscomb, W. N. (1989) Acc. Chem. Res. 22,62-69. Copyright 1989 American Chemical Society.]...

The anti stereoisomer was thought to arise from the allenylzinc reagent through a transition state in which the allenyl and aldehyde substituents adopt an anti arrangement (equation 6). The alternative transition state leading to the minor syn adducts would be disfavored by eclipsing interactions between these two substituents. In the proposed transition states, complexation between the zinc halide and the carbonyl oxygen was not considered. 

When the guest used is p-nitrophenylcholine carbonate (PNPCC) the Lewis acid zinc(n) activates the well-positioned carbonyl group in the P PCC Zn-cavitand towards reactions with external nucleophiles. The energy minimized structure of the PNPCC Zn-cavitand complex shows that cation-n interactions and C —O -Zn coordination bond occurs simultaneously. 

Fig. 4. Schematic drawing showing inhibitors of thermolysin and their interactions with the zinc atom and with a backbone carbonyl oxygen. Attraction occurs where X = NH, forced repulsion where X = O or CHi.

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